FGFR3 inhibitor compounds

Abstract

The present invention provides FGFR3 inhibitor compounds 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

FGFR3 INHIBITOR COMPOUNDSBackgroundFibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as morphogenesis during development, fibrosis, and angiogenesis. 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.SummaryProvided herein are compounds of the formula:(I)or a pharmaceutically acceptable salt thereof, wherein A, Xi, X2, X3, X4, Y, Yi, Y2, Y3,Y4, Z, Z1, R2 and R6 are as defined herein.Provided herein are compounds of the formula:or a pharmaceutically acceptable salt thereof, wherein A, Xi, X2, Y, Yi, Y2, Z, Zi, R2, R3,R4, R5, R6 and R9 are as defined herein.Provided herein are compounds of the formula:or a pharmaceutically acceptable salt thereof, wherein A, Xi, X2, Y, Yi, Y2, Z’, R2, R3, R4,R5 and R6 are as defined herein.Provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, with one or i0 more pharmaceutically acceptable carriers, diluents, or excipients.Disclosed are methods of using the compounds of formula (I), (II), (IIA) or (III), 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 nigricans15 (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), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, to a patient in need.Provided herein are compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided herein, are the compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer, particularly for use in the treatment of FGFR3-associated cancer. The use of compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer, particularly for use in the treatment of FGFR3-associated cancer, is also provided.In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.DescriptionProvided 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.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).The compounds provided herein are of formula:whereinA is pyrazole, triazole, thiadiazole or oxadiazole, substituted with R1 and R1A;R1 is hydrogen or C1-C3 alkyl;R1A is hydrogen, halo, CN, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3;X1 and X2 are independently selected from N and C, wherein when one of X1 or X2 is N the other is C;X3 is N or CH;X4 is N or C-R9;Y is NH, O, S or a bond;Y1 is a bond, CHR7, CH2-CHR7, CHR7-CH2, CF2, CH2-CF2 or CF2-CH2;Y2 is a bond, CHR3, CH2-CHR3, CHR3-CH2, CF2, CH2-CF2 or CF2-CH2;Y3 is CR4R5 or CF2;Y4 is CR3R4, or CF2;Z is a bond, CHR9A, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine;Z1 is a bond when Z is a bond, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine, or Z1 is CH2 or CH2-CH2 when Z is CHR9A;Z2 is a bond, C(O), SO2 or -NR4C(O);Z3 is a bond, C(O), SO2 or -NR4C(O);R2 is 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-R11 and 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;R3 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R3 is fused with R5 or R7 to form CH2, CH2-CH2 or CH2OCH2;R4 is hydrogen or C1-C3 alkyl;R4A is hydrogen, halo, OH, or C1-C3 alkyl;R5 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2;R6 is 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;R7 is hydrogen, F, OH, OCH3, C1-C3 alkyl or is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2;R8 is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R8A is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R9 is hydrogen, C1-C3 alkyl, or is fused with R9A to form CH2 or CH2-CH2;R10 is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R11 is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-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,N-dimethylamine and CN;R12 is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-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; and5          R8, R10 and R8A are optionally substituted with one or more substituentsindependently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R12 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;10          or a pharmaceutically acceptable salt thereof; and of formula:or a pharmaceutically acceptable salt thereof; and of formula:(III)or a pharmaceutically acceptable salt thereof. In formula (II),15          X1 and X2 are independently selected from N and C, wherein when one of X1 orX2 is N the other is C;Z is a bond, CHR9A, azetidine, pyrrolidine or piperidine;Z1 is a bond when Z is a bond, azetidine, pyrrolidine or piperidine, or Z1 is CH2 orCH2-CH2 when Z is CHR9A; andR9 is hydrogen or is fused with R9A to form CH2 or CH2-CH2.In formula (III),X1 and X2 are independently selected from N and C, wherein when one of X1 or X2 is N the other is C; andZ’ is a bond, azetidine, pyrrolidine or piperidine.In formula (II) and (III),A is pyrazole, triazole, thiadiazole or oxadiazole, optionally substituted with R1;R1 is C1-C3 alkyl;Y is NH, O, or a bond;Y1 is a bond, CHR7, CH2-CHR7 or CHR7-CH2;Y2 is a bond, CH2, CF2, CHR3, CH2-CHR3 or CHR3-CH2;R2 is C1-C5 alkyl or R8, wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R10;R3 is hydrogen, C1-C3 alkyl, or one R3 is fused with R5 or R7 to form CH2 or CH2-CH2;R4 is hydrogen, or C1-C3 alkyl;R5 is hydrogen, or is fused with one R3 to form CH2 or CH2-CH2;R6 is hydrogen, CH3, CN, Cl or F;R7 is hydrogen, or is fused with one R3 to form CH2 or CH2-CH2;R8 is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused with R8A;R8A is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R10 is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A; andR8, R10 and R8A are optionally substituted with one or more substituents independently selected from halogen, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)2CH3, C(O)NH2, N,N-dimethylamine and C(O)N,N-dimethylamine.In the compounds of formula (I), (II) or (III), X1 can be C, and X2 can be N; or X1 can be N, and X2 can be C.In the compounds of formula (I), (II) or (III), X1 can be C, and X2 can be N, forming:wherein * indicates the connection point to A in formula (I), (II) or (III).In the compounds of formula (I), (II) or (III), X1 can be N, and X2 can be C, forming:wherein * indicates the connection point to A in formula (I), (II) or (III).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.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 C1-C4 alkyl include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-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.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(O)0-1, N, O and S(O)0-2. 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(O)0-2, the remainder being C(O)0-1. 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, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl oxozolid-2-onyl and isothiazolid-2-onyl.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.As used herein the term "halogen" or "halo" refers to F (fluoro), Cl (chloro), Br (bromo) and I (iodo).As used herein the term "halomethyl" refers to -CH3, in which one or more hydrogen atoms is / are replaced with an independently selected halo.As used herein the term “oxo” refers to the substitution of CH2 with O to form C(O).As used herein the term “N(C1-C3 alkyl)2” allows the independent selection of each C1-C3 alkyl substituent, for example, N may be substituted by methyl and ethyl.As used herein the substituent -NR4C(O) is connected to R2 through N.Also provided is a compound of the formula:whereinA is pyrazole, triazole, thiadiazole or oxadiazole, optionally substituted with R1;R1 is C1-C3 alkyl;X1A and X2A are independently selected from N and CH, wherein when one of X1A or X2A is N the other is CH;Y is NH, O, or a bond;Y1 is a bond, CHR7, CH2-CHR7 or CHR7-CH2;Y2 is a bond, CH2, CF2, CHR3, CH2-CHR3 or CHR3-CH2;Z is a bond, CHR9A, azetidine, pyrrolidine or piperidine;Z1 is a bond when Z is a bond, azetidine, pyrrolidine or piperidine, or Z1 is CH2 or CH2-CH2 when Z is CHR9A;R2 is C1-C5 alkyl or R8, wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R10;R3 is hydrogen, C1-C3 alkyl, or one R3 is fused with R5 or R7 to form CH2 or CH2-CH2;R4 is hydrogen, or C1-C3 alkyl;R5 is hydrogen, or is fused with one R3 to form CH2 or CH2-CH2;R6 is hydrogen, CH3, CN, Cl or F;R7 is hydrogen, or is fused with one R3 to form CH2 or CH2-CH2;R8 is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R8A is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R9 is hydrogen or is fused with R9A to form CH2 or CH2-CH2;R10 is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A; andR8, R10 and R8A are optionally substituted with one or more substituents independently selected from halogen, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)2CH3, C(O)NH2, N,N-dimethylamine and C(O)N,N-dimethylamine;or a pharmaceutically acceptable salt thereof.In the compound of formula (IIA), X1A can be CH, and X2A can be N, forming:wherein * indicates the connection point to A in formula (IIA), forming a compound of the formula:In the compound of formula (IIA), X1A can be N, and X2A can be CH, forming:wherein * indicates the connection point to A in formula (IIA), forming a compound of the formula: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 R1 and R1A.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is C1-C3 alkyl.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is CH3.In the compounds of formula (II), (IIA) or (III), 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, optionally substituted with R1.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, optionally substituted with R1.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with CH3.In the compounds of formula (I), (II), (IIA) or (III), A can be:, wherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); and R1 can be C1-C3 alkyl;.In the compounds of formula (I), Z can be CHR9A, cyclobutyl, azetidine, pyrrolidine or piperidine.In the compounds of formula (I), Z can be a bond,,,,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I).In the compounds of formula (I), Z can be a bond,or,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I).In the compounds of formula (II) or (IIA), Z can be CHR9A, azetidine, pyrrolidine or piperidine.In the compounds of formula (II) or (IIA), Z can be a bond,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (II) or (IIA).In the compounds of formula (II) or (IIA), Z can be:**orwherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (II) or (IIA).In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be selected from CH2 or CH2-CH2, and R9 can be fused with R9A to form CH2 or CH2-CH2.In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be CH2, and R9 can be fused with R9A to form CH2 or CH2-CH2.In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be CH2-CH2, and R9 can be fused with R9A to form CH2 or CH2-CH2.In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be selected from CH2 or CH2-CH2, and R9 can be fused with R9A to form CH2.In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be selected from CH2 or CH2-CH2, and R9 can be fused with R9A to form CH2-CH2.In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be CH2, and R9 can be fused with R9A to form CH2.In the compounds of formula (I), (II) or (IIA), Z can be CHR9A, Z1 can be CH2-CH2, and R9 can be fused with R9A to form CH2-CH2.In the compounds of formula (III), Z’ can be:orwherein ** indicates the connection point to A and * indicates the other connection point from Z’ in formula (III).In the compounds of formula (III), Z’ can be:orwherein ** indicates the connection point to A and * indicates the other connection point from Z’ in formula (III).In the compounds of formula (I), (II) or (IIA), Z can be a bond.In the compounds of formula (III), Z’ can be a bond.In the compounds of formula (I), (II) or (IIA), Z1 can be a bond.In the compounds of formula (I), (II), (IIA) or (III), Y can be NH or O.In the compounds of formula (I), (II), (IIA) or (III), Y can be O.In the compounds of formula (I), Y1 can be a bond, CHR7, CH2-CHR7 or CHR7-CH2, wherein R7 is selected from hydrogen, F, OH and CH3; and Y2 can a bond, CHR3,CH2-CHR3 or CHR3-CH2, wherein R3 is selected from hydrogen, F, OH and CH3.In the compounds of formula (I), Y1 can be a bond or CHR7, wherein R7 is hydrogen, F, OH or CH3; and Y2 can a bond or CHR3, wherein R3 is hydrogen, F, OH or CH3.In the compounds of formula (I), Y1 can be a bond, CHR7, CH2-CHR7 or CHR7-CH2, wherein R7 is hydrogen, F, OH or CH3; and Y2 can a bond, CHR3, CH2-CHR3 or CHR3-CH2, wherein R3 is hydrogen, F, OH or CH3, forming:wherein * indicates the connection point to Z1 in formula (I).In the compounds of formula (I), Y1 can be a bond or CHR7, wherein R7 is hydrogen, F, OH or CH3; and Y2 can a bond or CHR3, wherein R3 is hydrogen, F, OH orCH3, forming:wherein * indicates the connection point to Z1 in formula (I).In the compounds of formula (II), (IIA) or (III), Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2 or CH2-CH2, forming:wherein * indicates the connection point to Z1 in formula (II) or (IIA), or Z’ in formula(III).5          In the compounds of formula (II), (IIA) or (III), Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, or CF2, forming:wherein * indicates the connection point to Z1 in formula (II) or (IIA), or Z’ in10 formula (III).In the compounds of formula (I), R1A can be hydrogen, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3.In the compounds of formula (I), R1A can be hydrogen or CH3.In the compounds of formula (I), R1A can be hydrogen.In the compounds of formula (I), (II), (IIA) or (III), R1 can be methyl, ethyl or propyl.In the compounds of formula (I), (II), (IIA) or (III), R1 can be methyl.In the compounds of formula (I), R2 can 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-R11 and 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.In the compounds of formula (I), R2 can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10.In the compounds of formula (I), R2 can be:* * * . * *^R       R X ^R ^X ^R .       R,                     ,                    ,                         andoptionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and 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).In the compounds of formula (I), R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I).In the compounds of formula (I), R2 can be:\o10 y\o10      y \ri°lx                       lx ,                     lx,                 and                    ,10           optionally substituted with one, two, three or four substituents independentlyselected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and 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).15          In the compounds of formula (I), R2 can be:\o10 y\D10      y \ri°,                 and                    ,optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl and R10, wherein * indicatesthe connection point to Y in formula (I).In the compounds of formula (II), (IIA) or (III), R2 can be C1-C4 alkyl optionallysubstituted with one or more substituents independently selected from OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), R2 can be C1-C3 alkyl optionallysubstituted with one or two substituents independently selected from OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), R2 can be C1-C3 alkyl optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), R2 can be C1-C2 alkyl optionally substituted with one or two substituents independently selected from OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), R2 can be:..oroptionally substituted with one or two substituents independently selected from OH, CF3 and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).In the compounds of formula (II), (IIA) or (III), R2 can be:\D10 S\D10    ___\D10r\       S r\                     r\,                      ..or                            ,optionally substituted with one or two substituents independently selected from OH, CF3and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).In the compounds of formula (II), (IIA) or (III), R2 can be:oroptionally substituted with one or two substituents independently selected from OH, CF3and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).In the compounds of formula (I), Y3 can be CR4R5 or CF2, wherein R4 is hydrogen or CH3 and R5 is hydrogen, F, OH or CH3; and Y4 is CR3R4 or CF2 wherein R4 is hydrogen or CH3, and R3 is hydrogen, F, OH or CH3.In the compounds of formula (I), Y3 can be CR4R5, wherein R4 is hydrogen and R5 is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2; and Y4 is CR3R4 wherein R4 is hydrogen, and R3 is fused with R5 to form CH2, CH2-CH2 or CH2OCH2.In the compounds of formula (I), Y3 can be CR4R5, wherein R4 is hydrogen and R5 is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2; and Y4 is CR3R4 wherein R4 is hydrogen, and R3 is fused with R5 to form CH2, CH2-CH2 or CH2OCH2, forming:wherein * indicates the connection point to Z1 in formula (I).In the compounds of formula (I), X4 can be N or C-R9 wherein R9 is hydrogen orCH3.In the compounds of formula (I), X4 can be C-R9 wherein R9 is fused with R9A to form CH2 or CH2-CH2; and Z1 is CH2 or CH2-CH2.In the compounds of formula (I), X4 can be N or CH.In the compounds of formula (II), (IIA) or (III), R3 can be hydrogen, C1-C3 alkyl, or fused with R5 to form CH2 or CH2-CH2.In the compounds of formula (II), (IIA) or (III), R3 can be hydrogen, C1-C2 alkyl, or fused with R5 to form CH2 or CH2-CH2.In the compounds of formula (II), (IIA) or (III), R3 can be hydrogen or methyl.In the compounds of formula (II), (IIA) or (III), R4 can be hydrogen or C1-C2 alkyl.In the compounds of formula (II), (IIA) or (III), R4 can be hydrogen or methyl.In the compounds of formula (II), (IIA) or (III), R3 and R4 can be hydrogen.In the compounds of formula (II), (IIA) or (III), R5 can be hydrogen.In the compounds of formula (II), (IIA) or (III), R5 can fuse with one R3 to form CH2-CH2.In the compounds of formula (I), R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl.In the compounds of formula (I), R6 can be CN, F or Cl.In the compounds of formula (I), (II), (IIA) or (III), R6 can be CN or Cl.In the compounds of formula (I), (II), (IIA) or (III), R6 can be CN.In the compounds of formula (II), (IIA) or (III), R7 can be hydrogen.In the compounds of formula (II), (IIA) or (III), R7 can fuse with one R3 to form CH2.In the compounds of formula (I), (II), (IIA) or (III), R8 can be 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A.In the compounds of formula (I), (II), (IIA) or (III), R8 can be 5-6 membered cycloalkyl, or 5-6 membered heterocycloalkyl, optionally fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R8 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, optionally fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R8 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R8 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, fused with R8A, wherein R8A can be phenyl or 6 membered heteroaryl.In the compounds of formula (I), (II), (IIA) or (III), R9 can be hydrogen.In the compounds of formula (I), (II), (IIA) or (III), R10 can be 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, optionally fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 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.In the compounds of formula (I), (II), (IIA) or (III), R10 can 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.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, optionally fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 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.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.In the compounds of formula (II), (IIA) or (III), R10 can be 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R8A.In the compounds of formula (I, (II), (IIA) or (III), R10 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be cyclopentyl, cyclohexyl, phenyl or pyridinyl, fused with R8A.In the compounds of formula (I), (II), (IIA) or (III), R10 can be phenyl or pyridinyl, fused with R8A wherein R8A can be 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl.In the compounds of formula (I), (II), (IIA) or (III), R10 can be phenyl or pyridinyl, fused with R8A wherein R8A can 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.In the compounds of formula (I), (II), (IIA) or (III), R10 can be phenyl or pyridinyl, fused with R8A wherein R8A can 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.In the compounds of formula (I), (II), (IIA) or (III), R10 can be phenyl or pyridinyl, fused with R8A wherein R8A can be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-only or isothiazolid-2-onyl.In the compounds of formula (I), (II) or (IIA), where both Z and Z1 are a bond, together they form a single bond.In the compounds of formula (I), Z can be CHR9A, Z1 can be CH2, X4 can be C-R9, and R9 can be fused with R9A to form CH2, forming:wherein * indicates the connection point to A.In the compounds of formula (II) or (IIA), Z can be CHR9A, Z1 can be CH2, andR9 can be fused with R9A to form CH2, forming:wherein * indicates the connection point to A.In the compounds of formula (I), (II), (IIA) or (III), R5 can be fused with one R3 to form CH2-CH2, for example forming:wherein * indicates the connection point to Zi in formula (I) or Z’ in formula (II), (IIA) or(III).In the compounds of formula (I), (II), (IIA) or (III), R8 can be cyclopentyl, fused with R8A, wherein R8A can be pyridinyl, for example forming:or wherein * indicates the connection point to Y.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; and Y can be NH or O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is C1-C3 alkyl; and Y can be NH or O.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; and Y can be NH or O.In the compounds of formula (I), (II), (IIA) or (III), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R1 can be C1-C3 alkyl; and Y can be NH or O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; and Y can be O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is C1-C3 alkyl; and Y can be O.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; and Y can be O.In the compounds of formula (I), (II), (IIA) or (III), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the otherconnection point from A in formula (I), (II), (IIA) or (III); R1 can be C1-C3 alkyl; and Ycan be O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; and R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is C1-C3 alkyl; and R6 can be CN, F, Cl or CF3.In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the otherconnection point from A in formula (I); and R6 can be CN, F, Cl, CH3, CF3 orcyclopropyl.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 R6 can be CN, F, Cl or CF3.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; and R6 can be CN or Cl.In the compounds of formula (I), (II), (IIA) or (III), A can be:or                          ,wherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R1 can be C1-C3 alkyl; and R6 5 can be CN or Cl.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be NH or O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,410 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is C1-C3 alkyl; R6 can be CN, F, Cl or CF3; and Y can be NH or O.In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the other15 connection point from A in formula (I); R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be NH or O.In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can be CN, F, Cl or CF3; and Y can be NH or O.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; R6 can be CN or Cl; and Y can be NH or O.In the compounds of formula (I), (II), (IIA) or (III), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R1 can be C1-C3 alkyl; R6 can be CN or Cl; and Y can be NH or O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A, wherein R1A is hydrogen and R1 is C1-C3 alkyl; R6 can be CN, F, Cl or CF3; and Y can be O.In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.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); R6 can be CN, F, Cl or CF3; and Y can be O.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; R6 can be CN or Cl; and Y can be O.In the compounds of formula (I), (II), (IIA) or (III), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R1 can be C1-C3 alkyl; R6 can be CN or Cl; and Y can be O.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2 can 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-R11 and 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.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2 can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl or CF3; Y can be NH or O; and R2 can be:*optionally substituted with one, two, three or four substituents independentlyselected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10,wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or moresubstituents independently selected from halo, OH, OCH3, methylamine, N,N-10 dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can CN, F, Cl or CF3; Y can be NH or O; and R2can be:*optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl or CF3; Y can be NH or O; and R2 can be:\p10    / \o'°      y \Rio5                                          ,                 and                    ,optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or moresubstituents independently selected from halo, OH, OCH3, methylamine, N,N-10 dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4triazole, substituted with R1 and R1A; R6 can CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I).In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the otherconnection point from A in formula (I); R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y 5   can be NH or O; and R2 can be C1-C3 alkyl optionally substituted with one, two, three orfour substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and 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.10          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); R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2 can be C1-C4 alkyl optionally substituted with one or more15 substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10.In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can be CN, F, Cl or CF3; Y can be NH or O; and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10,wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or moresubstituents independently selected from halo, OH, OCH3, methylamine, N,N-10 dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).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); R6 can CN, F, Cl or CF3; Y can be NH or O; and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the5 connection point to Y in formula (I).In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can be CN, F, Cl or CF3; Y can be NH or O;and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10,15   wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or moresubstituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).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); R6 can CN, F, Cl or CF3; Y can be NH or O; and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I).In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; Y can be O; R6 can be CN or Cl; and R2 can be C1-15   C3 alkyl optionally substituted with one, two or three substituents independently selectedfrom OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (II), (IIA) or (III); Y can be O; R6 can be CN or Cl; and R2 canbe C1-C3 alkyl optionally substituted with one, two or three substituents independently5 selected from OH, methoxy, halomethyl and R10.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; Y can be O; R6 can be CN or Cl; and R2 can be:optionally substituted with one or two substituents independently selected from OH, CF310 and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).In the compounds of formula (II), (IIA) or (III), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the other connectionpoint from A in formula (II), (IIA) or (III); Y can be O; R6 can be CN or Cl; and R2 can15 be:optionally substituted with one or two substituents independently selected from OH, CF3and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2 can 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-R11 and 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,or,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2 can 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,or,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl or CF3; Y can be NH or O; and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10,wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or moresubstituents 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,,                              or                                   ,wherein * indicates the connection point to Z1 and ** indicates the connection10 point to A in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can CN, F, Cl or CF3; Y can be NH or O; and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I); and Z can be a bond,wherein * indicates the connection point to Z1 and ** indicates the connectionpoint to A in formula (I).In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2 can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C510   cycloalkyl, -Z2-R11 and R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionallysubstituted 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 Z1 and ** indicates the connection15 point to A in formula (I).In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the otherconnection point from A in formula (I); R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Ycan be NH or O; R2 can 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,or,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I).In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can be CN, F, Cl or CF3; Y can be NH or O; R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10,wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or moresubstituents 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 Z1 and ** indicates the connectionpoint to A in formula (I)..In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z’ and ** indicates the otherconnection point from A in formula (I); R6 can CN, F, Cl or CF3; Y can be NH or O; andR2 can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I); and Z can be a bond,orwherein * indicates the connection point to Z1 and ** indicates the connectionpoint to A in formula (I).In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2 can 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-R11 and 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 Z1 and ** indicates the connection point to A in formula (I); Y1 can be a bond or CHR7, wherein R7 is hydrogen, F, OH or CH3; and Y2 can a bond or CHR3, wherein R3 is hydrogen, F, OH or CH3.In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1 and R1A; R6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2 can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10; Z can be a bond,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I); Y1 can be a bond or CHR7, wherein R7 is hydrogen, F, OH or CH3; and Y2 can a bond or CHR3, wherein R3 is hydrogen, F, OH or CH3.In the compounds of formula (I), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (I); R6 can CN, F, Cl or CF3; Y can be NH or O; and R2 can be:optionally substituted with one, two, three or four substituents independentlyselected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates theconnection point to Y in formula (I); Z can be a bond,wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I); Y1 can be a bond or CHR7, wherein R7 is hydrogen, F, OH or CH3; and Y2 can a bond or CHR3, wherein R3 is hydrogen, F, OH or CH3.In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; Y can be O; R6 can be CN or Cl; R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10; Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2 or CH2-CH2.In the compounds of formula (II), (IIA) or (III), A can be:orwherein * indicates the connection point to Z or Z’ and ** indicates the other connection point from A in formula (II), (IIA) or (III); Y can be O; R6 can be CN or Cl; R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10; Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2 or CH2-CH2.In the compounds of formula (II) or (IIA), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; Y can be O; R6 can be CN or Cl; R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10; Y1 can be a bond, CH2, or CH2-CH2; Y2 can be a bond, CH2, CF2 or CH2-CH2; Z can be CHR9A; Z1 can be CH2; and R9 can be fused with R9A to form CH2.In the compounds of formula (II) or (IIA), A can be:wherein * indicates the connection point to Z and ** indicates the other connection point from A in formula (II) or (IIA); Y can be O; R6 can be CN or Cl; R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10; Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2 or CH2-CH2; Z can be CHR9A; Z1 can be CH2; and R9 can be fused with R9A to form CH2.In the compounds of formula (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1; Y can be O; R6 can be CN or Cl; R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10; Y1 can be a bond, CH2, or CH2-CH2; Y2 can be a bond, CH2, CF2 or CH2-CH2; and Z’ can be:wherein ** indicates the connection point to A and * indicates the other connection point from Z’.In the compounds of formula (III), A can be:wherein * indicates the connection point to Z’ and ** indicates the other connection point from A in formula (I); Y can be O; R6 can be CN or Cl; R2 can be C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10; Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2 or CH2-CH2; and Z’ can be:wherein ** indicates the connection point to A and * indicates the other connection point from Z’.In one embodiment, the compounds of Formula (I) are selected from the group consisting of:,N^N 0 NN^—NN^—NN^—N,N^NN^N,ClNNOH NandN^—Nor a pharmaceutically acceptable salt thereof,wherein the bond at the * position is as represented, For example, for the compound of formula:N^-where the bond at the * position is as represented,forms thecompounds:NIn a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:N=—NN =—Nor a pharmaceutically acceptable salt thereof, where the bond at the * position is asrepresented,5          In a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:N^—or a pharmaceutically acceptable salt thereof, where the bond at the * position is asrepresented,In a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:N=—IN^Nor a pharmaceutically acceptable salt thereof, where the bond at the * position is asrepresented,, orIn a further embodiment, the compounds of Formula (I) are selected from the group consisting of:,5 or a pharmaceutically acceptable salt thereof, where the bond at the * position is asrepresented,In a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:N^—IN=—NN^NN^N,N^NN^—NN =—NN^—IN^Nandor a pharmaceutically acceptable salt thereof, where the bond at the * position is as5 represented,, orIn a further embodiment, the compounds of Formula (I) are selected from the group consisting of:andor a pharmaceutically acceptable salt thereof, where the bond at the * position is asrepresented,In a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:andor a pharmaceutically acceptable salt thereof, where the bond at the * position is asrepresented,In a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:5 or a pharmaceutically acceptable salt thereof.In a further embodiment, the compounds of Formula (I) are selected from thegroup consisting of:or a pharmaceutically acceptable salt thereof.The compounds of formula (I), (II), (IIA) or (III), 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 deuteriumor 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 C2DxH5-x.The compounds of formula (I), (II), (IIA) or (III) 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, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011); S.M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).The compounds of formula (I), (II), (IIA) or (III) 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), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be formulated as pharmaceutical compositions. Such pharmaceutical compositions and processes for preparing the same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., eds., 21st ed., Mack Publishing Co., 2005)).The compounds of formula (I), (II), (IIA) or (III) 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.The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents.The compounds of formula (I), (II), (IIA) or (III) 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.The compounds of formula (I), (II), (IIA) or (III) 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.The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents for simultaneous, separate or sequential administration.The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, and their pharmaceutical compositions can be used in the methods described herein.The compounds of formula (I), (II), (IIA) or (III) 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 of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.Certain compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, selectively target FGFR3. For example, certain compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), (II),(IIA) or (III), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over FGFR1. For example, certain compounds of formula (I), (II), (IIA) or (III), 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.As used herein, the term "selectivity" of a compound refers to the compound having more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value of a compound for the second target (e.g., FGFR1) by the IC50 value of the same compound for the first target (e.g., FGFR3). An IC50 value can be determined by any method known in the art. For example, an IC50 value can be determined as described in the assays below.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.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.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.As used herein, the term “patient” refers to a mammal, particularly a human.Provided herein, are compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.Provided herein, are compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.Provided herein, are compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.Provided herein, are compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.Provided herein, are the use of compounds of formula (I), (II), (IIA) or (III),or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.Provided herein, are the use of compounds of formula (I), (II), (IIA) or (III),or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.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 thecompounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof.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), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof.Provided in the methods and uses herein, 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, 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. 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, 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, 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).The compounds provided herein can be prepared as illustrated in the preparations and examples below.Certain abbreviations are defined as follows: “ACN” refers 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)-1,1'-binaphthyl; “Pd(DtBPF)Cl2”refers to [1,1-Bis(di-tert-butylphosphino) ferrocene]dichloropalladium(II); NBS”refers to N-bromosuccinimide;“n-BuOH” refers to n-butyl alcohol or n-butanol;“BOC”refers to tert-butyloxycarbonyl;“Boc2O” refers to di-tert-butyl dicarbonate; "BuLi" refers to butyl lithium; “CuSO4 5H2O” refers to copper sulfate pentahydrate; ‘CsF” refers to cesium fluoride; “F-TEDA” refers to 1-chloromethyl-4-fluoro-1,4-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-diisopropylethylamine; “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; “IPA” refers to isopropyl amine; “T3P” refers to propylphosphonic anhydride; “KOAc” refers to potassium acetate; “LiBH4” refers to lithium borohydride; “LDA” refers to lithium diisopropylamide; “MsCl” refers to methanesulfonyl chloride; “MTBE” refers to methyl tert-butyl ether; “NCS” refers to N-chlorosuccinimide; “NIS” refers to N-iodosuccinimide; ‘MeMgBr” 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; “PCy3” refers to tricyclohexylphosphine; “Pd(AcO)2” refers to palladium(II) acetate; “Pd(dba)2” refers to bis(dibenzylideneacetone)palladium(0);“Pd2(dba)3” refers to tris(dibenzylideneacetone) dipalladium(0); “Pd2(dba)3.CHCl3” refers to tris(dibenzylideneacetone)dipalladium-chloroform adduct; “Pd(dppf)Cl2” refers to [1,1’-bis(diphenylphosphino)ferrocene] dichloropalladium (II); “Pd(dppf)Cl2.CH2Cl2” refers to 1,1'-bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex; “PE” refers to petroleum ether; “K3PO4” refers to potassium phosphate; “RT” refers to room temperature; “PPh3” refers to triphenylphosphine; “Pd(PPh3)4” 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; “TFA” refers to trifluoroacetic acid; “Tf2O” refers to trifluoromethane sulfonic anhydride; “THF” refers to tetrahydrofuran; “TsCl” referes to 4-toluenesulfonyl chloride; “TMSCF3” refers to (trifluoromethyl)trimethylsilane; “TMSOTf” refers to trimethylsilyltrifluoro methanesulfonate; “(CF3SO2)2O” refers to trifluoromethanesulfonic anhydride; “t(R)” refers to retention time; “Xantphos” refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; “X-Phos” refers to 2-dicyclohexyl phosphino-2,4,6-triisopropylbiphenyl; “XPhos Pd G2” refers to chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II); and“XPhos Pd G4” refers to CAS # 1599466-81-5; “ZnCl2” refers to zinc chloride.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 subsequentintermediates 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 first 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).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), (II), (IIA) or (III) are intended to be included in this description.PGScheme 1PG ^Z.Ox OA-Br(3)Br(10)(9)(10)(11)(13)(12)Scheme 1 depicts the preparation of compounds of (4) and (8) that lead to5 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 substituted10 bromide (3) that when reacted with mesylate (2) directly affords compounds of (8).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 underMitsunobu 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).5          Scheme 1 further depicts the preparation of compounds of (12) and (13) that willbe further elaborated to formula (I). A skilled artisan will recognize that compounds of (4) and (8) may be deprotected to give (9) and (11) that when reacted with triflate (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 may10 be substituted for the triflate 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(19)                                   (13)                                         (12)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 5 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).Additionally, compound (13) may also be synthesized from alternative routes as10 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 substituted15 trimethylsilylalkyne to afford trimethylsilyl analog (19). Reaction of (19) with NBS in the presence of silicon dioxide provides compounds of (13). Scheme 3(20)                 (21)                  (22)R—OH(23)(24)(27)                                                          (28)Formula (I)(29)Scheme 3 depicts the preparation of compounds of formula (I). Reaction of (20) with chloroacetaldehyde provides heteroaryl chloride (21) that may be demethylated to5 give (22). Compound (22) may react with alcohol (23) via Mitsunobu conditions to provide a R2 substituted heteroaryl chloride (24). A skilled artisan will recognize that when R2 is methyl, it is unnecessary to demethylate (22) to arrive at a R2 substituted (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 provides (27) that may 5 be further elaborated to provide R6 substituted compounds of (28). Alternatively, aswould be known to one skilled in the art, compounds of (26) may be reacted with reagents such as NCS or NBS to afford R6 as 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 10 formula (I).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 R6 substituted heteroaryl chloride (24). Next, the R6 substituted heteroaryl chloride (24) may be converted to a R6 substituted boronic acid R6 15 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(32)(13)(35)(34)(36)(37)(37a)Scheme 4 depicts the preparation of compounds of (37a). Reaction of (30) in the 5 presence of 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diiumtetrafluoroborate affords the fluorinated bicyclic 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-thiol10 provides hydroxy bicyclic analog (35). Alkylation of (35) with the appropriate bromidegives compound (36). Deprotection of (36) followed by N-cyanation results in N-cyanoamino compounds of (37a).Scheme 5(30)R—OH(22)(41)(13)PG Y3^Y<I IY4                  _Br'Y2x xZ< ^a-"^(13)(40)(42)Formula (I)(28)(29)Scheme 5 depicts an alternative preparation of cyanoamino compounds ofFormula (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 10 Mitsunobu conditions to provide R2 substituted bromide compounds (39). Alternatively,Compound (39) may be alkylated by substituting R2OH (22) with the corresponding iodo analog R2I of (22). Conversion of R2 substituted 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) throughSuzuki 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) throughSuzuki coupling. A skilled artisan will recognize that compounds of (42) are also compounds of (28) where R2 is methyl. Lastly, compounds of (28) may be deprotected to provide amine (29). N-Cyanation of amine (28) gives N-cyanoamino compounds of formula (I).(42)Scheme 6R?—OH(22)(43)(29)                                                          (28)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 R2 is methyl. Compounds (42) are demethylated to provide compounds of (43) that are reacted with alcohol (22) under Mitsunobu conditions to provide R2 substituted5 compounds of (28) where the R2 group is not methyl. R2 substituted (28) may be deprotected to give compound (29) and then N-cyanated to give N-cyanoamino compounds of formula (I).One skilled in the art will recognize alternative reactants may also result in compounds of (28). For instance, alcohol (22) may be converted to triflate analog (R2-10 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 triflate compounds of (35) that may then be reacted with R2-NH2 analogs of (22) to afford an amine-R2 substituted compounds of (28).Scheme 7Br(8)(41, R2 = Me)PG(8)(40)R6R2(47)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).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(48)(47)Formula (I)(50)(47)(10)                             (47)5          Scheme 8 depicts the preparation of compounds of Formula (I). Reductiveamination of compounds of (47), as prepared in Scheme 7, with ketone (48) affords compounds of Formula (I). Alternatively, alkylation of (47) with triflate (49) gives compounds of Formula (I). A skilled artisan will also appreciate that mesylate (-OMs) compounds of (49) may be substituted for triflate (49).10          Additionally, a skilled artisan will recognize that N-protected ketone compoundsof (50) and triflate compounds of (10) may also be used instead of N-cyanoamino compounds (48) and (49). Reductive amination of compounds of (47), as prepared inScheme 7, with N-protected ketone (50) affords N-protected (28). Alkylation of compounds of (47) with N-protected triflate (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).Scheme 9R10    +2 OHO RIPG'°(51)R‘IPG'°(52)(43)(54)IOHPG(53)R6R10(54a)Scheme 9 depicts the preparation of compounds of (54a). Compounds of R10, where R10 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 R2 aldehyde (51) to convert the aldehyde into the alcohol (52). Protecting groups other than TBDMS may be used to protect the R2 alcohol 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).(59)Scheme 10 depicts the preparation of compounds of (60a). 4,6-dichloropyridin-2-amine is reacted with a solution of 2-bromo-1,1-dimethoxypropane previously treated5 with aq. HCl in EtOH to afford 5,7-dichloro-3-methylimidazo[1,2-a]pyridine. The 5,7-dichloro intermediate is treated with sodium methoxide to yield 7-chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine. The boronate ester (55) is formed by Pd catalyzed reaction of 7-chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine with bis(pinacolato)diboron. Suzuki coupling of boronate ester (55) with bromide (56) affords compound (57).10 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).Scheme 11(61)OH(62)Yo-Y-, / 3   \ ZPG —N X4-Z< AY4-Y2(13)(64)(63)(65)                                               (65a)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 1,3-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).Scheme 12(66)                       (67)                                             (68)(69)(70)(71)(71a)Scheme 12 depicts the preparation of (71a). Treatment of 7-chloro-6H-imidazo[1,2-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).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 isolatedand / 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, the order in which moieties 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 ExamplesPreparation 13-BenzyloxycyclobutanolA mixture of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol) and NaBH4 (4.29 g, 113.5 mmol) in MeOH (50 mL) is stirred for 2 hr at RT under N2. The reaction is quenched with H2O at 0° C, extracted with EtOAc (3 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to afford the title compound (20 g, 98.9%) as a light-yellow oil. 1H NMR (400 MHz, DMSO-d6) 8 7.42-7.21 (m, 5H), 4.45(s, 2H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 1H),2.82-2.63(m, 2H), 1.97-1.92(m, 2H).Preparation 2tert-Butyl (2S,4S)-2-cyclopropyl-4-hydroxy-piperidine-1-carboxylateTo trans-2-cyclopropylpiperidin-4-ol hydrochloride (3.00 g, 16.9 mmol) in H2O (15.00 mL) and DCM (15.00 mL) is added NaOH (2.03 g, 50.7 mmol) in portions at 0° C under N2. The mixture is stirred for 10 min at RT then Boc2O (4.05 g, 18.6 mmol) is added in portions. The reaction is stirred for 2 hr at RT. The mixture is diluted with H2O (100 mL) and extracted with DCM (2 x 120 mL). The combined organic layers are washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate is concentrated in vacuo to afford the title compound (5g, crude) as a yellow solid, which is taken on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 8 4.69 (d,1H), 3.98-3.79 (m, 2H), 3.40-3.33 (m, 1H), 2.99-2.85 (m, 1H), 1.94-1.74 (m, 2H), 1.37 (s, 9H), 1.31-1.18 (m, 2H), 1.15-1.08 (m, 1H), 0.54-0.45 (m, 1H), 0.42-0.26 (m, 2H), 0.22-0.12 (m, 1H).Preparation 3N-diazo-1,1,1-trifluoro-methanesulfonamide°-s? / "NNx _ "NTo a solution of NaN3 (9.22 g, 142 mmol) and hydrogen tetra(but-1-yl)ammonium sulfate (481mg, 1.42 mmol) in distilled H2O (30 mL) to 0°C is added slowly a solution of (CF3SO2)2O (8.00 g, 28.4 mmol) in heptane (25 mL). The reaction is stirred 1-2 hr at 0 °C. Heptane (25 ml) is added to the reaction and the layers are separated. The aqueous layer is extracted with heptane (3 x 10 ml). The combined organic layers are dried over NaOH pellets. The organic layer is decanted and the solution is used immediately in the subsequent reaction.Preparation 4(1r,3r)-3-AzidocyclobutanolHO".N N.+ n-A solution of (1r,3r)-3-aminocyclobutan-1-ol (1.23 g, 14.2 mmol), NaHCO3 (4.05g, 48.2 mmol), and CuSO4 5H2O (1.77 g, 7.08 mmol) in MeOH (15 mL) and H2O (15mL) (v / v) is treated with a freshly prepared stock solution of N-diazo-1,1,1-trifluoro-methanesulfonamide in heptane (4.96 g, 28.3 mmol). Additional MeOH is added to the reaction in 5mL increments until a homogeneous mixture results (20 mL total added). The reaction is stirred overnight at RT. EtOAc is added and the layers are separated. The aqueous layer is extracted with EtOAc (3x). The combined organic layers are concentrated in vacuo to afford a dark green solution. Assumed quantitative yield. 1H NMR (400 MHz, DMSO-d6) 8 2.05 - 2.31 (m, 4 H) 4.07 - 4.18 (m, 1 H) 4.29 (br s, 1 H) 5.14 - 5.32 (m, 1 H).Preparation 5 tert-Butyl 4-(2-azido-1,1-dimethyl-ethyl)piperazine-1-carboxylateTo a stirred solution of tert-butyl 4-(1-hydroxy-2-methylpropan-2-yl)piperazine-1-carboxylate (6.00 g, 23.22 mmol) and DBU (4.24 g, 27.87 mmol) in toluene (100 mL) is added DPPA (7.67 g, 27.89 mmol) dropwise at 0° C under N2. The mixture is stirred overnight at RT then concentrated in vacuo. The residue is purified by silica gel chromatography eluting with PE;EtOAc (20:1 to 10:1) to afford the title compound (6g, 91.2%) as a light yellow oil. ES / MS m / z: 284.3 [M+H]+.Preparation 6tert-Butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylateTo tert -butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (10 g, 41.44 mmol) and PPh3 (15.22 g, 58.01 mmol) in THF (150 ml) is added DEAD (10.10 g, 58.01 mmol) dropwise at 0 °C under N2. The reaction is stirred 1 hr at 0 °C then DPPA (13.68 g, 49.72 mmol) is added dropwise. The reaction is stirred overnight at RT. The reaction isconcentrated in vacuo then purified by silica gel chromatography, eluting with PE:EtOAc(30:1 to 20:1) to afford the title compound (14.5 g, crude) as a colorless oil which is carried forward without a further purification. 1H NMR (300 MHz, CDCI3) 8 3.98 -3.84 (m, 1H), 3.39 -3.28 (m, 4H), 2.32 -2.20 (m, 2H), 1.94 -1.80 (m, 2H), 1.60 -1.52 (m, 4H), 1.47 (s, 9H).5          The following compounds are prepared essentially as described for tert-butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. DIAD can be substituted for DEAD.Table 1Prep No. Chemical Name Structure 1H NMR (400 MHz, CDCls), 8 71 tert-Butyl 4-azidoazepane-1-carboxylate \ O N / N + 1 0               N 3.67-3.61 (m, 1H), 3.52 -3.28 (m, 4H), 2.25-1.62 (m, 6H), 1.52 (s, 9H) 82 tert-Butyl (3R)-3-azidopiperidine-1 -carboxylate c / ° .z ,z Z' + 1 a 9 Cis-3-(Azidocyclobutoxy) methyl benzene / =\ /   \    / \z '' + \\ / / --- N N- 2.44 -2.27 (m, 4H), 4.16-4.08(m, 1H), 4.28-4.21(m, 1H), 4.41 (s, 2H), 7.39 -7.28 (m, 5H) 10 tert-butyl (2S,4R)-4-azido-2-cyclopropyl-piperidine-1-carboxylate 0 / —\ -4—0 )— / N + <J        N" a 113, 4 tert-Butyl (3R,4S)-4-azido-3-fluoro-piperidine-1-carboxylate F °   / —( V- N O \-- / N + /               N- 4.89-4.82(m, 1H), 4.09-4.01(m, 1H), 3.95 -3.60 (m, 2H), 3.15 (dd, 2H), 1.90 -1.64 (m,2H), 1.40 (s, 9H) 124, 5tert-Butyl (3S,4S)-4-azido-3-fluoro-piperidine-1-carboxylate136, 7tert-Butyl (3S,4R)-4-azido-3-fluoro-piperidine-1-carboxylate144tert-Butyl (3R,4R)-4-azido-3-fluoro-piperidine-1-carboxylate154tert-butyl (3RS,4RS)-4-azido-3-methyl-piperidine-1-carboxylate164, 8tert-Butyl (3RS,4SR)-4-azido-3-methyl-piperidine-1-carboxylate4.41 -4.36 (m, 1H), 4.06 -3.85 (m, 2H), 3.68 -3.57 (m, 1H), 3.06 -2.97 (m, 2H), 1.93 -1.83 (m, 1H), 1.40 (s, 10H) 4.98 -4.76 (m, 1H), 4.12 -3.96 (m, 1H), 3.97 -3.64 (m, 2H), 3.26 -2.82 (m, 2H), 1.85 -1.63 (m, 2H), 1.39 (s, 9 4.63 -4.24 (m, 1H), 4.09 -3.83 (m, 2H), 3.80 -3.55 (m, 1H), 3.20 -2.84 (m, 2H), 2. 06 -1.78 (m, 1H), 1.42 -1.36 (m, 10H)4.02 -3.84 (m, 2H), 3.38 - 3.27 (m, 1H), 3.02 -2.87 (m, 1H), 2.03 (d, 1H), 1.55 -1.37 (m, 12H), 1.06 -0.97 (m, 3H) 3.97-3.89 (m,1H), 3.47-3.38 (m, 2H), 3.37-3.29 (m,1H), 3.28 -3.16 (m, 1H),1.90-1.79 (m, 1H), 1.67-1.55 (m, 2H), 1.43-1.33 (m, 9H), 0.87 (d, 3H)1Purified by Prep-TLC, PE:EtOAc (6:1 to 4:1)2 Purified by silica gel chromatography, eluting with PE:EtOAc (2:1).3 Purified by reverse phase chromatography; C18 column; eluting with 40% to 50% ACNin H2O.5  4 1H NMR (300 MHz, DMSO-d6).5 Purified by silica gel chromatography, eluting with PE: EA (20:1).6 Purified by silica gel chromatography, eluting with PE: EA (15:1).7 1H NMR (400 MHz, DMSO-d6).8 Purified by silica gel chromatography, eluting with PE / EA (30:1 to 20:1).5 a Material is used without further purification.Preparation 17tert-Butyl (3S,4S)-4-azido-3-hydroxy-piperidine-1-carboxylateohImidazole-1-sulfonyl azide (3.75 g, 21.63 mmol) is added to a mixture of tert-5 butyl (3S,4S)-4-amino-3-hydroxypiperidine-1-carboxylate (3.9 g, 18.03 mmol), K2CO3 (1.25 g, 9.02 mmol) and CuSO4.5H2O (0.45 g, 1.80 mmol) in MeOH (25 mL) at RT under N2. The reaction is stirred overnight at RT. The reaction is quenched with H2O and the mixture is extracted with EA (2 x 500 mL). The combined organic layers are washed with brine (2 x3 00 mL), dried over Na2SO4, filtered, and concentrated in vacuo 10 to afford the title compound (4.3 g, crude) as a light-yellow oil. 1H NMR (400 MHz,DMSO-d6) 8 5.67 (d, 1H), 3.95 -3.77 (m, 2H), 3.48 -3.35 (m, 1H), 3.33 -3.17 (m, 1H), 2.67 (d, 2H), 1.89 -1.80 (m, 1H), 1.39 (s, 9H), 1.24 -1.16 (m, 1H).The following compounds are prepared essentially as described for tert-butyl (3S,4S)-4-azido-3-hydroxy-piperidine-1-carboxylate using the appropriate reagents and15 adjusting the reaction times to determine completion of the reactions. DIAD can besubstituted for DEAD.Table 2Prep No. Chemical Name Structure 1H NMR (400 MHz, DMSO-d6), 8 18 tert-Butyl (3R,4S)-4-azido-3-hydroxy-piperidine-1-carboxylate OH OA    / ( \\ n y. n o x' N+ '                      ' N- 5.50-5.13 (m, 1H), 3.75 -3.69 (m, 3H), 3.67-3.58 (m, 3H), 1.80 -1.68 (m, 1H), 1.62 -1.52 (m, 1H), 1.38 (s, 9H) 19 tert-Butyl (3S,4R)-4-azido-3-hydroxy-piperidine-1-carboxylate OH x Vn y.N ^-0 \— / N + /                N“ 5.39 (s, 1H), 4.17 - 4.03 (m, 1H), 3.68 -3.62 (m, 1H), 3.38 -3.30 (m, 4H), 1.80 -1.69 (m, 1H), 1.63 -1.53 (m, 1H), 1.39 (s, 9H). tert-Butyl (3R,4R)-4-azido-3-hydroxy-piperidine-1-carboxylate5.58 (s, 1H), 3.98 -3.86 (m, 1H), 3.85 -3.75 (m, 1H), 3.43 -3.34 (m, 1H), 3.33 -3.19 (m, 1H), 2.662.57 (m, 1H), 1.89 -1.76 (m, 1H), 1.39 (s, 9H), 1.28 -1.11 (m, 2H).Preparation 21(2S)-2-HydroxypropanehydrazideHO ON-NH2H2A mixture of ethyl lactate (3.00 g, 25.40 mmol), hydrazine hydrate (7.63 g, 152.37 mmol, 80% in H2O) and EtOH (10.00 mL) is heated for 12 hr at 50 °C under N2. Upon cooling to RT, the reaction is concentrated in vacuo to afford the title compound (3.0 g, crude). The title compound is taken on to the next step without further purification. ES / MS m / z: 105.2 [M+H]+.Preparation 22(2S)-N-[(E)-dimethylaminomethyleneamino]-2-hydroxy-propanamide-NA mixture of (2S)-2-hydroxypropanehydrazide (3.0 g, crude), (dimethoxymethyl) dimethylamine (6.44 g, 43.22 mmol) and i-PrOH (15mL) is heated at 50 °C for 5 hr under N2. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with DCM:MeOH (10:1 to 8:1) to afford the title compound (3.0 g, 62.1%) as a white solid. ES / MS m / z: 160.2 [M+H]+.Preparation 23tert-Butyl 4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylateoN^Nx\\ n N-NA solution of 1-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine (500 mg, 2.99 mmol) in THF (3 mL) and H2O (0.25 mL) is added TEA (605 mg, 5.98 mmol). After stirring 15 minutes BOC2O (783 mg, 3.59 mmol) is added. The reaction is stirred at 50 °C for 15 minutes. Upon cooling to RT pH is adjusted to ~14 by addition of 19N NaOH (aq.). The mixture is extracted with 3:1 CHCl3:iPrOH. Organic layers are combined and washed with brine (ensuring pH remains near 12), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a pale-yellow solid (647 mg, 2.42 mmol). ES / MS m / z: 168.1 [M+2H-BOC]+.Preparation 242-(1-Bromoethyl)-N,N-dimethyl-benzamideA reaction flask containing 2-ethyl-N,N-dimethylbenzamide (0.81 g, 4.6 mmol), AIBN (75 mg, 0.46 mmol) and NBS (0.89 g, 5.0 mmol) is evacuated and backfilled with N2 (3X). CCl4 (5 mL) is added, and the reaction is stirred 2 hr at 80 °C. Upon cooling to RT, the reaction is filtered, insoluble material is washed with CCl4 (2 x 10 mL), then concentrated in vacuo to obtain the title compound as a clear oil (0.8 g, 70 %), which is carried forward without a further purification. 1H NMR (400 MHz, CdCh), 8 7.67 (m, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.25 (m, 1H), 5.45 (m, 1H), 3.18 (3H), 2.91 (3H), 2.08 (3H).Preparation 252-Fluoro-N-methoxy-N-methyl-acetamide। IITo N,O-dimethylhydroxylamine hydrochloride (3.68 g, 37.70 mmol) under N2 is added DCM (40 mL) and the solution is cooled to -10 °C. 2M Trimethylaluminum in hexanes (2.72 g, 37.70 mmol) is slowly added to the reaction. Once the addition is complete the reaction is allowed to warm to RT and stirred at RT for 1 hr. In a separate flask ethyl-2-fluoroacetate (2.00 g, 18.85 mmol) and DCM (20 mL) is added under N2, and the reaction mixture is cooled -10 °C. Next, the solution prepared from trimethylaluminium and N,O-dimethylhydroxylamine is slowly transferred to the reaction containing ethyl-2-fluoroacetate, warmed to RT, and is stirred for 18 hr. The reaction is quenched by slowly adding 1M Rochelle's salt (10 mL). The mixture is stirred for 1 hr, diluted with H2O, layers separated, and the aq. layer is extracted with DCM (3 x 10 mL). The combined organics are washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a light-brown oil (1.6 g, 13 mmol). 1H NMR (400 MHz, CDCI3) 8 3.15 (m, 3H), 3.63 (s, 3H), 5.01 (d, J = 47.6 Hz, 2H).Preparation 26 7-Fluoro-N-methoxy-N-methyl-isoquinoline-4-carboxamideO ITo a mixture of 7-fluoroisoquinoline-4-carboxylic acid (900 mg, 4.71 mmol), N,O-dimethylhydroxylamine hydrochloride (551 mg, 5.65 mmol) in DCM (5mL) is added dropwise DIEA (2.43 g, 18.8 mmol). The solution is stirred for 5 min, followed by dropwise addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (4.49 g, 14.1 mmol). The mixture is stirred for 3 hr at RT, diluted with H2O and extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The crude product is purified by silica gel column chromatography column with 0% to 100% EtOAc in heptane to afford the title compound (1.03 g, 93.4 %). 1H NMR (400 MHz, CDCl3) 8 3.47 (br s, 6 H), 7.50 - 7.61 (m, 1 H), 7.65 (dd, J=8.44, 2.20 Hz, 1 H), 7.97 (dd, J=9.11, 5.07 Hz, 1 H), 8.60 (s, 1 H), 9.26 (s, 1 H).The following compounds are prepared essentially as described for 7-fluoro-N-methoxy-N-methyl-isoquinoline-4-carboxamide using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.Table 3Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 271 N-Methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide / J H ' F \ Jk o 198.1 28 N-Methoxy-N,5-dimethyl-pyridazine-3-carboxamide o \ z-z   z— a 29 5-Chloro-N-methoxy-N-methyl-pyridazine-3 -carboxamide \ N. / 0 NJk XI b 302 N, 1-Dimethoxy-N-methyl-cyclopropanecarboxamide °\ °\ 160.2 31 N-Methoxy-N,4-dimethyl-isothiazole-5-carboxamide o \ z \__ / \ ° c 323 N-Methoxy-N-methyl-2-(trifluoromethoxy)acetamide FtFo 1 ox 188.1 334 N-methoxy-N-methyl-5-(trifluoromethoxy)pyridine-3-carboxamide A 0 o=\ z-O / \ 251.1 34 (4R)-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide 0 \ \ 0 NT ' < 1 \ / \ / 0 Vo\ e 1 O-Dimethylhydroxylamine is used instead of HCl salt. EtOAc is used as solvent.2 Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 4:1).3 Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 1:1).4 Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1).a Material carried forward to next step without being characterized.b 1H NMR (400 MHz, CDCI3) 8 3.43 (br s, 3 H), 3.84 (br s, 3 H), 7.78 (br s, 1 H), 9.24 (brs, 1 H).c1H NMR (400 MHz, CDCl3) 8 2.59 (br s, 3 H), 3.37 (br s, 3 H), 3.79 (br s, 3 H), 8.30 (brs, 1 H).d sodium 2-(trifluoromethoxy)acetate is used.e 1H NMR (400 MHz, CdCl3) 8 1.45 (s, 3 H) 1.51 (s, 3 H) 3.23 (s, 3 H) 3.73 (s, 3 H) 4.04- 4.11 (m, 1 H) 4.24 - 4.33 (m, 1 H) 4.84 - 4.92 (m, 1 H).Preparation 354-Oxopiperidine-1-carbonitrileA solution of BrCN (256 mg, 2.42 mmol) in DCM (3.00 mL) is added dropwise to a stirred mixture of 4-piperidinone (200 mg, 2.02 mmol) and NaHCO3 (509 mg, 6.05 mmol) in H2O (4.50 mL) and DCM (1.50 mL) at 0 °C. The mixture is stirred for 30 min at 0 °C then stirred at RT overnight. The mixture is quenched with H2O (10 mL) and extracted with DCM (3x15 mL). The combined organic extracts are washed with sat. NaHCO3 (3x5 mL) and brine (3x10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow oil (120 mg, 48%). 1H NMR (400 MHz, d6-DMSO) 8 3.54 (t, 4H), 2.47 (t, 4H).Preparation 36Ethyl 1-methylpyrrolo[2,3-c]pyridine-4-carboxylateA mixture of 4-bromo-1-methyl-pyrrolo[2,3-c]pyridine (500 mg, 1 mmol), diethyl oxalate (415 mg, 2.84 mmol), PdCb(PPh3)2 (9.98 mg, 14.2 ^mol), and N,N-dimethylpyridin-4-amine (347 mg, 2.84 mmol) in EtOH (327 mg, 7.11 mmol) is heated at 170 °C for 1 hr with microwave irradiation. The mixture is diluted with EtOAc (10 mL) and washed with sat. aq. NH4Cl (10 mL). The aq. layer is extracted with EtOAc (3 x 10 mL) and the combined organic layers are concentrated in vacuo. The residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in water to afford the title compound (265 mg, 54.8 %). ES / MS m / z: 205.1 [M+H]+.Preparation 37(1-Methylpyrrolo[2,3-c]pyridin-4-yl)methanolTo a solution of ethyl 1-methylpyrrolo[2,3-c]pyridine-4-carboxylate (265 mg, 1.30 mmol) in THF (3 mL) at -78 °C is added a 1M solution of LiAlH4 (73.9 mg, 1.95 mmol) in Et2O. The reaction is stirred for 20 min then allowed to warm to RT and stirred for 1 hr. The mixture is diluted with Et2O and after cooling to 0 °C, H2O (0.1 mL) is slowly added. Then a 15% aq. soln. of NaOH (0.07 mL) is added, followed by H2O (0.2 mL), and the mixture is warmed to RT. After stirring for 15 min, MgSO4 is added, and the mixture is stirred for an additional 15 min. The solids are removed by filtration andthe filtrate is concentrated in vacuo to afford the title compound (190 mg, 90.3 %).ES / MS m / z 163.1 [M+H]+.Preparation 381-Methylpyrrolo[2,3-c]pyridine-4-carbaldehydeTo a solution of (1-methylpyrrolo[2,3-c]pyridin-4-yl)methanol (190 mg, 1.175 mmol) in DCM (4 ml) at 0 °C is added DMP (646 mg, 1.52 mmol) and the reaction is stirred for 1 hr. The mixture is diluted with DCM (10 mL) and washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL). The volatiles are removed in vacuo and the residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in water to afford the title compound (70 mg, 37 %). ES / MS m / z 161.1 [M+H]+.10                                       Preparation 392-Morpholino-5-(trifluoromethyl)pyridine-3-carbaldehyde2-Chloro-5-(trifluoromethyl)nicotinaldehyde (700 mg, 3.34 mmol) andmorpholine (291 mg, 3.34 mmol) are dissolved in EtOH (10 mL) and treated with TEA15   (338 mg, 3.34 mmol) at RT. The reaction is heated to 80 °C for 6 hr. The reaction iscooled to RT, concentrated in vacuo, and purified by flash silica gel chromatography eluting with a gradient of 0% to 20% MeOH in DCM to afford the title compound as a clear oil (0.7 g, 80%). ES / MS m / z 261.1 [M+H]+.Preparation 405,7-Dichloroimidazo[1,2-a]pyridineTo a 1 L pressure tank is added 4,6-dichloropyridin-2-amine (100.00 g, 614 mmol), NaHCO3 (154.6 g, 1840 mmol), chloroacetaldehyde (180.5 g, 920 mmol, 40% in water) and n-BuOH (500 mL) at RT under a N2. The resulting mixture is stirred overnight at 80 °C. Upon cooling to RT, the mixture is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (8:1 to 5:1) to give the title compound as a yellow solid (88 g, 76.7%). ES / MS m / z 187.0 [M+H]+.Preparation 415,7-Dichloro-3-methylimidazo[1,2-a]pyridineTo a solution of 2-bromo-1,1-dimethoxypropane (16.84 g, 92 mmol) in EtOH (50 mL) at RT under N2 is added 12M HCl (33.55 g, 920 mmol). The reaction is stirred overnight at 80 °C. Upon cooling to RT, the pH of the mixture is adjusted to approximately pH 8 with NaHCO3 (90.19 g, 1074 mmol). Next, 4,6-dichloropyridin-2-amine (5.0 g, 30.68 mmol) is added to the reaction and the mixture is stirred overnight at 80 °C. Upon cooling to RT, the mixture is filtered, and the filter cake is washed with EtOAc (3 x 100 mL). The filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography, eluting with PE:EtOAc (10:1), to give the title compound as a yellow solid (2.5 g, 40.5%). ES / MS m / z 201.1 [M+H]+.The following compound is prepared essentially as described for 5,7-dichloro-3-methylimidazo[1,2-a]pyridine using the appropriate reagents and adjusting the reaction temperature and time to determine completion of the reactions.Table 4Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 42 7-Bromo-5-chloro-imidazo[1,2-a]pyridine A Br'^^^CI (79Br / 81Br) 231.0 / 233.0 Preparation 437-Chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine5          To 5,7-dichloro-3-methylimidazo[1,2-a]pyridine (1.5 g, 7.46 mmol) in MeOH (20mL) at RT under N2 is added NaOMe (4.03 g, 74.61 mmol). The reaction is stirred at 80 °C for 1 hr then concentrated in vacuo. The residue is diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers are washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title10 compound as a yellow solid (1.35 g, 92.0%). ES / MS m / z 197.1 [M+H]+.Preparation 445,7-Dichloro-3-iodo-imidazo[1,2-a]pyridineTo 5,7-dichloroimidazo[1,2-a]pyridine (5.00 g, 26.73 mmol) in DCM (50.0015 mL) is added NIS (12.03 g, 53.47 mmol) in portions at RT under N2. The reaction is stirred for 2 hr then quenched with H2O (100 mL). The mixture is extracted with DCM (3 x 50 mL), organic layers are washed with brine (3 x 50 mL), and dried over Na2SO4.After filtration, the filtrate is concentrated in vacuo to afford the title compound as a darkyellow solid (12.0 g, crude). ES / MS m / z 312.9 [M+H]+.Preparation 456-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridineN =\1 J6-Bromo-4-methoxypyrazolo[1,5-a]pyridine (0.41 g, 1.81 mmol) and NIS (609 mg, 2.71 mmol) are dissolved in ACN (8 mL) and stirred at RT for 1 hr. The suspension is filtered, and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a linear gradient of 0% to 100% EtOAc in heptane. The fractions containing the title compound is concentrated in vacuo and combined with the filtered solid to afford the title compound (0.60 g, 94.1 %). ES / MS m / z (79Br / 81Br) 352.6 / 354.6 [M+H]+.Preparation 466-bromo-3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridineN=\J T BrIA solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5 g, 22.02 mmol) and 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.04 g, 22.021 mmol) in ACN (50 mL) is stirred overnight at RT under N2. The mixture is diluted with H2O (50 mL) then extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; mobile phase, 30% to 40% ACN in H2O (0.1% FA),over a 10 min. period to afford the title compound (810 mg, 15.01%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 8 8.56 (t, 1H), 8.04 (d, 1H), 6.77 (d, 1H),3.97(s, 3H).Preparation 476-Bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridineA mixture of 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (0.6 g, 1.7 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.5 g, 2.6 mmol), and CuI (0.4 g, 2.1 mmol) in DMF (6 mL) is heated for 6 hr. to 80 °C. The suspension is filtered and the filtrate is concentrated in vacuo. The residue is purified by normal phase chromatography eluting with a linear gradient of 0% to 100% EtOAc in heptaneto afford the title compound (0.125 g, 20 %) as a white solid. ES / MS m / z 249.9 [M+H]+.Preparation 485,7-Dichloroimidazo[1,2-a]pyridine-3-carbonitrileTo of 5,7-dichloro-3-iodoimidazo[1,2-a]pyridine (11.00 g, 35.15 mmol) in DMF (50.00 mL) is added in portions CuCN (6.30 g, 70.31 mmol) at RT under N2. The reaction is stirred for 2 hr at 100 °C. Upon cooling to RT, NH4OH (100 mL) is added dropwise over 5 minutes. The mixture is diluted with H2O (300 mL), stirred for 2 hr, then extracted with DCM (3 x 400 mL). The combined organic layers are washed with brine (3 x 300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (5:1 to 1:2), to afford the title compound as a yellow solid (3.5 g, 47.0%). ES / MS m / z (35Cl / 37Cl) 211.9 / 213.9 [M+H]+.Preparation 496-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrileN=xI 1 BrOHA stirred solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (5.60 g, 22.22 mmol) and NDM (5.39 g, 26.66 mmol) in DMA (20.0 mL) is treated with NaOH (5.33 g, 66.65 mmol, 50% in H2O) at RT under N2, and the mixture is stirred for 2 hrs at 50 °C under N2. The mixture is diluted with H2O (200 mL), acidified to pH 4-5 with conc. HCl, and extracted with EtOAc (3x200 mL). The combined organic extracts are washed with brine (3x100 mL) and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1) to give the title compound as a yellow solid (4.6 g, 90.7%) ES / MS m / z 235.9 / 237.9 [M-H]-.Preparation 50 6-Bromo-4-isopropoxy-pyrazolo[1,5-a]pyridine-3-carbonitrileA mixture of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.84 mmol) and Cs2CO3 (410.63 mg, 1.26 mmol) in DMF (2 mL) is treated with 2-iodopropane (0.1 mL, 1 mmol) and stirred for 7.5 hrs. The reaction mixture is purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc (0-100%) to give the title compound as a light-yellow solid (174.2 mg, 0.62 mmol, 74.02%). ES / MS m / z 282.00 [M+H]+.Preparation 512-[3-[tert-Butyl(dimethyl)silyl]oxyazetidin-1-yl]-5-(trifluoromethyl)pyridine-3-carbaldehyde2-Chloro-5-(trifluoromethyl)nicotinaldehyde (575 mg, 2.74 mmol) and 3-((tert-butyldimethylsilyl)oxy)azetidine (566 mg, 3.02 mmol) are dissolved in EtOH (8 mL) andtreated with NEt3 (305 mg, 3.02 mmol) at RT. The reaction is heated for 4 hr at 80 °C.Upon cooling to RT, the reaction is concentrated and purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to obtain the title compound (0.73 g, 2.03 mmol, 74 %) as a clear oil. 1H NMR (400 MHz, CDCI3) 8 9.90 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 4.75 (m, 1H), 4.50 (m, 2H), 4.08 (m, 2H), 0.91(s, 9H), 0.09 (s, 6H).Preparation 521-(4-Isoquinolyl)ethanolTo a solution of isoquinoline-4-carbaldehyde (500 mg, 3.18 mmol) in anhydrous THF (7 mL) at 0 °C is added 3M methylmagnesium bromide (455 mg, 3.82 mmol). The reaction is stirred at 0 °C for 20 minutes, allowed to warm to RT, then stirred for 2 hr at RT. The reaction is quenched with sat. NH4Cl, extracted with EtOAc (3 x 30mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0% to 100% in heptane to give the title compound. (540 mg, 98.0 %). 1H NMR (400 MHz, CDCl3) 8 1.73 (d, J=6.48 Hz, 3H), 2.72 (br s, 1H), 5.59 (q, J=6.48 Hz, 1H), 7.63 (ddd, J=8.10, 7.00, 1.04 Hz, 1H), 7.75 (ddd, J=8.47, 6.94, 1.34 Hz, 1H), 7.99 (d, J=8.07 Hz, 1H), 8.18 - 8.22 (m, 1H), 8.61 (s, 1H), 9.15 (s, 1H).The following compounds are prepared essentially as described for 1-(4-isoquinolyl)ethanol using the appropriate reagents and adjusting the reaction temperature and times to determine completion of the reactions.Table 5Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 53 1-(1-Isopropyltriazol-4-yl)ethanol V OH X N > ' N a 54 1-(2-Ethyltriazol-4-yl)ethanol OH b 55 1-(3-Ethyltriazol-4-yl)ethanol OH N c 56 1-(6-Methylpyrazin-2-yl)ethanol h°\t d 57 1-[2-Morpholino-5-(trifluoromethyl)-3-pyridyl]ethanol HO 0        1         1 N J F F e 58 1-(5-Methyl- 1,3,4-thiadiazol-2-yl)ethanol OH V > S \ f 59 1-Isothiazol-5-ylethanol OH s g 60 1-(3- Methylsulfonylphenyl)ethanol OH   00 kJ h 61 1-(5-Fluoro-3-pyridyl)ethanol OH Yj i 62 1-(5-Chloro-3-pyridyl)ethanol OH Tj 158.2 63 1-(1-Methylpyrrolo[2,3-c]pyridin-4-yl)ethanol )—O __ /  1 / / \\ z z^ / 177.1 64 1-[2-Chloro-5- (trifluoromethyl)-3-pyridyl]ethanol LL LL LL—X / Z T /  \ O j 65 1-[2-[3-[tert-Butyl(dimethyl)silyl] oxyazetidi n-1 -yl]-5-(trifluoromethyl)-3 -pyridyl]ethanol O   ^0H sr          | d 1 f F k a 1H NMR (400 MHz, CDCI3) 8 1.55 -1.67 (m, 9H), 2.80 (br s, 1 H), 4.14 (q, J=6.77 Hz, 1H), 4.84 (dt, J=12.96, 6.36 Hz, 1H), 5.11 (q, J=5.91 Hz, 1H), 7.50 (s, 1H).b 1H NMR (400 MHz, d6-DMSO) 8 1.35 - 1.46 (m, 6H), 4.37 (m, 2H), 4.81 (m, 1H), 5.30 (br s, 1H), 7.61 (br s, 1H).5   c 1H NMR (300 MHz, d6-DMSO) 8 7.58 (s, 1H), 5.50 (d, 1H), 4.95-4.85 (m, 1H), 4.50 -4.32 (m, 2H), 1.56 - 1.38 (m, 6H).d 1H NMR (400 MHz, CDCl3) 8 8.46 (s, 1H), 8.39 (s, 1H), 4.91 - 5.02 (m, 1H), 2.59 (s, 3H), 1.56 (br d, J=6.36 Hz, 3H).e 1H NMR (400 MHz, CDCI3) 8 1.57 (br d, J=6.11 Hz, 3H), 3.24 (br s, 4H), 3.48 (br s, 1H), 3.87 (br s, 4H), 5.08 - 5.19 (m, 1H), 7.92 (br s, 1H), 8.51 (br s, 1H).f1H NMR (400 MHz, CDCl3) 8 1.66 (br d, J=6.11 Hz, 3 H), 2.73 - 2.80 (m, 3 H), 2.97 -3.27 (m, 1 H), 5.21 - 5.35 (m, 1 H).g1H NMR (400 MHz, CDCI3) 8 8.41-8.29(m, 1H), 7.13-7.03 (m, 1H), 5.34-5.21(m, 1H), 1.62 (t,3H).h 1H NMR (400 MHz, CDCl3) 8 1.55 (d, J =6.7 Hz, 3H), 3.08 (s, 3 H), 4.96 - 5.07 (m, 1 H), 7.52 - 7.61 (m, 1 H), 7.68 (br t, J=6.8 Hz, 1 H), 7.78 - 7.91 (m, 1 H), 7.96 - 8.01 (m, 1 H).i 1H NMR (400 MHz, CDCl3) 8 8.36 (t, 1H), 8.32 (d, 1H), 7.62-7.39 (m, 1H), 4.99 (q, 1H), 2.82 (s, 1H), 1.53 (d, 3H).j 1H NMR (400 MHz, CDCl3) 8 8.56 (s, 1H), 8.32 (s, 1H), 5.28 (m, 1H), 1.54 (d, 3H). k 1H NMR (400 MHz, CDCl3) 8 8.34 (s, 1H), 7.84 (s, 1H), 4.95 (m, 1H), 4.73 (m, 1H), 4.39 (m, 2H), 4.04 (m, 2H), 1.50 (d, 3H), 0.90 (s, 9H), 0.09 (s, 6H).Preparation 66 1-(5-Fluoro-3-methyl-2-pyridyl)ethanoneO 1To 2-bromo-5-fluoro-3-methylpyridine (3 g, 15.8 mmol) in toluene (50 mL) is added i-PrMgCl (12 mL, 23.7 mmol, 2 M in THF) dropwise at RT under N2. After stirring 3 hr at RT, N-methoxy-N-methylacetamide HCl (2.4 g, 23.7 mmol) is added. The reaction is stirred 2 hr then quenched with H2O (100 mL). The mixture is extracted with EtOAc (3 x 100 mL). The organic layers are combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (2 g, 83%). ES / MS m / z 154.1 [M+H]+.The following compounds are prepared essentially as described for 1-(5-fluoro-3-methyl-2-pyridyl)ethanone using the appropriate reagents and adjusting the reaction temperature and times to determine completion of the reactions.Table 6Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 67 2,2-Difluoro-1-(5-fluoro-2-pyridyl)ethanone 0 F 174.0 [M-H] 68 (5-Fluoro-2-pyridyl)-[1-(trifluoromethyl)cyclopropyl] methanone F ,F O / \ H 1 n^Af 233.8 691 (5-Fluoro-2-pyridyl)-(1-methoxycyclopropyl) methanone ll 4 / ) / z 196.1 702 1-[5-(trifluoromethoxy)-3-pyridyl] ethanone 0 I J F " 205.9 1 Purified by silica gel column chromatography, eluting with PE:EA (12:1 to 10:1).2 Purified by silica gel column chromatography, eluting with PE:EA (20:1 to 4:1).Preparation 711-(7-Fluoro-4-isoquinolyl)ethanoneTo a solution of 7-fluoro-N-methoxy-N-methylisoquinoline-4-carboxamide (500mg, 2.13 mmol) in THF (10mL) at 0 °C is added dropwise a solution of 3M MeMgBr inEt2O (255 mg, 2.13 mmol, 0.71 ml). The reaction is stirred at 0 °C for 20 min, then allowed to warm to RT and stirred for an additional 2 hr. The reaction is quenched with 10 sat. aq. NH4Cl solution. Layers are separated and the aq. layer is extracted with EtOAc.Combined organics are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 0% to 10%MeOH in DCM to give the title compound (389 mg, 96.3%). 1H NMR (400 MHz, CDCl3) 8 2.81 (s, 3 H), 7.59 - 7.67 (m, 2 H), 8.99 (dd, J=9.11, 5.32 Hz, 1 H), 9.05 (s, 1 H), 9.33 (s, 1 H).The following compounds are prepared essentially as described for 1-(7-Fluoro-4-5 isoquinolyl)ethanone using the appropriate reagents and adjusting the reaction temperature and times to determine completion of the reactions.Table 7Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 721 1-(5-Methylpyridazin-3-yl)ethanone a 73 1-(5-Chloropyridazin-3-yl)ethenone I || XI b 741 1-(4-Methylisothiazol-5-yl)ethanone \ N^7 c 1 Purified by flash chromatography eluting with 0% to 100% EtOAc in heptane.a 1H NMR (400 MHz, d6-DMSO) 8 2.42 (s, 3H), 2.77 (s, 3H), 7.96 (br s, 1H), 9.31 (br s,10   1H).b 1H NMR (300 MHz, d6-DMSO) 8 9.63 (br s, 1H), 8.26 (br s, 1H), 2.79 (br s, 3H).c 1H NMR (400 MHz, CDCl3) 8 2.54 (br s, 3H), 2.60 (br s, 3H), 8.35 (br s, 1H).Preparation 752-Fluoro-1-(5-fluoro-2-pyridyl)ethanoneA solution of 2-bromo-5-fluoropyridine (1.1 g, 6.3 mmol) in toluene (6 mL) is cooled to -78 °C under N2 then a soln of n-BuLi (0.44 g, 2.8 ml, 6.9 mmol, 2.5M in hexanes) is slowly added. The reaction mixture is then stirred at -78 °C for 30 min. 2-Fluoro-N-methoxy-N-methylacetamide (0.83 g, 6.9 mmol) in toluene (2.0 mL) is added to the reaction. After stirring at -78 °C for 30 min the cooling bath is removed, and the reaction is quenched with sat. aq NH4Cl and extracted with DCM. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the title compound (0.9 g, 90 %) as a brown solid. 1H NMR (400 MHz, CDCh) 8 5.77 (d, J = 47.6 Hz, 2 H) 7.46 - 7.55 (m, 1 H) 8.05 - 8.12 (m, 1 H) 8.39 - 8.44 (m, 1 H)Preparation 761-[5-Fluoro-6-(2-methoxyethoxy)-2-pyridyl]ethanoneOTo 6-bromo-3-fluoro-2-(2-methoxyethoxy)pyridine (1.7 g, 6.80 mmol) in THF (50 mL, 617.2 mmol) is added n-BuLi (2.72 mL, 6.80 mmol, 2.5 M in hexane) dropwise at -78 °C under N2. The reaction is stirred for 0.5 hr at -78 °C. Next, N-methoxy-N-methylacetamide (2.10 g, 20.39 mmol) is added and stirring continues for an additional 1 hr at -78 °C. The reaction is quenched by the addition of H2O (50 mL) at -78 °C. Upon warming to RT the reaction is extracted with EtOAc (3 x 50 mL). Organic layers are combined and washed with brine (3 x 50 mL), dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used in a subsequent step directly without further purification. ES / MS m / z 213.9 [M+H]+.The following compound is prepared essentially as described for 1-[5-Fluoro-6-(2-methoxyethoxy)-2-pyridyl]ethanone using the appropriate reagents and adjusting thereaction temperature and time to determine completion of the reaction. Table 8Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 77 [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-(5-fluoro -2-pyridyl)methanone O \ 'o-' a a 1H NMR (400 MHz, CdCh) 8 1.43 (s, 3H) 1.47 (s, 3H) 3.92 (dd, J=8.56, 6.48 Hz, 1 H) 4.50 - 4.59 (m, 1H) 5.61 - 5.68 (m, 1H) 7.45 - 7.54 (m, 1H) 8.08 - 8.15 (m, 1H) 8.39 -8.44 (m, 1H).Preparation 78(1E)-2-Bromobenzaldehyde oximeHO'NA mixture of 2-bromobenzaldehyde (10g, 54.05 mmol) and NH2OH.HCI (4.1 g, 59.45 mmol) in EtOH (100mL) is stirred for 2 hr at 80 °C under N2. The reaction is concentrated in vacuo. The residue is dissolved in EtOAc (100mL) and washed with H2O (3 x 50mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as an off-white solid (12 g) which is carried forward without a further purification. ES / MS m / z (79Br / 81Br) 200 / 202 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 8 11.69 (s, 1H), 8.32 (s, 1H), 7.80 (dd, 1H), 7.67 (dd, 1H), 7.45 -7.38 (m, 1H), 7.34 (td, 1H).Preparation 79 3-(2-Bromophenyl)isoxazoleTo a stirred solution of (E)-N-[(2-bromophenyl)methylidene]hydroxylamine (5g, 25.00 mmol) and NCS (4.33g, 32.49 mmol) in CCl4 (50mL) is added calcium carbide(11.19 g, 175.00 mmol) and H2O (6.30 g, 349.93 mmol) dropwise at RT under N2. The reaction is stirred overnight. The suspension is filtered, the filter cake is washed with DCM (3 x 30 mL). The filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (12:1) to afford the title compound as an off-white solid (3.5 g, 62.50%). ES / MS m / z (79Br / 81Br) 224 / 226 [M+H]+.Preparation 802-(1-Ethoxyvinyl)-6-(trifluoromethyl)pyrazineTo a stirred solution of 2-chloro-6-(trifluoromethyl)pyrazine (2000 mg, 10.957 mmol) and tributyl(1-ethoxyethenyl)stannane (4748.68 mg, 13.148 mmol) in dioxane (25 mL) is added Pd(PPh3)4 (1266.16 mg, 1.096 mmol) at RT under N2. The resulting mixture is stirred for 4 hr at 80 °C. The mixture is allowed to cool down to RT and is concentrated under vacuum. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (8:1 to 4:1) to afford the title compound as a yellow oil (1.8 g, 75.29%). 1H NMR (300 MHz, d6-DMSO) 8 9.18 - 9.16 (m, 2H), 5.47 - 5.41 (m, 1H), 4.75 - 4.69 (m, 1H), 4.03 (q, 2H), 1.40 (t, 3H).The following compound is prepared essentially as described for 2-(1-Ethoxyvinyl)-6-(trifluoromethyl)pyrazine using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.Table 9Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 811 3-[2-(1- Ethoxyvinyl)phenyl]isoxazole crN 216.1 1 Purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 5:1).Preparation 821-(2-Isoxazol-3-ylphenyl)ethanoneTo 3-[2-(1-ethoxyethenyl)phenyl]-1,2-oxazole (2.20 g, 10.22 mmol) in MeOH (20 mL) is added 4M HCl in MeOH (20 mL) at RT. The reaction is stirred for 1 hr under N2. The reaction is quenched with H2O (100 mL). The mixture is extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (3:1) to afford the title compound as a yellow oil (1.6 g, 83.6%). ES / MS m / z 188.1 [M+H]+.Preparation 831-[6-(Trifluoromethyl)pyrazin-2-yl]ethanoneoA mixture of 2-(1-ethoxyethenyl)-6-(trifluoromethyl)pyrazine (1.20 g, 5.50 mmol) and 12 M HCl (2.29 mL, 27.50 mmol) in THF (20 mL) is stirred for 2 hr at RT under N2. The resulting mixture is concentrated in vacuo to afford the title compound which is carried forward without a further purification. 1H NMR (400 MHz, d6-DMSO) 8 9.45 (s, 1H), 9.41 (s, 1H), 2.67 (s, 3H).Preparation 842-Methoxy- 1-[5-(trifluoromethyl)pyridin-3-yl]ethanoneA solution of i-PrMgCl (3.3 mL, 6.61 mmol) is added dropwise under N2 at 0 °C to a solution of 3-bromo-5-(trifluoromethyl)pyridine (1.00 g, 4.42 mmol) in dry THF (40 mL). The solution is stirred for 1 hr under N2 at 50 °C. To the above solution is added N-5 2-dimethoxy-N-methylacetamide (1.18 g, 8.86 mmol) in dry THF (1 mL) under N2 at RT.The solution is stirred for 2 hr under N2 at RT. The residue is acidified to pH 6 with conc. aq HCl. The mixture is diluted with H2O (50 mL), the pH adjusted to 11 with solid Na2CO3, and extracted with EtOAc (3x50 mL). The organic layers are combined, washed with brine (3x50 mL), and dried over anhydrous Na2SO4. The mixture is filtered and the 10 filtrate is concentrated under reduced pressure. The crude product (5.00 g) is used without further purification. 1H NMR (300 MHz, CDCh) 8 9.38 - 9.30 (d, 1H), 9.14 -9.05 (m, 1H), 8.56 - 8.48 (m, 1H), 4.69 (s, 2H), 3.55 - 3.53 (m, 3H).The following compounds are prepared essentially as described for 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanone using the appropriate reagents and adjusting the 15 reaction times to determine completion of the reactions.Table 10Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 85 3,3,3-Trifluoro-1-(5-fluoro-2-pyridyl)propan-1 -one 0 / 0, F a 861 2-Pyridyl-[1 -(trifluoromethyl) cyclopropyl]methanone / / y—z O=( u- 216.1 872 1-(5-Fluoro-2-pyridyl)-2-methoxy-ethanone 0 XX 170.1 88 1-(5-Fluoro-2-pyridyl)-2-(trifluoromethoxy)ethanone 0 . / 0, fX F b 1 2.5 M BuLi used instead of iPrMgCl. Reaction run in toluene at -78 °C.2 Purification by silica gel column chromatography, eluting with PE:EtOAc (12:1).a 1H NMR (400 MHz, CDCI3) 8 5.83 (d, J = 47.6 Hz, 2H), 7.54 -7.61 (m, 1H), 8.15 (dd, J=8.68, 4.65 Hz, 1H), 8.47 (s, 1H).b Material is used without further purification.Preparation 892-Methoxy- 1-[5-(trifluoromethyl)pyridin-3-yl]ethanolNaBH4 (860 mg, 22.73 mmol) is added in portions at RT under N2 to a stirred mixture of 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanone (5.00 g) in MeOH (20 mL). The reaction is quenched with H2O (5 mL) at RT and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 2:1) to give the title compound (500 mg, 9.91%) as a yellow liquid.ES / MS m / z 222.0 [M+H]+.The following compounds are prepared essentially as described for 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanol using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.Table 11Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 901 1-(5-Methylpyridazin-3-yl)ethanol x oh A a 911 2-Fluoro-1 -(5-fluoro-2-pyridyl)ethanol OH b 921 1-(7-Fluoro-4- isoquinolyl)ethanol LL I \   / o c 93 1-[6- (Trifluoromethyl)pyrazin -2-yl]ethanol OH N F d 94 1 -(2-Pyridyl)propan-1 -ol OH 138.1 95 1-(5-Chloropyridazin-3-yl)ethanol \OH 1             || XI e 96 1-(5-Methyl-3-pyridyl)ethanol OH ^l\T f 97 1-[5-(Difluoromethyl)-3-pyridyl]ethanol T / °--( (\    Z 4_7 g 98 3,3,3-Trifluoro-1-(5-fluoro-2-pyridyl) propan-1-ol OH F<^F     V F 210.1 99 (5-Fluoro-2-pyridyl)-( 1-methoxycyclopropyl) methanol HO 198.1 1002 2-Pyridyl-[1-(trifluoromethyl)cyclopro pyl]methanol "XL -n )—O zX T / / N\ 218.0 101 1-(2- Methylsulfonylphenyl) ethanol O O \ —"w X° \__ / I 183.1 [M-OH]+ 102 1-(5-Fluoro-3-methyl-2-pyridyl)ethanol Xo / / NX___ 156.1 1033 2,2-Difluoro- 1-(5-fluoro-2-pyridyl)ethanol OH F^X^ F 178.3 1044 1-(2-Isoxazol-3-ylphenyl)ethanol t / \ OX 7=z x° 188.0 [M-H]- 105 1-(5-Fluoro-2-pyridyl)-2-methoxy-ethanol OH / X / N\ o lLX 172.1 106 1-(2-Isothiazol-3-ylphenyl)ethanol OH s-N h 1071 1 -(4-Methylisothiazol-5-yl)ethanol S-N i 108 1-(5-Fluoro-2-pyridyl)-2-(trifluoromethoxy) ethanol o—\ / V LL LL 226.1 109 1-[5-Fluoro-6-(2-methoxyethoxy)-2-pyridyl]ethanol OH o 1 216.1 110 1- [5-(trifluoromethoxy)-3-pyridyl] ethanol OH X / \ / O^F 208.0 111 [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-(5-fluoro-2-pyridyl)methanol OH X7n3l.f j 112 (5-Fluoro-2-pyridyl)-[1-(trifluoromethyl) cyclopropyl]methanol F F OH A h 1 N ^J F 236.0 1 Purified by silica gel column chromatography, eluting with 0% to 100% EtOAc in heptane.2 Purified by silica gel column chromatography, eluting with PE:EtOAc (6:1 to 2:1).3 Purified by silica gel column chromatography, eluting with PE:EtOAc (9:1).4 Purified by silica gel column chromatography, eluting with PE:EtOAc (1:1).5 Purified by silica gel column chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane.a 1H NMR (400 MHz, d6-DMSO) 8 1.41 (d, J=6.60 Hz, 3H), 2.33 (s, 3H), 4.93 (qd, J=6.56, 4.65 Hz, 1H), 5.59 (d, J=4.65 Hz, 1H), 7.58 (d, J=0.98 Hz, 1H), 8.97 (d, J=2.08 Hz, 1H).b 1H NMR (400 MHz, CdCh) 8 ppm 4.61 (dd, J = 47.2, 5.3 Hz, 2 H) 5.02 (dt, J = 16.1, 5.3 Hz, 1H) 7.46 - 7.53 (m, 2 H) 8.46 (s, 1 H).c 1H NMR (400 MHz, CDCh) 8 1.73 (d, J=6.48 Hz, 3H), 2.42 (br s, 1H), 5.56 (q, J=6.56 Hz, 1H), 7.50 - 7.57 (m, 1H), 7.61 (br d, J=8.68 Hz, 1H), 8.29 (dd, J=9.23, 5.20 Hz, 1H), 8.59 (s, 1H), 9.13 (s, 1H).d 1H NMR (400 MHz, d6 -DMSO) 8 9.11 (s, 1H), 9.07 (s, 1H), 5.82 (d, 1H), 4.95 - 4.88 (m, 1H), 1.44 (d, 3H).e Material is used without further purification.f 1H NMR (400 MHz, CDCh) 8 1.51 (br d, J=6.11 Hz, 3H), 2.34 (s, 3H), 2.75 - 2.90 (m, 1 H), 4.87 - 4.97 (m, 1H), 7.55 (br s, 1H), 8.31 (br s, 1H), 8.36 (br s, 1H).g 1H NMR (400 MHz, CDCh) 8 1.56 (br d, J=6.24 Hz, 3H), 2.54 (br s, 1H), 5.04 (q, J=5.79 Hz, 1H), 6.72 (t, J = 55.8 Hz, 1H,) 7.91 (br s, 1H), 8.65 (br s, 1H), 8.72 (br s, 1H). h 1H NMR (400 MHz, CDCh) 8 1.55 (d, J=6.6 Hz, 3H) 4.95 (q, J=6.6 Hz, 1H) 7.37 - 7.46 (m, 1H) 7.46 - 7.52 (m, 2H) 7.53 - 7.59 (m, 1H) 7.66 (br d, J=7.58 Hz, 1H) 8.79 (d, J=4.65 Hz, 1H).i 1H NMR (400 MHz, CdCh) 8 2.54 - 2.58 (m, 3H), 2.61 - 2.64 (m, 3 H), 3.39 (m, 1H), 3.80 (m, 1H), 8.37 (br s, 1H).j 1H NMR (400 MHz, CdCl3) 8 1.35 (s, 3H) 1.44 (s, 3H) 3.92 - 3.98 (m, 1H) 4.00 - 4.07 (m, 1H) 4.40 - 4.47 (m, 1H) 4.76 - 4.80 (m, 1H) 7.42 - 7.55 (m, 2H) 8.41 - 8.46 (m, 1H) Preparation 113Cis-3-BenzyloxycyclobutanolA mixture of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol) and NaBH4 (4.29 g, 113.5 mmol) in MeOH (50 mL) is stirred for 2 hr at RT under N2. The reaction is quenched with H2O at 0°C, extracted with EtOAc (3 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to afford the title compound (20 g, 98.9%) as a light-yellow oil. 1H NMR (400 MHz, DMSO-d6) 8 7.42-7.21 (m, 5H), 4.45(s, 2H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 1H),2.82-2.63(m, 2H), 1.97-1.92(m, 2H).Preparation 114 3-(5-Fluoro-2-pyridyl)-3-hydroxy-2,2-dimethyl-propanenitrile OHLithiumdiisopropylamide in THF (2.57 g, 24.0 mmol, 2M in THF) is slowly added to a cooled solution of isobutyronitrile (1.66 g, 24.0 mmol) in THF (25 mL) at -78 °C under N2. The reaction is stirred at -78 °C for 30 minutes. Next, 5-fluoro picolinaldehyde (2.00 g, 16.0 mmol) in THF (6 mL) is slowly added to the reaction. After stirring for an additional hour, the reaction is allowed to warm to RT. The reaction is quenched with sat. NH4Cl, extracted in EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by phase silica gel flash chromatography eluting with a gradient of 0% to 100% EtOAc in Heptane to afford the title compound (1.60 g, 51.5 %) as a white solid. 1H NMR (400 MHz, CdCh) 8 8.46 (s, 1H), 7.55-7.47 (m, 2H), 4.68 (s, 1H), 4.54 (brs, 1H), 1.44 (s, 3H), 1.21 (s, 3H).Preparation 1152,2,2-Trifluoro-1 -(5-fluoropyndm-2-yl)ethanolOHTo 5-fluoropyridine-2-carbaldehyde (2 g, 15.99 mmol) and TMSCF3 (3.41 g, 23.98 mmol) in THF (5.00 mL) is added TBAF (3.20 mL, 3.200 mmol) dropwise at 0 °C under N2. The resulting mixture is stirred at RT for 3 hr then concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with 50% EtOAc in PE to afford the title compound as a white solid (2 g, 64.12%). ES / MS m / z 196.1 [M+H]+.Preparation 1162-[tert-Butyl(dimethyl)silyl]oxy-1-(4-isoquinolyl)ethanolTo 4-bromoisoquinoline (2.00 g, 9.61 mmol) dissolved in THF (8mL) under N2 is added dropwise 2M isopropylmagnesium chloride (1.48 g, 14.42 mmol) at RT. The reaction is stirred 30 minutes at RT, then 2-(( tert-butyldimethylsilyl)oxy)acetaldehyde (3.35 g, 19.23 mmol) is added dropwise. The reaction is stirred at RT for 2 hr, then is quenched with aq. sat. NH4CL The mixture is extracted with EtOAc (2 x 100mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane. The isolated material is further purified by silica gel chromatography eluting with 20% DCM in EtOAc to afford the title compound which is contaminated with the isoquinoline biproduct (400 mg, 13.7%). 1H NMR (400 MHz, CDCl3) 8 0.07 (s, 6H), 0.93 (s, 9H), 3.72 - 3.91 (m, 1H), 3.99 (dd, J=10.27, 3.42 Hz, 1H), 5.47 (dd, J=8.38, 3.36 Hz, 1H), 7.58 - 7.78 (m, 7H), 7.84 (d, J=8.31 Hz, 2H), 7.96 - 8.04 (m, 2H), 8.12 (d, J=8.44 Hz, 1H), 8.54 (d, J=5.62 Hz, 1H), 8.70 (s, 1H), 9.22 (s, 1H), 9.27 (s, 1H).Preparation 1172-[( tert-Butyldimethylsilyl) oxy]- 1-(5-fluoropyridin-2-yl) ethanolOHA solution of i-PrMgCl (5.11 mL, 10.23 mmol, 2 M in THF) is added dropwise at 0 °C under N2 to a stirred solution of 2-bromo-5-fluoropyridine (1.2 g, 6.82 mmol) in toluene (10.00 mL). The mixture is stirred for 30 min at 0 °C under N2. 2-[( tert -5 Butyldimethylsilyl)oxy] acetaldehyde (1.78 g, 10.23 mmol) is added dropwise over 10 min at 0 °C to the mixture. The mixture is stirred 2 hr at 0 °C. The reaction is quenched with H2O and extracted with EtOAc (3x20 mL). The combined organic layers are washed with brine (2x10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column10 chromatography, eluting with PE:EtOAc (10:1 to 5:1) to give the title compound (420 mg, 22.69%) as a colorless oil. ES / MS m / z 272.2 [M+H]+The following compounds are prepared essentially as described for 2-[( tertButyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.15 Table 12Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 118 2-[ tert -Butyl(dimethyl)silyl]oxy-1-[5-(trifluoromethyl)-3-pyridyl]ethanol OH x  0  L \ Si        ] 1      d i] >F 322.1 1191 2-[ tert -Butyl(dimethyl)silyl]oxy-1-(3,5-difluoro-2-pyridyl)ethanol OH F x O \ Si             F 290.1 120 3-[ tert -Butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)propan- 1-ol OH XXX \ 1 286.2 1212 2-[ tert -Butyl(dimethyl)silyl]oxy-1-(5-chloro-2-pyridyl)ethanol OH x ,° NUU| \ Si          u 288.1 122 Cyclopropyl-(5-fluoro-2-pyridyl)methanol OH ^X^ N\ v T 1 F 150.0 [M-OH]+ 123 (1-Fluorocyclopropyl)-(5 -fluoro-2-pyridyl)methanol F a 1243 2-[ tert -Butyl(dimethyl)silyl]oxy-1-(2-pyridyl)ethanol OH \ .0 \ Si X 1 254.0 1 Purified by silica gel column chromatography, eluting with PE:EtOAc (20:01 to 10:1).2 Purified by silica gel column chromatography, eluting with PE:EtOAc (5:1-3:1).3 Quenched with saturated NH4Cl.a 1H NMR (400 MHz, DMSO-d6) 8 0.78 - 1.04 (m, 4 H), 4.56 - 4.64 (m, 1 H), 6.00 (d,5   J=5.01 Hz, 1 H), 7.52 - 7.78 (m, 2 H), 8.52 (d, J=2.69 Hz, 1H.)Preparation 1252-[( tert -Butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol, Isomer 1 and2-[( tert -Butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol, Isomer 2OHSeparation of the 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (70 g, 257.915 mmol) enantiomers is performed using the following conditions: Column: CHIRALPAK IG, 7*25cm, 10 um; eluting with 60% ACN in H2O (0.05% diethylamine); Flow rate: 200 mL / min; 266 / 204 / 208 nm; to afford 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 1, t(R) is 7.5 min (20.0g) and 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 2, t(R) is 11.2 min (20.5 g).2-[(tert-Butyldimethylsilyl)oxy]- 1-(5-fluoropyridin-2-yl)ethanol, Isomer 1is further purified by silica gel column chromatography, eluting with PE / EA (20:1 to 4:1) to afford 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 1 (15.0g, 21% yield) with 98.6% ee, ES / MS m / z 272.1 [M+H]+.2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 2 is further purified by silica gel column chromatography, eluting with PE / EA (30:1 to 20:1) to afford 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 2 (14.0g, 20% yield) with 93.1% ee, ES / MS m / z 272.1 [M+H]+.Preparation 126 2-[tert-Butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethyl] 4-methylbenzenesulfonate, Isomer 2To a solution of 2-[(tert-butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol, Isomer 2 (30.4 g, 112 mmol), DMAP (1.37 g, 11.2 mmol), and Et3N (22.7 g, 224 mmol) in DCM (0.2 L) cooled to 0 °C is added TsCl (27.8 g, 146 mmol). The reaction is stirred at 0 °C for 3 hours then stored overnight at 0 °C. The resultant suspension is filtered andthe insoluble material is rinsed with MTBE. H2O (5 ml) is added to the filtrate. The filtrate is then concentrated in vacuo and the material is purified by silica gel chromatography eluting with 0% to 100% EA in heptane to afford the title compound (39.8 g, 93.5 mmol) as a white, waxy solid. ES / MS m / z 426.0 [M+H]+.Preparation 127 2,2,2-Trifluoro-1-(oxan-4-yl)ethanol F F--FHO'Ay^ 1^0TMSCF3 (3.74 g, 26.28 mmol) and TBAF (3.50 mL, 3.50 mmol, 1 mol / L) is added dropwise at 0 °C under N2 to a stirred solution of oxane-4-carbaldehyde (2.00 g, 17.52 mmol) in THF (20.00 mL) and the mixture is stirred for 4 hrs at RT under N2. The reaction is quenched by the addition of MeOH (5 mL), and the mixture is dried under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (4:1) to give the title compound as a yellow solid (3.1 g, 96.07%). 1HNMR (300 MHz, d6-DMSO) 8 6.16 (d, 1H), 3.93 - 3.81 (m, 2H), 3.81 -3.68 (m, 1H), 3.39 - 3.20 (m, 2H), 1.92 - 1.72 (m, 1H), 1.60 (d, 1H), 1.56 - 1.35 (m, 3H).Preparation 128 2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 1 and2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 2OHTo a stirred solution of 2-iodopyridine (10.0 g, 48.78 mmol) in THF (150.0 mL) is added a soln of n-BuLi (21.4 mL, 53.65 mmol, 2.5M) in hexanes dropwise at -75 °C under N2. The resulting mixture is stirred at -75 °C for 1 hr. To the above mixture isadded pivaldehyde (5.0 g, 58.51 mmol) dropwise over a 10-minute period. After beingstirred at -75 °C for 1 hr, the reaction is allowed to warm to RT then is quenched with H2O (100.0 mL). The mixture is extracted with EtOAc (3 x 200 mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 15:1) to afford the title compound as a white solid (2.6 g, 32%). ES / MS m / z 166.3 [M+H]+.Separation of the 2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol (1.1 g, 6.7 mmol) enantiomers is performed using the following conditions: Column: CHIRALCEL AY-H, 2*25cm, 5um; eluting with 5% EtOH in Hex (10 mM NH3 in MeOH); 260 / 216 nm; to afford 2,2-dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 1 as a light-yellow solid (400 mg, 36%). t(R) = 5.3 min. and 2,2-dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 2 as a white solid (440 mg, 40%). t(R) = 6.2 min. Analytical column used for Rt: CHIRALCEL AY-3, 4.6*50cm; eluting with 5% EtOH in hexanes; 254 nm.Preparation 1291-(2-Pyridyl)propyl acetate., Isomer 2To a stirred solution of 1-(pyridin-2-yl)propan-1-ol (2.00 g, 14.58 mmol) and Ac2O (2.98 g, 29.16 mmol) in DCM (10.00 mL) is added TEA (4.43 g, 43.74 mmol) at RT under a N2. The reaction is stirred overnight, quenched with H2O (20 mL), and extracted with DCM (2 x 20 mL). The combined organic layers are washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 50% ACN in water; UV 254 nm to afford a brown oil (2.50 g, 95.7%). ES / MS m / z 180.3.The brown oil (1.00 g, 5.58 mmol) is subjected to the following conditions: Column: CHIRALPAK IG, 20*250mm, 5 ^m; eluting with 15% EtOH in CO2; 203 nm; to afford and 1-(pyridin-2-yl)propyl acetate, Isomer 2 (400 mg), t(R) is 3.86 min with ee = 100%; ES / MS m / z 180.3 [M+H]+.The following compound is prepared essentially as described for 1-(2-pyridyl)propyl acetate, Isomer 1 using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.Table 13Prep No. Chemical Name Structure ES / MS m / z [M+H]+ t(R) min 1301 [2-Methoxy-1 -(2-pyridyl)ethyl] acetate, Isomer 1 \ / 0 0 196.2 3.27 1 Column: CHIRALPAK IG, 2*25cm, 5 ^m; eluting with 15% EtOH in CO2, 254 nm.Preparation 1311-(2-Pyridyl)propan-1-ol, Isomer 2OHTo 1-(pyridin-2-yl)propyl acetate, Isomer 2 (380 mg, 2.12 mmol) in MeOH (3.00 mL) and H2O (3.00 mL) is added LiOH (101.55 mg, 4.24 mmol) in portions at RT under N2. The reaction is stirred for 1 hr. The reaction is diluted with H2O (20 mL), then extracted with EtOAc (2 x 20 mL). The combined organic layers are washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a light-yellow oil (260 mg, 90%). ES / MS m / z 138.1 [M+H]+.The following compound is prepared essentially as described for 1-(2-pyridyl)propan-1-ol, Isomer 2 using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.Table 14Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 132 2-Methoxy- 1-(2-pyridyl)ethanol, Isomer 1 OH 154.1 Preparation 1331-[2-(2-Methoxyethylamino)-5-(trifluoromethyl)-3-pyridyl]ethanolA solution of 1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (0.200 g,0.89 mmol), 2-methoxyethan-1-amine (200 mg, 2.66 mmol), and DIPEA (573 mg, 4.43 mmol) in i-PrOH (4 mL) is stirred for18 hr at 100 °C. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a linear gradient of 0% to 30% MeOH in DCM to afford the title compound (30 mg, 13 %)10 as a brown oil. ES / MS m / z 265.1 [M+H]+.Preparation 134(1S)-1-[4-(2,2,2-Trifluoroethyl)-1,2,4-triazol-3-yl]ethanolFN-NA mixture of (2S)-N'-[(1E)-(dimethylamino)methylidene]-2-hydroxypropane15 hydrazide (3.0 g, 18.8 mmol), ACN (10.0 mL) and HOAc (2.26 g, 37.7 mmol) is heated at 90 °C under N2. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is taken on to the next step without further purification. ES / MS m / z 196.1 [M+H]+.Preparation 135(1S)-1-(5-Fluoropyridin-2-yl)ethyl methanesulfonateTo a stirred solution of (1S)-1-(5-fluoropyridin-2-yl)ethanol (500.0 mg, 3.54 mmol) and TEA (1.07 g, 10.63 mmol) in DCM (10.0 mL) is added dropwise MsCl (608.69 mg, 5.313 mmol) at RT under N2. The reaction is stirred for 1 hr at RT, diluted with water (20 mL) and extracted with EtOAc (2 x20 mL). The combined organic layers are washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a light-yellow oil (740 mg, 95.2%). ES / MS m / z 220.0 [M+H]+.Preparation 136 [2,2,2-Trifluoro-1-(5-fluoro-2-pyridyl)ethyl] trifluoromethanesulfonateTo 2,2,2-trifluoro-1-(5-fluoropyridin-2-yl)ethanol (700.00 mg, 3.59 mmol) and TEA (1.09 g, 10.76 mmol) in DCM (5.00 mL) is added Tf2O (2.02 g, 7.17 mmol) dropwise at 0 °C under N2. The resulting mixture is stirred for 3 hr at RT, diluted with water (5 mL) and separated. The aq. layer is extracted with EtOAc (3 x 5 mL). The combined organic layers are concentrated in vacuo to give the title compound as a crude product (1 g) which is carried forward without a further purification. ES / MS m / z 328.0 [M+H]+.Preparation 137 2,2,2-Trifluoro-1-(oxan-4-yl)ethyl trifluoromethanesulfonateTf2O (766.02 mg, 2.715 mmol) is added dropwise to stirred solution of 2,2,2-trifluoro-1-(oxan-4-yl)ethanol (500.00 mg, 2.72 mmol) and DIEA (1052.71 mg, 8.14mmol) in DCM (10.00 mL) at 0 °C under N2. The mixture is stirred for 1 hr at RT under5   N2 and then used directly without further purification.The following compounds are prepared essentially as described for 2,2,2-trifluoro-1-(oxan-4-yl)ethyl trifluoromethanesulfonate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from -70 °C to 0 °C.Table 15Prep No. Chemical Name Structure 138 tert-Butyl (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate / o °-DF / /        F 0 F 139 tert -Butyl (2S,4S)-2-methyl-4-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate o 140 tert-Butyl (2R,4S)-2-methyl-4-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate \ / —z O ° -n 'W / O -n m 141 tert-Butyl (3R)-3-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate o cn=O 6 Preparation 142tert-Butyl 4-(methanesulfonyloxy)-2,2-dimethylpyrrolidine-1-carboxylateTEA (940.02 mg, 9.29 mmol) is added dropwise to a stirred mixture of tert-butyl 4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (800.00 mg, 3.72 mmol) in DCM (10.00 mL) at RT under N2. MsCl (553.35 mg, 4.83 mmol) is added dropwise to the10 solution over 2 min at 0 °C, and the mixture is stirred for 2 hrs at RT. The reaction is quenched with H2O (150 mL) and the mixture is extracted with DCM (2x200 mL). Thecombined organic extracts are washed with brine (2x150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a brown-yellow solid (1.1 g, crude), which is used directly without further purification. 1H NMR (400 MHz, d6-DMSO) 8 5.23-5.18 (m, 1H), 3.66-3.60 (m, 1H),5   3.51-3.45 (m, 1H), 3.22 (s, 3H), 2.40-2.14 (m, 2H), 1.41 (s, 9H), 1.23 (d, 3H).The following compounds are prepared essentially as described for tert-butyl 4-(methanesulfonyloxy)-2,2-dimethylpyrrolidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.Table 16Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 143 tert -Butyl (2S,4S)-4-(methanesulfonyloxy)-2-methylpyrrolidine-1-carboxylate M / z \ O a 144 tert -Butyl (2R,4R)-4-(methanesulfonyloxy)-2-methylpyrrolidine-1-carboxylate A Y 280.3 145 tert-Butyl (2S,4R)-4-(methanesulfonyloxy)-2-methylpyrrolidine-1-carboxylate M / o i " ,o ,cz> \\ o b 146 tert-Butyl (2R,4S)-4-(methanesulfonyloxy)-2-methylpyrrolidine-1-carboxylate \,0^NC / "°o-,0 a y c 147 [(1S)-1-[4-(2,2,2-Trifluoroethyl)-1,2,4-triazol-3-yl] ethyl] methanesulfonate 0 0 ''e / ? N-N 274.0 10   a 1H NMR (400 MHz, CDCh) 8 5.21-5.15 (m, 1H), 4.05-3.80 (m, 2H), 3.56 (dd, 1H), 3.03(s, 3H), 2.51-2.40 (m, 1H), 1.90-1.81(m, 1H), 1.47 (s, 9H), 1.28 (d, 3H).b 1H NMR (400 MHz, d6 -DMSO) 8 5.23-5.18 (m, 1H), 3.94-3.84 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.45 (m, 1H), 3.22 (s, 3H), 2.46-2.34 (m, 1H), 1.93-1.83 (m, 1H), 1.41 (s, 9H), 1.23 (d, 3H).c 1H NMR (300 MHz, d6-DMSO) 8 5.23-5.19 (m, 1H), 3.5 - 3.80 (m, 1H), 3.63 (dd, 1H), 3.48 (dt, 1H), 3.24 (s, 3H), 2.49-2.34 (m, 1H), 1.87 (d, 1H), 1.41 (s, 9H), 1.23 (d, 3H).Preparation 1482-(1-Bromoethyl)-N,N-dimethyl-benzamide2-ethyl-N,N-dimethylbenzamide (0.81 g, 4.6 mmol), AIBN (75 mg, 0.46 mmol) and NBS(0.89 g, 5.0 mmol) are added into a vial that is evacuated and backfilled with N2 (3X). CCl4 (5 mL) is added and the reaction mixture is stirred at 80 °C for 2 hr. Upon cooling to RT, the reaction is filtered, and the solids are rinsed with CCl4 (2 x 10 mL). The filtrate is concentrated to obtain the title compound as a clear oil (0.8 g, 70 %), which is carried forward without further purification.Preparation 149tert-Butyl 4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoro-piperidine-1-carboxylateA mixture of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (10.00 g, 42.51 mmol), tert-butoxycarbohydrazide (3.09 g, 23.38 mmol) and AcOH (2.55 g, 42.51 mmol) in MeOH (40 mL) is stirred for 30 min at 50 °C under N2. Upon cooling to RT NaBH3CN (8.01 g, 127.53 mmol) is added in portions. The reaction is stirred for 2 hr at 50 °C. The mixture is basified to pH 8 with sat. aq. NaHCO3. The mixture is extracted with EtOAc (3 x 150 mL), organic layers combined and washed with brine (3x50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silicagel column chromatography, eluting with PE:EtOAc (10:1 to 5:1) to afford the title compound as an off-white oil (5 g, 67%). ES / MS m / z 240.2 [M+H-C8H16]+.Preparation 1503,3-Difluoro-4-(5-methylpyrazol-1-yl)piperidineF FA mixture tert -butyl 4-[[( tert -butoxycarbonyl)amino]amino]-3,3-difluoropiperidine-1-carboxylate (5.50 g, 15.7 mmol) and 4,4-dimethoxybutan-2-one (3.10 g, 23.5 mmol) in AcOH (100 mL) is stirred overnight at 50 °C under N2. To the above mixture is added HBr (25 mL) at RT. The reaction is stirred overnight. No brominated product is detected by LCMS. The mixture is concentrated in vacuo. The residue is carried forward to the next step without a further purification. ES / MS m / z 202.3 [M+H]+.Preparation 151tert-Butyl 3,3-difluoro-4-(5-methylpyrazol-1-yl)piperidine-1-carboxylateTo 3,3-difluoro-4-(5-methyl-1H-pyrazol-1-yl)piperidine (5.50 g, 27.33 mmol) and TEA (27.66 g, 273.3 mmol) in DCM (100 mL) is added Boc2O (29.83 g, 136.67 mmol) at RT under N2. The reaction is stirred 2 hr then concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 10:1) to give crude product. The crude product is purified by reverse phase chromatography with the following conditions: column, C18; mobile phase, eluting with 40% to 60% ACN in water (0.1% FA) to afford the title compound as a yellow oil (3g, 36.4%). ES / MS m / z 302.3 [M+H]+.Preparation 152 tert-Butyl 4-[3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylateTo methyl 2-(5-methyl-1H-pyrazol-3-yl)acetate (6 g, 38.92 mmol) and CS2CO3 (25.36 g, 77.83 mmol) in DMF (80 mL) at RT is added tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (16.31 g, 58.39 mmol). The reaction is stirred for 3 hr at 60 °C under N2. Upon cooling to RT, the reaction is poured into H2O (400 mL), extracted with EtOAc (3 x 500mL), organic layers are combined and washed with brine (3 x 200 mL), dried over Na2SO4, filtered, and rinsed with EtOAc (3 x 80mL). The filtrate is concentrated in vacuo and the residue is purified by Prep-HPLC using the following conditions: Column: HEXI SpringXB-C18, 50*250, 10um; eluting with a gradient of 30% to 55% ACN in H2O (0.05% TFA), flow rate:100mL / min; to afford the title compound (420mg, 3.20%) as a yellow oil. ES / MS m / z 338.3 [M+H]+.Preparation 153 tert-Butyl 4-(5-bromo-4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylateON-NA solution of tert -butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine-1-carboxylate (538 mg, 2.01 mmol) and NBS (430 mg, 2.41 mmol) in MeOH (5 mL) is heated to 40 °C for 20 minutes. Upon cooling to RT the reaction is extracted with 3:1 (v / v) chloroform:iPrOH. Organic phase is washed with 10% Na2S2O3, H2O, brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. The oil is purified by silica gel chromatography eluting with 5 to 20% MeOH in DCM to afford the title compound as a colorless oil (620 mg, 89.0 %). ES / MS m / z 246.1, 248.8 (79Br / 81Br) [M+2H-Boc]+.The following compounds are prepared essentially as described for tert-butyl 4-(5-bromo-4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate using the appropriatereagents and solvents and adjusting the reaction times to determine completion of the reactions.Table 17Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 1541,2 tert-Butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)-3,3-difluoro-piperidine-1-carboxylate o „ VBr \ Vn VN J -Xo /        F F (79Br / 81Br) 379.7 / 381.7 155 tert-Butyl 4-[4-bromo-3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate \ Br \ '^N / Vn (79Br / 81Br) 416.1 / 418.1 1 DCM used as solvent2 Purified by silica gel column chromatography, eluting with DCM:MeOH (30:1 to 15:1).Preparation 156A solution of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (4.00 g) in DCM (20 mL) is basified to pH~10 with DIEA (3 mL) then cooled to -60 oC under N2. tert-Butyl (3R)-3-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate is added dropwise and the reaction is stirred for 4 hr at -60 oC. The mixture is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: column, C18; eluting with 20% to 30% ACN in H2O (0.1% FA), 220 nm. To afford the title compound as a light-yellow solid (7.00 g). ES / MS m / z (79Br / 81Br) 385.1 / 387.1 [M+H]+.Preparation 157 tert-Butyl (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateCS2CO3 (19.20 g, 58.941 mmol) is added in portions to a stirred RT mixture of 4-bromopyrazole (2.89 g, 19.65 mmol) and tert-butyl (1R,3s,5S)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.00 g, 19.65 mmol) in DMF (50 ml) and the5 mixture is stirred overnight at 70 °C under N2. The mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1-5:1) to give a crude product (5.2 g). The crude product is repurified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 80% ACN in H2O (0.1% FA), 220 nm to10 give the title compound as an off-white solid (3.5 g, 47.5%). ES / MS m / z 341.1 / 343.1 [M+H-tBu+ACN]+.The following compounds are prepared essentially as described for tert-butyl (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of15 the reactions. K2CO3 can also be used as the base. Temperature is varied from 70 °C to 80 °C.Table 18Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 1581 tert-Butyl (3R)-3-(4-bromopyrazol-1-yl)pyrrolidine-1-carboxylate K° z— z a 1592 tert -Butyl (3S)-3-(4-bromopyrazol-1-yl)pyrrolidine-1-carboxylate VC Br b 16031614162416351644tert-Butyl (2S,4R)-4-(4-bromopyrazol-1-yl)-2-methylpyrrolidine-1-carboxylatetert-Butyl (2R,4R)-4-(4-bromopyrazol-1-yl)-2-methylpyrrolidine-1-carboxylatetert-Butyl (2R,4S)-4-(4-bromopyrazol-1-yl)-2-methylpyrrolidine-1-carboxylatetert-Butyl (2S,4S)-4-(4-bromopyrazol-1-yl)-2-methylpyrrolidine-1-carboxylatetert-Butyl 4-(4-bromopyrazol-1-yl)-2,2-dimethylpyrrolidine-1-carboxylate330.1 / 332.1330.1 / 332.1344.1 / 346.11 The mixture is filtered, the filter cake is washed with EtOAc (3 x 20 mL), and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc.2 Crude product is not repurified.3 The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; mobile phase, ACN in H2O (0.1% NH4HCO3). Not repurified.4 The mixture is filtered, the filter cake is washed with DCM (2x10 mL), and the filtrate is concentrated under reduced pressure prior to purification by reverse Combi-flash chromatography.5 Purified with only reverse Combi-flash chromatography.a 1H NMR (300 MHz, d6-DMSO) 8 8.08 (s, 1H), 7.59 (s, 1H), 4.97 - 4.89 (m, 1H), 3.733.65 (m, 1H), 3.57 - 3.51 (m, 1H), 3.46-3.37 (m, 2H), 2.36-2.24 (m, 2H), 1.40 (d, 9H).b 1H NMR (400 MHz, CDCl3) 8 7.55-7.50 (m, 2H), 4.89-4.83 (m, 1H), 3.77-3.51 (m, 4H), 2.38-2.33 (m, 2H), 1.48 (s, 9H).c 1H NMR (300 MHz, CDCl3) 8 7.61 (d, 1H), 7.49 (d, 1H), 4.77-4.61 (m, 1H), 4.15-4.01 (m, 1H), 4.05-3.94 (m, 1H), 3.63 (dd, 1H), 2.71-2.55 (m, 1H), 2.25-2.10 (m, 1H), 1.49 (s, 9H), 1.31 (d, 3H).d 1H NMR (300 MHz, d6 -DMSO) 8 8.04 (s, 1H), 7.58 (s, 1H), 5.03-4.93 (m, 1H), 3.723.57 (m, 1H), 3.68 - 6.58 (m, 2H), 2.55-2.44 (m, 1H), 2.15-1.85 (m, 1H), 1.39 (s, 9H), 1.20 (d, 3H).Preparation 165tert-Butyl 2-(4-bromopyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate--0   / —\    A^Br X^N J O  \— / VCS2CO3 (18.36 g, 56.35 mmol) is added in portions at RT under N2 to a stirred mixture of tert-butyl 2-(methanesulfonyloxy)-7-azaspiro[3.5]nonane-7-carboxylate (6.00 g, 18.78 mmol) and 4-bromopyrazole (2.76 g, 18.78 mmol) in DMF (50.00 mL) and the mixture is stirred for 2 hrs at 100 °C under N2. The mixture is cooled to RT, diluted with H2O (100 mL), and extracted with EtOAc (3x150 mL). The combined organic layers are washed with brine (2x200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18 eluting with a gradient of 40% to 50% ACN in H2O (0.1% FA), 220 nm, to give the title compound (5 g). The product is dissolved in DCM (100 mL), washed with brine (2x150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as an off-white solid (4.5 g, 64.7%). 1H NMR (300 MHz, CDCl3) 8 7.50 (s, 1H), 7.45 (s, 1H), 4.80-4.69 (m, 1H), 3.47-3.38 (m, 2H), 3.38-3.29 (m, 2H), 2.512.38 (m, 2H), 2.38-2.25 (m, 2H), 1.69-1.61 (m, 4H), 1.47 (s, 9H).The following compounds are prepared essentially as described for tert-butyl 2-(4-bromopyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate using the appropriate reagents,adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. Temperature is varied from 70 °C to 100 °C.Table 19Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 166 tert -Butyl (1R,3s,5S)-3-(4-bromo-1 H-pyrazol-1 -yl)-8- azabicyclo[3.2.1]octane-8-carboxylate -Vo           Br J>"'N 1 O b 1671 tert -Butyl (4R)-4-(4-bromopyrazol-1-yl)azepane-1-carboxylate , O x_y c 168 tert-Butyl (4S)-4-(4-bromopyrazol-1-yl)azepane-1-carboxylate >° 0 z M 344.1 / 346.1 1692 tert-Butyl 3-(4-bromo-3-methylpyrazol-1 -yl)azetidine-1-carboxylate 301.1 / 303.1 1703 tert-Butyl 4-(4-bromo-3-methylpyrazol-1 -yl)piperidine-1-carboxylate O.       ^Br 344.1 / 346.1 1 The mixture is filtered, the filter cake is washed with DCM (3x20 mL), the filtrate is5 concentrated under reduced pressure, and the residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; 40-60% ACN in H2O.2 The crude product is used directly without further purification.3 The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography eluting with (6:1-1:1 PE / EtOAc.10 a 1H NMR (300 MHz, CDCh) 8 7.51 (d, 2H), 4.28-4.18 (m, 2H), 4.00-3.89 (m, 1H), 3.353.25 (m, 1H), 3.05-2.95 (m, 1H), 2.35 - 1.93 (m, 2H), 1.67 - 1.56 (m, 2H), 1.48 (s, 9H). b 1H NMR (400 MHz, d6-DMSO) 8 7.98 (s, 1H), 7.54 (s, 1H), 4.82-4.64 (m, 1H), 4.23-4.09 (m, 2H), 2.04 - 1.82 (m, 6H), 1.81-1.72 (m, 2H), 1.42 (s, 9H)c 1H NMR (300 MHz, CDCI3) 8 7.46 (d, 1H), 7.43 (d, 1H), 4.25 (ddt, 1H), 3.75-3.20 (m,4H), 2.35-1.84 (m, 6H), 1.50 (s, 9H)Preparation 171tert-Butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylateA stirred solution of tert-butyl 3-(4-bromopyrazol-1-yl)azetidine-1-carboxylate (7.50 g, 24.82 mmol) in THF (160 mL) at 0 °C under N2 is treated with LDA (2 mmol / L in THF) (37 mL, 74.46 mmol) and the mixture is stirred for 30 min. CH3I (10.57 g, 74.46 mmol) is added and the mixture is stirred for 2 hrs at RT under N2. The reaction is quenched with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts are washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (9:1~5:1) to give the title compound as a yellow solid (4.13 g, 52.62%), which is used directly without further purification. 1H NMR (300 MHz, CDCl3) 8 7.53 (s, 1H), 5.04-4.93 (m, 1H), 4.484.40 (m, 2H), 4.36-4.28 (m, 2H), 2.27 (s, 3H), 1.48 (s, 9H).The following compounds are prepared essentially as described for tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions and adjusting the purification system as appropriate. Temperature is varied from -78 °C to RT. The reaction can also be quenched with NH4Cl.Table 20Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 1721 tert -Butyl (3R)-3-(4-Bromo-5-methylpyrazol-1 -yl)pyrrolidine-1-carboxylate -V 0 0^ p z.'\ a 1731 tert-Butyl (3S)-3-(4-bromo-5-methylpyrazol-1 -yl)pyrrolidine-1-carboxylate ^,0     N= b 174 tert-Butyl 2-(4-bromo-5-methylpyrazol-1 -yl)-7-azaspiro[3.5]nonane-7-carboxylate 0^.0 z M" c 175 tert -Butyl (3R)-3-(4-bromo-5-methylpyrazol-1 -yl)piperidine-1-carboxylate p Z'z\ 344.1 / 346.1 176 tert-Butyl (3S)-3-(4-bromo-5-methylpyrazol-1 -yl)piperidine-1-carboxylate co —cil Z'Z rx d 177 tert-Butyl (1R,3r,5S)-3-(4-bromo-5-methyl-1 H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 4-0        \ Br / VN J / -N 370.2 / 372.2 178 tert -Butyl (1R,3s,5S)-3-(4-bromo-5-methyl-1 H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate \ Q           \   Br 0^O"'V 370.2 / 372.2 1791 tert -Butyl (4R)-4-(4-bromo-5-methylpyrazol-1 -yl)azepane-1-carboxylate O                    1 ! >- \PN-VBr -P0      fU e 180 tert-Butyl (4S)-4-(4-bromo-5-methylpyrazol-1 -yl)azepane-1-carboxylate O -N^__ / "nA N= 358.1 / 360.1 181 tert -Butyl (2S,4R)-4-(4-bromo-5-methylpyrazol- 1-yl)-2-methylpyrrolidine-1-carboxylate N-—7 O "'Br f 1821 tert -Butyl (2R,4S)-4-(4-bromo-5-methylpyrazol- 1-yl)-2-methylpyrrolidine-1-carboxylate \^o. Y N~^ o \ a N 344.09 / 346.09 1831 tert -Butyl (2S,4S)-4-(4-bromo-5-methylpyrazol- 1-yl)-2-methylpyrrolidine-1-carboxylate O ^Br 344.1 / 346.1 1841 tert-Butyl 4-(4-bromo-5-methylpyrazol-1 -yl)-2,2-dimethylpyrrolidine-1 -carboxylate K° N— Z'Z\__ ,Br 358.1 / 360.1 1852 tert-Butyl (2R,4R)-4-(4-bromo-5-methylpyrazol- 1-yl)-2-methylpyrrolidine-1-carboxylate x° 0 z Br g 1 Crude product used directly without further purification.2 Dried extract is filtered and the filtrate is concentrated under reduced pressure.a 1H NMR (300 MHz, d6-DMSO) 8 7.53 (s, 1H), 5.00 (d, 1H), 3.67 (d, 1H), 3.50 - 3.42 (m, 2H), 2.27 (s, 3H), 2.24 - 2.10 (m, 2H), 1.40 (d, 9H).b 1H NMR (400 MHz, d6-DMSO) 87.53 (d, 1H), 5.00 (s, 1H), 3.71-3.65 (m, 1H), 3.543.42 (m, 3H), 2.27 (s, 3H), 2.19-2.06 (m, 2H), 1.41-1.39 (m, 9H).c 1H NMR (300 MHz, d6-DMSO) 87.53 (s, 1H), 4.91-4.86 (m, 1H), 3.33-3.18 (m, 4H), 10   2.40-2.14 (m, 7H), 1.64-1.59 (m, 2H), 1.52-1.47 (m, 2H), 1.40 (s, 9H).d 1H NMR (300 MHz, CDCI3) 8 7.42 (d, 1H), 4.05 - 3.95 (m, 1H), 3.20-3.00 (m, 1H), 2.77 - 2.68 (m, 1H), 2.29 (s, 3H), 2.20 - 2.10 (m, 3H), 2.07 - 2.04 (m, 1H), 1.89 - 1.82 (m, 1H), 1.67-1.57 (m, 1H), 1.45 (s, 9H).e 1H NMR (400 MHz, CDCl3) 8 7.35 (s, 1H), 4.05-3.99 (m, 1H), 3.75-3.10 (m, 4H), 2.19 (s, 3H), 2.18 -1.81 (m, 6H), 1.41 (s, 9H).f 1H NMR (400 MHz, CDCl3) 8 7.44 (s, 1H), 4.64-4.54 (m, 1H), 3.98 - 3.90 (m, 2H), 3.62 -3.45 (m, 1H), 2.54-2.45 (m, 1H), 2.35 - 2.21 (m, 4H), 1.48 (s, 9H), 1.37 (d, 3H).g 1H NMR (300 MHz, d6-DMSO) 8 7.51 (s, 1H), 5.09 - 4.94 (m, 1H), 4.11 - 3.95 (m, 1H), 3.70-3.60 (m, 1H), 3.52 (dd, 1H), 2.50-2.40 (m, 1H), 2.28 (s, 3H), 2.02 - 1.91 (m, 1H), 1.39 (s, 9H), 1.22 (d, 3H).Preparation 1861-(Azetidin-3-yl)-4-bromo-5-methylpyrazoleA solution of tert -butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate(3.00 g, 9.488 mmol) in TFA (10 mL) and DCM (20 mL) is stirred for 2 hrs at RT. The solution is concentrated under reduced pressure to give the title compound as a brown oil (4 g, crude, TFA salt), which is used directly without further purification. 1H NMR (300 MHz, CDCl3) 8 7.50 (s, 1H), 5.16-5.06 (m, 1H), 4.30 (t, 2H), 3.88 (t, 2H), 2.25 (s, 3H). The compound is used directly without further purification.The following compound is prepared essentially as described for 1-(Azetidin-3-yl)-4-bromo-5-methylpyrazole using the appropriate reagents, and adjusting the reaction time to determine completion of the reaction.Table 21Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 187 4-(4-Bromo-5-methyl-triazol-1 -yl)piperidine HCl w HN^J n HCl (79Br / 81Br) 245.1 / 247.1 Preparation 188tert-Butyl (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylateTf2O (3.62 g, 12.82 mmol) is added dropwise to a stirred mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (2.00 g, 10.68 mmol) and DIEA (4.14 g, 32.05 mmol) in DCM (30 mL) at -40 °C under N2. The mixture is added drop wise to a stirred solution of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (4 g, crude) in DCM (30 mL). The mixture is made basic to pH~10 with DIEA (3 mL) at -40 °C under N2. The mixture is stirred for an additional 4 hrs at -40 °C and then concentrated under vacuum. The solution is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 20% to 30% ACN in H2O (0.1% FA); 220 nm to give the title compound as a light-yellow solid (500 mg, 12%). ES / MS m / z (79Br / 81Br) 385.1 / 387.1 [M+H]+.Preparation 189 tert-Butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylatetert-Butyl (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (2.05 g, 6.41 mmol, crude) is added dropwise to a stirred solution of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (3 g, 13.88 mmol, crude) in DCM (30 mL). The solution is made basic to pH~10 with DIEA (3mL) at -40 °C under N2 and the mixture is stirred for 4 hrs at -40 °C. The solution is quenched by H2O (30 mL) and extracted with DCM (2x100 mL). Thecombined organic extracts are washed with brine (2x80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 30% to 50% ACN in H2O (0.1% FA) to give the title compound as a light-yellow oil (520 mg, 38.5%). ES / MS m / z (79Br / 81Br) 385.0 / 387.0 [M+H]+.The following compound is prepared essentially as described for tert-butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from -70 °C to -40 °C.Table 22Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 1901 tert -Butyl (2R,4R)-4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin- 1-yl] -2-methylpyrrolidine-1 -carboxylate „                  N=\ 492.3 1 Prep TLC (EtOAc).Preparation 191tert-Butyl 3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylateNaBH3CN (2.18 g, 34.709 mmol) is added in portions to a stirred mixture of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (5.00 g, 23.14 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (5.53 g, 27.77 mmol) in MeOH (50 mL) at RT and the mixture is stirred for 2 hrs. The reaction is quenched with H2O (50 mL) and extracted with EtOAc (3x100 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with agradient of PE:EtOAc (5:1~1:1) to give the title compound as a brown solid (4.0 g, 43.2%). ES / MS m / z (79Br / 81Br) 399.1 / 401.1 [M+H]+.The following compounds are prepared essentially as described for tert-butyl 3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. Temperature is varied from RT to 50 °C.Table 23Prep No.Chemical NameStructureES / MS m / z [M+H]+tert -Butyl 4-[3-(4-bromo-51921     methylpyrazol-1-yl)azetidin-1 -yl]-3,3-difluoropiperidine-1-__carboxylate______tert-Butyl 3-[3-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-1932 6-yl)-5-methyl-pyrazol-1-yl]azetidin- 1-yl]-6-azabicyclo[3.2.1]octane-6-carboxylate(79Br / 81Br)435.1 / 437.1518.41TFA and catalytic AcOH is added to the initial solution before NaBH3CN is added.2 Purified by silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1)Preparation 194tert-Butyl (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylatePreparation 195tert-Butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylatetert-Butyl-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate (1.0 g) is separated by Prep-chiral with the following conditions: Column, Phenomenex Lux 5p Cellulose-4, AXIA Packed, 2.12*25 cm, 5 ^m; eluting with 20% MeOH in CO2, flow rate 40 mL / min; 210 nm; Analytical LC conditions are: Column Lux Cellulose-4, 0.46*10 cm, 3.0 pm eluting with 10% to 50% MeOH (0.1% DEA) in CO2, flow rate of 2 mL / min to give t(R) tert -butyl (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-yl]piperidine-1-carboxylate, t(R) is 1.85 min with 100% ee as a light-yellow solid (460 mg); t(R) tert -butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-yl]piperidine-1-carboxylate is 2.18 min with 100% ee as a light-yellow solid (450 mg). ES / MS m / z 399.1 / 401.1 [M+H]+.Preparation 196 tert-Butyl (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylateA mixture of tert-butyl (3R,4S)-4-azido-3-fluoro-piperidine-1-carboxylate (1.00 g, 4.09 mmol) and trimethyl(prop-1-yn-1-yl)silane (1.38 g, 12.28 mmol) is irradiated with microwave radiation for 1 hr at 150 °C. The reaction is concentrated in vacuo to afford the title compound (1.5 g,) as a white solid, which is used in the next step without further purification. ES / MS m / z 357.1 [M+H] +The following compounds are prepared essentially as described for tert-butyl (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylateusing the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.Table 24Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 197 tert-Butyl (3S,4S)-3-fluoro-4-(5 -methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate n     -F V 357.2 198 tert-Butyl (3S,4R)-3-fluoro-4-(5 -methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate 0 F V / 'Si' 357.2 199 tert -Butyl (3R,4R)-3-fluoro-4-(5 -methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate \  ^N\ / NM-N —^—0 x / N- 357.2 2001, 2 (1r,3r)-3-(5-methyl-4-(trimethylsilyl)-1H-1,2,3-triazol- 1-yl)cyclobutan-1 -ol \ / \ Si_ N \Z a 2012, 3 tert-Butyl (3S,4S)-3-hydroxy-4-(5-methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate o 4V 355.3 [M-H]+ 2022 tert-Butyl (3R,4S)-3-hydroxy-4-(5-methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate o ^0H ka \ ^N\ / Nwn —^—0   \' N- 355.2 2033 tert-Butyl (3S,4R)-3-hydroxy-4-(5-methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate 0     9H \ sC \ ^n\ 355.2 2044 tert-Butyl (3R,4R)-3-hydroxy-4-(5-methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate O ^0H kA' \ ^N\ / "NirN 355.3 2055 tert-butyl (3RS,4RS)-3-methyl-4-(5-methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate \ / \  ^N\   / Nm-N 353.15 2066 tert-butyl (3RS,4SR)-3-methyl-4-(5-methyl-4-trimethylsilyl-triazol-1 -yl)piperidine-1-carboxylate \ / \  ^N\ / Nm-N 353.2 1 Purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane.2 Reaction was run in toluene3 Purified by silica gel chromatography, eluting with PE:EA (4:1).4 Purified by silica gel chromatography, eluting with PE:EA (2:1).5   5 Purified by silica gel chromatography, eluting with PE:EA (5:1).6 Purified by silica gel chromatography, eluting with PE:EA (6:1 to 5:1).a 1H NMR (400 MHz, DMSO-d6) 8 0.26 (s, 9 H) 2.24 (s, 3 H) 2.36 - 2.47 (m, 2 H) 2.65 -2.75 (m, 2 H) 4.42 - 4.59 (m, 1 H) 4.97 (ttd, J=8.38, 8.38, 5.14, 5.14, 0.73 Hz, 1 H) 5.31 (d, J=4.89 Hz, 1 H).10                                       Preparation 207tert-Butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylateK2CO3 (414.00 mg, 3.00 mmol) is added in portions to a stirred solution of tertbutyl 4-azidopiperidine-1-carboxylate (226.00 mg, 1.00 mmol) and EAA (130.00 mg, 1.20 mmol) in DMSO (5.00 mL) at RT under N2. The mixture is stirred for 6 hrs at 80 °C under N2. The mixture is cooled to RT, H2O (10 mL) is added, and the mixture is extracted with EtOAc (3x30 mL). The combined organic extracts are washed with brine (2x20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1 to 0:1) to give the title compound as a yellow oil (330 mg, 66.8%). ES / MS m / z 339.3 [M+H]+.The following compounds are prepared essentially as described for tert-butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. DMF can also be used as the solvent. Temperature is varied from RT to 80 °C. Table 25Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 208 Ethyl 1-[1-(tert-butoxycarbonyl)azetidin-3-yl] -5-methyl-1,2,3-triazole-4-carboxylate 0      \ X KnXn —0      n^n 311.2 2091 Ethyl 1-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-methyl-1,2,3-triazole-4-carboxylate 0       N=N 325.3 2101 Ethyl 1-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-5-methyl-1,2,3-triazole-4-carboxylate 0       N=N 325.1 211 tert-Butyl 2-(4-ethoxycarbonyl-5-methyl-triazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate z J o a 212 tert-Butyl 4-(4-ethoxycarbonyl-5-methyl-triazol- 1-yl)azepane-1-carboxylate 0 .               n-n 1 0 353.2 2132 tert-Butyl (3S)-3-(4-ethoxycarbonyl-5-methyl-triazol-1 -yl)piperidine-1 -carboxylate o \ ° ..... / n^n 339.3 214 tert-Butyl 4-(4-ethoxycarbonyl-5-methyl-triazol- 1-yl)azepane-1-carboxylate o z K. o 353.2 2153 tert-Butyl (3R)-3-(4-ethoxycarbonyl-5-methyl-triazol-1 -yl)piperidine-1 -carboxylate N— / tK 0 1 z % 0 339.1 2164, 2 Cis-Ethyl 1-(3-benzyloxycyclobutyl)-5-methyl-triazole-4-carboxylate 0 O^" n- b 217 tert-Butyl 4-[2-(4-ethoxycarbonyl-5-methyl-triazol- 1-yl)-1,1 -dimethyl-ethyl]piperazine- 1-carboxylate 396.4 2186 tert-Butyl (2SR,4RS)-2-cyclopropyl-4-(4-ethoxycarbonyl-5-methyl-triazol-1 -yl)piperidine-1 -carboxylate 0 \ K-n7 \ 7 / ° \~y 0 n-n 379.3 1 The mixture is filtered, the filter cake is washed with DCM (3x50 mL), and the filtrate isconcentrated under reduced pressure.2 Purified by silica gel column chromatography, eluting with PE:EtOAc (1:1).3 Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 2:1).5   4 DMF used as solvent.5 Purified by silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1).6 Reverse flash chromatography: Column, C18, 55% to 60% ACN in H2O (0.1%NH4HCO3).a 1H NMR (400 MHz, CDCI3) 8 4.86 -4.73 (m, 1H), 4.49 -4.38 (m, 2H), 3.47 -3.40 (m, 10   2H), 3.38 -3.30 (m, 2H), 2.67 -2.58 (m, 2H), 2.57 -2.47 (m, 5H), 1.76 -1.64 (m, 4H),1.46 (s, 9H), 1.44 -1.39 (m, 3H).b 1H NMR (300 MHz, DMSO-d6) 8 7.43 -7.25 (m, 5H), 5.22 -4.99 (m, 1H), 4.50 -4.37 (m, 3H), 4.30 (q, 2H), 2.88 -2.75 (m, 2H), 2.70 -2.58 (m, 2H), 2.47 (s, 3H), 1.30 (t, 3H).Preparation 2191-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazole-4-carboxylic acidHOA solution of tert-butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate (300.00 mg, 0.890 mmol) and KOH (100.00 mg, 1.780 mmol) in H2O (5.00 mL) is stirred for 2 hrs at 50 °C under N2. The mixture is acidified to a pH of 4 with HCl (aq.) (1N) at 0 °C and extracted with EtOAc (3x30 mL). The10 combined organic extracts are washed with brine (2x15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow oil (250 mg, 90%). ES / MS m / z 311.3 [M+H]+.The following compounds are prepared essentially as described for 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazole-4-carboxylic acid using the 15 appropriate reagents and adjusting the reaction times to determine completion of the reactions. The solvent can be DMSO and the base can be NaOH.Table 26Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 220 1-[1-(tert-Butoxycarbonyl)azetidin-3-yl]-5-methyl- 1,2,3-triazole-4-carboxylic acid HO --0 N O        N'N 283.1 221 1-[(3R)-1-(tert- Butoxycarbonyl)pyrrolidin-3-yl]-5-methyl-1,2,3-triazole-4-carboxylic acid / —I   OH O       N=N 297.2 2221 1-[(3S)-1-(tert-Butoxycarbonyl)pyrrolidin-3-yl]-5-methyl-1,2,3-triazole-4-carboxylic acid -A 0       N=N 241.0 223 1-(1-tert-Butoxycarbonylazepan-4-yl)-5-methyl-triazole-4-carboxylic acid 0 nV0" N'N 1 0 325.2 224 1-[(3S)-1-tert- Butoxycarbonyl-3-piperidyl] -5-methyl-triazole-4-carboxylic acid o \ ° / n=n 311.3 225 1-[(3R)-1-tert- Butoxycarbonyl-3-piperidyl] -5-methyl-triazole-4-carboxylic acid o ryNV°H N-y n-n 0 311.2 226 Cis-1-(3-Benzyloxy cyclobutyl)-5-methyl-triazole-4-carboxylic acid 0 \A-oh / =\ / n 288.3 227 1-[2-(4-tert- Butoxycarbonylpiperazin-1-yl)-2-methyl-propyl]-5-methyl-triazole-4-carboxylic acid / \ N=N 368.3 228 1-[(2SR,4RS)-1-tert- butoxycarbonyl-2-cyclopropyl-4-piperidyl]-5-methyl-triazole-4-carboxylic acid I O Z' Z'"\_ 351.2 1 Precipitated solids are collected by filtration, washed with H2O (3x20 mL), and dried invacuo.Preparation 229tert-Butyl 4-[4-bromo-3-(2-hydroxyethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylateOHTo a solution of tert- butyl 4-[4-bromo-3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (390 mg, 0.94 mmol) in MeOH (5 mL) is added LiBH4 (24.49 mg, 1.12 mmol) at 0 °C under N2. The reaction is stirred 1 hr at RT, cooled to 0 °C and quenched with H2O (10 mL). The mixture is extracted with EtOAc (3 x 20 mL). The organic layers are combined, washed with brine (2 x 10 mL), dried over Na2SO4, and filtered. The filtrate is concentrated in vacuo to afford the title compound (350 mg, 96.22%) as a yellow oil. ES / MS m / z (79Br / 81Br) 388.1 / 390.1 [M+H]+.Preparation 230 7-Chloro-5-[[(1R)-1-(5-fluoro-2-pyridyl)ethyl]amino]imidazo[1,2-a]pyridine-3-carbonitrileTo 5,7-dichloroimidazo[1,2-a]pyridine-3-carbonitrile (600 mg, 2.83 mmol) and (1R)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (749.7 mg, 4.25 mmol) in toluene (10 mL) is added Cs2CO3 (5532 mg, 16.98 mmol), BINAP (176.2 mg, 0.28 mmol) and Pd(AcO)2 (4.33 mg, 0.005 mmol) at RT under N2. The reaction is stirred for 2 hr at 100 °C. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE / EtOAc (5:1 to 1:3), to afford the title compound as a yellow solid (250 mg, 28%). ES / MS m / z 316.1 [M+H]+.Preparation 2317-Chloro-5-methoxyimidazo[1,2-a]pyridineClA solution of 4-chloro-6-methoxypyridin-2-amine (7.00 g, 44.14 mmol), chloroacetaldehyde (8.32 g, 52.99 mmol, 50%) and NaHCO3 (11.12 g, 132.42 mmol) in n-butanol (140.00 mL) is divided into fourteen batches and stirred overnight at 65 °C in sealed tubes. The solution is cooled to RT, diluted with H2O (200 mL) and extracted with EtOAc (3x200 mL). The organic extracts are dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (PE:EtOAc 1:1) to give the title compound as a light-brown solid (6.1 g, 75.68%). ES / MS m / z 183.10 [M+H]+.The following compound is prepared essentially as described for 7-Chloro-5-methoxyimidazo[1,2-a]pyridine using the appropriate reagents and adjusting the reaction time to determine completion of the reactions.Table 27Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 232 6-Bromo-3-fluoro-pyrazolo[1,5-a]pyridin-4-ol N=\ I      \ N     F f J (79Br / 81Br) 231.0 / 233.0 Preparation 2337-Chloroimidazo[1,2-a]pyridin-5-olA mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine (2.00 g, 10.95 mmol), NaOH (50% in H2O) (1.31 g, 16.43 mmol) and NDM (3.33 g, 16.43 mmol) in DMA (10.00 mL) is stirred for 2 hrs at 50 °C under N2. The mixture is diluted with H2O (100 mL), acidified to pH 4-5 with 1 M HCl to give precipitated solids that are collected byfiltration and washed with PE (3x100 mL), H2O (3x10 mL), and dried in vacuo to give the title compound as a light-yellow solid (1.5 g, 81.24%). ES / MS m / z 169.2 [M+H]+.Preparation 234tert-Butyl-[2-(7-chloroimidazo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silaneTo 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (6.53 g, 24.06 mmol) in THF (50.00 mL) is added 60% NaH (0.96 g, 24.06 mmol) at 0 °C under N2. After being stirred at 0 °C for 0.5 hr, 5,7-dichloroimidazo[1,2-a]pyridine (3 g, 16.04 mmol) is added to the mixture. The reaction is stirred at RT for 2 hr under N2. The reaction is quenched with H2O (50 mL) then extracted with EtOAc (2 x 50 mL). The combined organic layers are washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE / EtOAc (5:1 to 4:1) to afford the title compound as a brown solid (2.5 g, 36.93%). ES / MS m / z 422.2. [M+H]+.The following compounds are prepared essentially as described for tert-butyl-[2-(7-chloroimidazo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane using the appropriate reagents and adjusting the reaction time to determine completion of the reactions.Table 28Prep No.Chemical NameStructureES / MS m / z[M+H]+2351 7-Chloro-5-[(5-fluoro-2-pyridyl)-(1-methoxycyclopropyl)methoxy] imidazo [ 1,2-a]pyridine-3-carbonitrile o 0 W 373.1 2362 [2-(6-Bromo-3 -fluoro-pyrazolo[1,5-a]pyridin-4-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-tert-butyl-dimethyl-silane N=x 1      \ N Z>--F J T \ Si            F d 1 (79Br / 81Br) 484.1 / 486.1 1 Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1).2 Purified by reverse phase chromatography: Column, C18; eluting with 0% to 100%ACN in H2O (0.1% NH3.H2O).Preparation 2375 6-Bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrileA solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (2.00 g, 8.40 mmol), (1S)-1-(pyridin-2-yl)ethanol (1.14 g, 9.24 mmol) and PPh3 (2.64 g, 10.08 mmol) in THF (20.0 mL) is stirred for 10 min at RT under N2. DEAD (1.76 g, 10.0810 mmol) is added dropwise to the mixture over 10 min at RT. After the mixture is stirred for an additional 2 hrs at RT, it is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (PE~3:1) to give the title compound as a green oil (1.48 g, 51.3%). ES / MS m / z 343.0 / 345.0 [M+H]+.The following compounds are prepared essentially as described for 6-bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 0 °C to RT.5 Table 29Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 238 6-Bromo-4-[( 1S)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3 -carbonitrile N=a " Il j N 343.0 / 345.0 239 7-Chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridine n jN 01^^-^0 JL, N 274.0 240 6-Bromo-4-[( 1R)-1-cyclobutylethoxy]pyrazolo[1,5-a]pyridine-3 -carbonitrile N=\ 1      \ N / -5N 320.1 / 322.1 241 6-Bromo-4-[( 1R)-1-cyclopropylethoxy]pyrazolo[1,5-a]pyridine-3 -carbonitrile N=a / \ N I JL a 242 6-Bromo-4-[( 1R)-1-phenylethoxy]pyrazolo[1,5-a]pyridine-3 -carbonitrile N=\ —SN £ A 341.8 / 343.8 243 7-Chloro-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine 0 o—( 0 292.0 2441 [2-(6-Bromopyrazolo[1,5-a]pyridin-4-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-tert-butyl-dimethyl-silane, Isomer 2 0 ” v°_ 7       <z>— \= / / \_ m        / \ 468.0 1 Purified by silica gel chromatography, eluting with PE:EtOAc (15:1 to 10:1).a 1H NMR (300 MHz, CDCI3) 8 8.32 (d, 1H), 8.15 (s, 1H), 6.75 (d, 1H), 4.22 - 4.12 (m, 1H), 1.53 (d, 3H), 1.35 - 1.27 (m, 1H), 0.75 - 0.60 (m, 2H), 0.60 - 0.36 (m, 2H).Preparation 2455     tert-Butyl (3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylateTo tert-butyl (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate (1.5 g) and SiO2 (505.58 mg, 8.41 mmol) in ACN (15mL) is added NBS (2.00 g, 11.22 mmol) at RT under N2. The reaction is stirred for 2 hr at 80°C.10 Upon cooling to RT, the reaction is quenched with H2O. The suspension is filtered and washed with EtOAc (2 x 5 mL). The filtrate is extracted with EtOAc (2 x 100 mL). The combined organic layers are washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with PE:EA (3:1) to afford the title compound (1.3 g, 85.1%) as a white solid. ES / MS m / z15   (79Br / 81Br) 363.0 / 365.0 [M+H]+.The following compounds are prepared essentially as described for tert-butyl(3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate using theappropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.Table 30Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 2461 tert -Butyl (3S,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate 0 ?F \vBr \ ^N\ -y—0  \— / N- (79Br / 81Br) 363.0 / 365.0 2472 tert-Butyl (3S,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate ° F Wr O \-- /    N" (79Br / 81Br) 404.0 / 406.0 [M+H+ACN]+ 2481 tert-Butyl (3R,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate Q __7 \ Br \ ^N\ >"VN -y—o \— / N" (79Br / 81Br) 363.1 / 364.9 2493 (1r,3r)-3-(4,5-dimethyl- 1H-1,2,3-triazol-1-yl)cyclobutan- 1-ol \    Br a 2501 tert-Butyl (3S,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-hydroxy-piperidine-1-carboxylate OH\   D 0     Vr \ ^N\ / \rN ^-0  \ / N- (79Br / 81Br) 361.08 / 363.0 2511 tert-Butyl (3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-hydroxy-piperidine-1-carboxylate o ^0H \  ^N\ / Nm-N —^—0   '-- / N- (79Br / 81Br) 361.08 / 363.0 2521 tert-Butyl (3S,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-hydroxy-piperidine-1-carboxylate 0 °H kvBr \ -y—o      ' n- (79Br / 81Br) 361.1 / 363.1 2534 tert-butyl (3R,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-hydroxy-piperidine-1-carboxylate O ^0H kvBr \         / N\rN -y—0  '— /   N- (79Br / 81Br) 361.1 / 363.1 2544 tert-butyl (3RS,4RS)-4-(4-bromo-5-methyl-triazol-1-yl)-3-methyl-piperidine-1-carboxylate / \ Br \  ^N\ / NM'N —O \' N' (79Br / 81Br) 359.1 / 361.1 2555 tert-butyl (3RS,4SR)-4-(4-bromo-5-methyl-triazol-1-yl)-3-methyl-piperidine-1-carboxylate Q    __ /   \ Br \  ^N\ / NM'N O   '—f   N' (79Br / 81Br) 359.1,361.1 1 Purified by silica gel chromatography, eluting with PE:EA (4:1).2 Purified by silica gel chromatography, eluting with PE:EA (3:1).3 Purified by silica gel chromatography eluting with 0% to 100% EA in heptane.4 Purified by silica gel chromatography, eluting with PE:EA (5:1).5 Purified by silica gel chromatography, eluting with PE :EA (5:1to 4:1).a 1H NMR (400 MHz, DMSO-d6) 8 2.20 (s, 3 H) 2.37 - 2.47 (m, 2 H) 2.69 - 2.77 (m, 2 H) 4.41 - 4.49 (m, 1 H) 4.99 - 5.09 (m, 1 H) 5.09 - 5.67 (m, 1 H).Preparation 256tert-Butyl 2-(4-bromo-5-methyl-triazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylateTo tert-butyl 2-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate (11.1 g, 29.3 mmol.) in H2O (100 mL) is added KOH (6.59g, 117.3 mmol) at RT under N2. The reaction is stirred for 2 hr at 50°C. The reaction mixture is used in the next step directly without further purification.To 1-(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)-5-methyl-triazole-4-carboxylic acid is added Br2 (6.95g, 43.99 mmol) dropwise at RT under N2. The reaction is stirred for 1 hr at RT then extracted with EtOAc (2 x 100 mL). The combined organic layers are washed with sat. Na2S2O3 (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated to afford the title compound as a white solid (8.7 g, 75.35%). 1H NMR (400 MHz, CDCI3) 8 4.84 -4.69 (m, 1H), 3.50 - 3.40 (m, 2H), 3.38 - 3.30 (m, 2H), 2.62 - 2.54 (m, 2H), 2.53 - 2.44 (m, 2H), 2.24 (s, 3H), 1.77 - 1.62 (m, 4H), 1.46 (s, 9H).Preparation 257tert-Butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateBr2 (154.00 mg, 0.96 mmol) is added in portions to a stirred solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazole-4-carboxylic acid (248 mg, 0.80 mmol) and KOH (54.00 mg, 0.96 mmol) in H2O (6 mL) and the mixture is stirred for 3 hrs at RT under N2. A precipitate results, and the mixture is extracted with EtOAc (3x30 mL). The combined organic extracts are washed with brine (2x15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow solid (190 mg, 69%). ES / MS m / z (79Br / 81Br) 345.2 / 347.2 [M+H]+, which is used directly without further purification.The following compounds are prepared essentially as described for tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 0 °C to RT. HBr / AcOH can be used as the solvent.Table 31PrepChemical NameStructureES / MS m / zNo. (79Br / 81Br) [M+H]+ 258 tert-Butyl 3-(4-bromo-5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate o      KzBr 317.1 / 319.1 259 tert-Butyl (3R)-3-(4-bromo-5-methyl-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate -Jyo      N=N 331.0 / 333.0 260 tert-Butyl (3S)-3-(4-bromo-5-methyl-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate ^,0      N=N 331.1 / 333.1 2611 tert-Butyl 4-(4-bromo-5-methyl-triazol-1-yl)azepane-1-carboxylate n-n 1 0 359.1 / 361.1 262 tert-Butyl (3S)-3-(4-bromo-5-methyl-triazol-1 -yl)piperidine-1-carboxylate 0 . —X / N—\  ^Br \   >-N 7 ' /   n=n 345.2 / 347.2 263 tert-Butyl (3R)-3-(4-bromo-5-methyl-triazol-1 -yl)piperidine-1-carboxylate / --v V / Br N- / N^N 345.0 / 347.0 2643 Cis-1-(3- Benzyloxycyclobutyl)-4-bromo-5-methyl-triazole \ Br / =\ __ / v N- a 26542665tert-Butyl 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]-3-oxo-piperazine-1-carboxylatetert-Butyl (2SR,4RS)-4-(4-bromo-5-methyl-triazol-1-yl)-2-cyclopropyl-piperidine-1-carboxylate415.8 / 417.8385.1 / 387.11 Reverse flash chromatography: Column, C18, 10% to 50% ACN in H2O(0.1%NH4HCO3).2 Silica gel column chromatography eluting with PE:EtOAc (5:1).3 Reverse flash chromatography: Column, C18, 50% to 80% ACN in H2O (0.1% FA).5   4 Reverse flash chromatography: Column, C18, 40% to 70% ACN in H2O (0.1% FA).5 Reverse flash chromatography: Column, C18, 50% to 55% ACN in H2O(0.1%NH4HCO3).a 1H NMR (400 MHz, DMSO-d6) 8 7.40-7.34 (m, 4H), 7.33 - 7.27 (m, 1H), 5.14 - 5.06(m, 1H), 4.45 (s, 2H), 4.42-4.34 (m, 1H), 2.81-2.72 (m, 2H), 2.66 - 2.56 (m, 2H), 2.22 (s, 10   3H).Preparation 267tert-Butyl 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]piperazine-1-carboxylateO15           To tert-butyl 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]-3-oxo-piperazine-1-carboxylate (1 g, 2.40 mmol) in THF (10.00 mL) is added BH3 (12.01 mL, 12.01 mol, 1M in THF) dropwise at 0 °C under N2. The reaction is stirred for 2 hr at RT, cooled to 0 °C and quenched with MeOH (10mL). The mixture is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with PE:EtOAc (4:1 to 2:1)to afford the title compound (0.53 g, 54.8%) as a light yellow oil. ES / MS m / z (79Br / 81Br) 401.8 / 403.8 [M+H]+.Preparation 268Cis-3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanolA mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.38 mmol) and FeCls (8.56 g, 52.76 mmol) in DCM (100 mL) is stirred for 2 hr at 50 °C under N2. Upon cooling to RT the reaction is diluted with H2O (50 mL). The mixture is extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with brine (2x100 mL), dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the title compound (8.00 g, crude) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 5 5.09 -4.99 (m, 1H), 4.55 -4.42 (m, 1H), 2.80-2.71 (m, 2H), 2.48 -2.37 (m, 2H), 2.21 (s, 3H).Preparation 269 3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanone \ Br °=ovA mixture of 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanol (4.00 g, 17.23 mmol) and Dess-Martin (10.97 g, 25.85 mmol) in DCM (40 mL) is stirred for 2 hr RT under N2. The mixture is diluted with H2O (100 mL), extracted with EtOAc (3 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: column, C18; mobile phase, 20% to 40% ACN in H2O (0.1% FA) to afford the title compound (2.10 g, 52.96%) as a white solid. ES / MS m / z (79Br / 81Br) 229.9 / 231.9 [M+H]+.Preparation 2701-Bromo-3-[(diphenylmethyl)amino]-3-methylbutan-2-oneBrA mixture of 3-[(diphenylmethyl)amino]-3-methylbutan-2-one (700.00 mg, 2.62 mmol) and Br2 (418.39 mg, 2.62 mmol) in HBr in AcOH (40%, 6.00 mL) is stirred for 2 hrs at RT under N2. The reaction is quenched with NaHCO3 / ice (300 mL) at 0 °C. The mixture is extracted with DCM (2x300 mL). The combined organic extracts are washed with brine (1x300 mL), dried over anhydrous Na2SO4, filtered and the filtrate is concentrated under reduced pressure to give the title compound (800 mg) as yellow solid which is used without further purification. ES / MS m / z (79Br / 81Br) 346.0 / 348.0 [M+H]+ .Preparation 271 1-(Diphenylmethyl)-2,2-dimethylazetidin-3-one OA mixture of 1-bromo-3-[(diphenylmethyl)amino]-3-methylbutan-2-one (2.10 g, 6.07 mmol) and NaHCO3 (764.21 mg, 9.10 mmol) in DMF (6.00 mL) and H2O (1.50 mL) is stirred for 12 hours at RT under N2. The mixture is diluted with EtOAc (100 mL) and washed with H2O (3x80 mL). The organic layer is washed with brine (2x80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 24% to 27% ACN in H2O to give the title compound as a yellow solid (1.30 g, 75.4%). ES / MS m / z 284.3 [M+H2O+H]+.Preparation 272 6-(1-[1-[1-(Diphenylmethyl)-2,2-dimethylazetidin-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrileA mixture of 4-methoxy-6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (300.00 mg, 0.89 mmol), 1-(phenylmethyl)-2,2-dimethylazetidin-3-one (473.29 mg, 1.78 mmol), AcOH (5.36 mg, 0.089 mmol) and NaBH3CN (140.11 mg, 2.23 mmol) in MeOH (4.00 mL) is stirred for 12 hours at 50 °C under N2. The reaction is quenched with NaHCO3 (50 mL) at RT and the aqueous layer is extracted with EtOAc (2x80 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 38% to 40% ACN in H2O (0.1% FA) to give the title compound as a yellow solid (400 mg, 76.57%). ES / MS m / z 586.3 [M+H]+.The following compounds are prepared essentially as described for 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazetidin-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The reaction can also be quenched with H2O, and the filtrate can be washed with EtOAc.Table 32Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 273 tert-Butyl 4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1 -yl]-2,2-dimethylpyrrolidine-1-carboxylate r z z MT \\ o 1 x II z 506.4 2741 Cis-tert-Butyl 4-[3-(4-bromo-5-methyl-triazol-1-yl) cyclobutyl] piperazine-1-carboxylate \-z 1 \x 7( z z z z^ 0^0 (79Br / 81Br) 400.0 / 402.0 1 Purified by silica gel column chromatography, eluting with 1% to 50% EA in P Preparation 275tert-Butyl 4-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate, Isomer 1andPreparation 276tert-Butyl 4-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate, Isomer 2The isomers of tert-Butyl 4-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate (1.9 g) are isolated by Chiral Prep-HPLC with the following conditions: Column, N--CHIRALPAK IG (Lot No. IG30CS-VL001), 4.6*100 mm, 3.0 ^m; eluting with a gradient of 10% - 50% MeOH (20 mM NH3); flow rate: 2 mL / min; 210 nm; t(R) Isomer 1 is 2.30 min with 100% ee as a white solid (810 mg, 42.63%); t(R) Isomer 2 is 2.52 min with 100% ee as a white solid (788 mg, 41.47%).Preparation 2776,6-Difluoro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-oneF-TEDA (23.95 g, 67.61 mmol) is added in portions to a stirred solution of 5H,6H-cyclopenta[b]pyridin-7-one (3.00 g, 22.53 mmol) and Na2SO4 (16.00 g, 112.64 mmol) in ACN (30 mL) at RT under N2, and the mixture is stirred for 3 hrs at 80 C under N2. The mixture is concentrated under reduced pressure. The residue is purified by silicagel column chromatography, eluting with a gradient of PE / EtOAc (3:1) to give the title compound as a light-yellow solid (2.2 g, 57.73%). 1H NMR (400 MHz, d6-DMSO) 8 8.88 (dd, 1H), 8.14 (dd, 1H), 7.78 (dd, 1H), 3.75 (t, 2H).Preparation 278 6,6-Difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol OHFA stirred solution of 6,6-difluoro-3H,4H,5H-cyclopenta[b]pyridin-7-one (1 g, 5.84 mmol) in MeOH (10 mL) is treated with NaBH4 (220 mg, 5.82 mmol) and stirred for 2 hrs at RT under N2. The mixture is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with a gradient of PE / EtOAc (3:1) to give the title compound as a white solid (800 mg, 80%). ES / MS m / z 172.0 [M+H]+ .Preparation 279 (R)-2,2,2-Trifluoro-1-(pyridin-2-yl)ethyl trifluoromethanesulfonateTf2O (597.33 mg, 2.12 mmol) is added dropwise at 0 °C to a stirred solution of (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanol (250 mg, 1.41 mmol) and TEA (428.47 mg, 4.23 mmol) in DCM (10 mL) and the mixture is stirred for 4 hrs at RT under N2. The mixture is diluted with H2O (20 mL) and extracted with EtOAc (3x20 mL). The combined organic extracts are washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow oil (280 mg, crude). The product is used directly without further purification. ES / MS m / z 309.8 [M+H]+.The following compound is prepared essentially as described for (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl trifluoromethanesulfonate using the appropriate reagents,adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.Table 33Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 2801 6,6-Difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl trifluoromethanesulfonate O' 0 rVX f QXf 304.0 1 The extracts are concentrated under vacuum, and are not washed with brine, dried over5   anhydrous Na2SO4, or filtered.Preparation 2814-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridineTo 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5.00 g, 22.02 mmol) and10 bis(pinacolato)diboron (6710.27 mg, 26.43 mmol) in dioxane (10 mL) are added KOAc (6.48 g, 66.06 mmol) and Pd(dppf)Cl2 (322.25 mg, 0.44 mmol, 0.02 equiv.) at RT under N2. The resulting mixture is stirred for 2 hr at 80 °C under N2. The mixture is carried forward without a further purification. ES / MS m / z 275.1 [M+H]+.Preparation 28215    [5-[2-[tert-Butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]boronic acidA mixture of tert-Butyl-[2-(7-chloroimidazo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane (1.8 g, 4.27 mmol), bis(pinacolato)diboron (1.62 g, 6.40 mmol), KOAc (1.05 g, 10.67 mmol) and XPhos (0.24 g, 0.51 mmol), Pd2(dba)3 (0.39 g, 0.427 mmol) in dioxane (20 mL) is stirred at 80 °C for 2 hr under N2. Upon cooling to RT, the reaction is carried forward to the next step without a further purification. ES / MS m / z 432.1 [M+H]+.Preparation 283 5-Methoxyimidazo[1,2-a]pyridin-7-ylboronic acidA stirred mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine(1.00 g, 5.48 mmol) and bis(pinacolato)diboron (1.67 g, 6.57 mmol) in 1,4-dioxane is treated with KOAc (1.61 g, 16.43 mmol) and Xphos Pd G4 (0.05 g, 0.06 mmol) at RT under N2 and stirred for 8 hrs at 80 °C. The mixture is diluted with H2O (100 mL), acidified to pH 4 with HCl aq. (1 N), and extracted with i-PrOH:CHCl3 (3:1)(3 x 200 mL). The combined organic extracts are dried over anhydrous Na2SO4 and concentrated under vacuum to give the title compound as a light-pink solid (1.4 g, crude). ES / MS m / z 193.0 [M+H]+.The following compounds are prepared essentially as described for 5-methoxyimidazo[1,2-a]pyridin-7-ylboronic acid using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. The catalyst can also be XPhos Pd G4.Table 34Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 284 3-Cyano-5-[(1R)-1- (pyridin-2-yl)ethoxy] imidazo[1,2-a]pyridin-7-ylboronic acid ,n 'n HO JI oh H 1 N^J 308.9 285 [5-[(1R)-1-(5-Fluoro-2-pyridyl)ethoxy]imidazo[1 ,2-a]pyridin-7-yl]boronic acid ZE O 0-03 0 C3 302.0 2861 (5-Methoxy-3-methyl-imidazo[1,2-a]pyridin-7-yl)boronic acid IV [il H%Vo OH । 207.1 1 0.1 eq Xantphos Pd G4 and 0.2 eq X-Phos usedPreparation 2874-[(1R)-1-(Pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-5                            yl)pyrazolo[1,5-a]pyridine-3-carbonitrileA stirred RT solution of 6-bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (1.40 g, 4.08 mmol), KOAc (1.20 g, 12.24 mmol) and bis(pinacolato)diboron (1.24 g, 4.90 mmol) in dioxane (20.00 mL) under N2 is treated10 with Pd(dppf)Cl2.CH2Cl2 (0.17 g, 0.20 mmol), and the mixture is stirred for 2 hrs at 100 °C under N2. The mixture is filtered, the filter cake is washed with EtOAc (3x20 mL), and the filtrate is concentrated under reduced pressure to give the title compound as ablack solid (2.5 g, crude), which is used directly without further purification. ES / MS m / z 391.3 [M+H]+.The following compounds are prepared essentially as described for 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-5 a]pyridine-3-carbonitrile using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 80 °C to 100 °C. The base can also be KF. The catalyst can also be Pd(PPh3)4, Pd2(dba)3 or Pd(dppf)Cl2 and can be used alone or in combination with XPhos Pd G4.Table 35Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 288 4-[(1S)-1-(Pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 1     ° s \\ / A zz / m-O ! \ 309.1 2891 5-[(1R)-1-(Pyridin-2-yl)ethoxy] imidazo[1,2-a]pyridin-7-ylboronic acid N"^ An V^Ao HO-B^ K / l OH 284.3 2902 4-[(1R)-1- Cyclobutylethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile z H / v / A z-z J m-O °A\ 368.2 2911 4-[(1R)-1- Cyclopropylethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile n / 1 o— z-z J cn-Qi 1   \ / °\Z\ 354.2 2921 4-[(1R)-1- Phenylethoxy] -6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile / A i O'® / Z Z \-O T J    ii o z 390.2 2933 4-Isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile N=\ / \ zN / A-5N 246.0 2944 (3-Cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)boronic acid h%AA0 OH । 218.0 2955 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile z 11 o— co-O i \ / 300.2 2961 [3-Cyano-5- [(5-fluoro-2-pyridyl)-(1-methoxycyclopropyl) methoxy]imidazo[1,2-a]pyridin-7-yl]boronic acid i o O-oo I \_ o 383.0 297 [3-Cyano-5-[[(1R)-1-(5-fluoro-2-pyridyl)ethyl] amino]i midazo[1,2-a]pyridin-7-yl]boronic acid \ I co-O / O I 326.1 298 3-Fluoro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine o / ' / O-oo / A J °\ ' 293.2 299 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine o CQ-O / \ / 0. / 4 275.2 300 tert- Butyl-[2-(5-fluoro-2-pyridyl)-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy-ethoxy] -dimethyl silane, Isomer 2 1 \ N V, ° N^^r- \ F 1 514.3 301 tert-Butyl-[2-(5-fluoro-2-pyridyl)-2-[3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy-ethoxy] -dimethyl silane, Isomer 2 4 / / u.      Vz " / ^(  V°_ Z'Z 7     CD — \= /     / V_ CQ-O     / \ 1    \ / 532.4 1 Mixture is used directly without further purification.2 Mixture is filtered, washed with 1,4-dioxane, concentrated under reduced pressure, and used directly without further purification.3 The reaction mixture is filtered and purified with reverse phase C18 chromatography.5   4 Upon workup the organic layers are combined, washed with H2O. The aqueous layer isacidified to pH 3-4 with conc. HCl. The precipitate is collected by filtration, washed with water, and dried in vacuo.5 Purified by silica gel column chromatography, eluting with PE / EtOAc (20:1 to 3:1).a Material is used without further purification.Preparation 3023-Chloro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridineN=x I \ N z^CI'°'A mixture of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5.06 g, 18.46 mmol) and NCS (2.47 g, 18.46 mmol) in CHCl3 (5 mL) is heated at 50°C for 1 hr. Upon cooling to RT, the reaction is washed with H2O, sat. aq. NaHCO3, brine, dried over Na2SO4 and filtered. The filtrate is concentrated to afford the title compound (5.79 g, 18 mmol) as a light brown solid. ES / MS m / z 227.0 [M+H-C6H12]+.Preparation 303tert-Butyl 4-[4-(5-chloroimidazo[1,2-a]pyridin-7-yl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylateTo 7-bromo-5-chloroimidazo[1,2-a]pyridine (700.0 mg, 3.02 mmol) and tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate(946.7 mg, 2.41 mmol) in dioxane / H2O (4:1, 10.0 mL) is added Pd(PPh3)4 (349.4mg, 0.30 mmol) and KF (527.0mg, 9.07 mmol) at RT under N2. The reaction is stirred for 2 hr at 100 °C under N2. The resulting mixture is filtered, the filter cake is washed with EtOAc (3 x 100 mL). The filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (1:2) to afford the title compound as a yellow solid (700 mg, 55.6%). ES / MS m / z 416.2 [M+H]+.Preparation 304tert-Butyl 4-[5-methyl-4-(5-oxo-6H-imidazo[1,2-c]pyrimidin-7-yl)pyrazol-1-yl]piperidine-1-carboxylate7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (300 mg, 1.77 mmol), tert-butyl 4-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.04 g, 2.65 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (127 mg, 0.27 mmol), and K3PO4 (1.13 g, 5.31 mmol) in 1,4-dioxane (4 mL) is treated with Pd2(dba)3 (243 mg, 0.27 mmol) and sparged with N2 for 5 min. The reaction is sealed and refluxed overnight. Upon cooling to RT, the reaction is diluted with H2O and extracted with EtOAc (3x). The combined organic layers are washed with H2O, followed by brine, dried over Na2SO4, filtered, and concentrated to a yellow oil. The oil is dissolved into DCM and purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM to afford the title compound (470 mg, 1.18 mmol, 66.7 %) as a solid. ES / MS m / z 399.2 [M+H]+.Preparation 305tert-Butyl 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateA mixture of tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (1.60 g, 4.63 mmol), 5-methoxyimidazo[1,2-a]pyridin-7-ylboronic acid (1.33 g, crude), K2CO3 (1.92 g, 13.90 mmol), Pd(PPh3)4 (0.27 g, 0.23 mmol), dioxane (8 mL) and H2O (2.00 mL) is stirred for 8 hrs at 90 °C under N2. The mixture is cooled to RT, diluted with EtOAc (100 mL), washed with H2O (50 mL), and then brine (80 mL). Thecombined organic layers are dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1 to 1:1) to give the title compound as a brown solid (520 mg, 18.2%). ES / MS m / z 413.3 [M+H]+.Preparation 306tert-Butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5 g, 18.24 mmol) and tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (6.93 g, 20.06 mmol) in dioxane (80 mL) and water (20 mL) is added K2CO3 (7.56 g, 54.72 mmol) and Pd(DtBPF)Cl2 (0.24 g, 0.36 mmol) RT under N2. The reaction is stirred overnight at 80 °C. Upon cooling to RT, the resultant mixture is diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with brine (2 x 80 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with a gradient of 30% to 60% EtOAc in PE to afford the title compound as a light-brown solid (4.5 g, 59.8%). ES / MS m / z 413.2 [M+H]+.Preparation 307 tert-butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylateA solution of tert-butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (16.1 g, 39.02 mmol) in CHCl3 (50 mL) is treated with PPTS (981 mg, 3.90 mmol) followed by NCS (5.21 g, 39.02 mmol). The reaction is stirred at 40 °C for 95 min. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by phase silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford the title compound (17.7 g, 101 %) as a colorless solid. ES / MS m / z 391.2 [M+2H-tBu]+.Preparation 308 tert-Butyl 3-[5-methyl-4-[5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]triazol-1-yl]azetidine-1-carboxylateTo 5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-ylboronic acid(1.00 g, 3.53 mmol), tert-butyl 3-(4-bromo-5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate (1.23 g, 3.89 mmol) and K2CO3 (1.46 g, 10.60 mmol) in dioxane (8.00 mL) and H2O (2.00 mL) is added Pd(PPh3)4 (0.41 g, 0.35 mmol) at RT under N2. The resulting mixtureis stirred at 100 °C for 2 hr under N2. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with a gradient of 5% to 10% MeOH in DCM to afford the title compound as a yellow solid (550 mg, 32.74%). ES / MS m / z 476.1 [M+H]+.Preparation 309tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateA mixture of 5-[2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-ylboronic acid (1.6 g, 3.71 mmol), tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (1.41 g, 4.08 mmol), K2CO3 (1.54 g, 11.13 mmol), Pd(DtBPF)Cl2 (242 mg, 0.37 mmol) in dioxane (20 mL) and H2O (5 mL) is stirred at 80 °C for 2 hr under N2. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (1:2 to 1:1) to afford the title compound as a brown solid (1.2 g, 49.63%). ES / MS m / z 652.4 [M+H]+.Preparation 310 tert-Butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a] yridine-6-yl]-5-methylpyrazol-1-yl)azetidine-1-carboxylateA stirred solution of tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate (2.50 g, 7.91 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (2.37 g, 7.91 mmol) in dioxane:H2O (80 mL:20 mL) is treated with K2CO3 (3.28 g, 23.72 mmol) and Pd(PPh3)4 (0.09 g, 0.08 mmol) at RT under N2, and the mixture is stirred overnight at 100 °C under N2. The mixture is cooled to RT, the reaction is quenched with H2O (100 mL) and extracted with EtOAc (3x150 mL). The combined organic extracts are washed with brine (1x150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, elutingwith a gradient of PE:EtOAc (10:1-1:1) to give the title compound as a white solid (1.88 g, 58.21%). 1H NMR (300 MHz, d6-DMSO) 8 8.61-8.51 (m, 2H), 7.95 (s, 1H), 7.09 (d, 1H), 5.41-5.26 (m, 1H), 4.37-4.26 (m, 2H), 4.18 (d, 2H), 4.06 (s, 3H), 2.41 (s, 3H), 1.43 (s, 9H).5          The following compounds are prepared essentially as described for tert-butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a] yridine-6-yl]-5-methylpyrazol-1-yl)azetidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 80 °C to 100 °C. The solvent can also be toluene: H2O. The base can also be KOAc, K3PO4, or KF. The catalyst can10 also be CsF, Pd(AcO)2, PCy3, Pd(dppf)Cl2 DCM, Pd2(dba)3.CHCl3 or Pd(dppf)Cl2, alone or in combination with X-Phos or Xphos Pd G4. Alternatively, the reaction can becarried out without a catalyst. The mixture can also be extracted with PE and CHCl3: i-PrOH.Table 36Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 311 tert-Butyl (3R)-3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)pyrrolidine-1-carboxylate o o-^ V z \ ( 7 z H\ J o \ / III z 423.2 312 tert-Butyl (3S)-3-(4-[3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)pyrrolidine-1-carboxylate z , / o ZH z' ° -AT 423.1 313 tert-Butyl 3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate N=\ / \ o        \ Jf J x __________i n-n 410.3 3141 tert-Butyl 4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate 0    / I 'Kn / N=\ — / n=n 438.2 315 tert-Butyl 4-(4-[3-cyano-4-isopropoxypyrazolo[ 1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate 0 I        N N=\ 1      \ — /  N=n 466.3 316 tert-Butyl (3R)-3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)piperidine-1-carboxylate Qr° / . O / N=\ K N      N \ J T N^f^^0^ ' n; 437.3 3172 tert-Butyl 3-(4-[3-cyano-4-isopropoxypyrazolo[ 1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate 0 / Knz N=a V f I N=n 318 tert-Butyl (3S)-3-(4-[3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)piperidine-1-carboxylate ZZZ 0=< ,0 N=\ r V^N N^^^0^ ' N ; 437.1 3193 tert-Butyl (3R)-3-(4-(3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1- o \ / III z 424.3 yl)pyrrolidine-1-carboxylate 3204 tert-Butyl (3S)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate z A O —\ z Z' ° 478.4 321 tert-Butyl (1R,3s,5S)-3-(4-(3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl)-5-methyl- 1H-pyrazol- 1-yl)-8-azabicyclo[3.2.1]oct ane-8-carboxylate 0 z L y-yy O     I x ill z 322 tert-Butyl 3-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[ 1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate N^\ °         \ Jt -j-o     n=n Ayy 501.4 3235 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[ 1,5-a]pyridin-6-yl]-5-methylpyrazol-1 -yl)piperidine-1-carboxylate 0 vHJ / ° / / z=\ III 528.4 3245 tert-Butyl 3-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[ 1,5-a]pyridin-6-yl]-5-methylpyrazol-1 -yl)azetidine-1-carboxylate N=\ O       \ J T ~T° 500.3 325 tert-Butyl (4R)-4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azepane-1-carboxylate th o Q ,z Z V— x III z 451.1 3266 tert-Butyl 4-(4-[3-cyano-4-[(1S)-1-(pyridin-2-yl)ethoxy]pyrazolo[ 1,5-a]pyridin-6-yl]-5-methylpyrazol-1 -yl)piperidine-1-carboxylate J z z 0 528.3 327 tert-Butyl (3S)-3-[3-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[ 1,5-a]pyridin-6-yl]-5-methylpyrazol-1 -yl)azetidin-1-yl]pyrrolidine-1-carboxylate o z ? z v-- v th z=<       / 1 / 569.4 328 tert-Butyl 4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl]pyrazol-1-yl)piperidine-1-carboxylate O ht O h? o T X III z 423.3 329 tert-Butyl (4S)-4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azepane-1-carboxylate th o ,z th o x III z 451.2 330 tert-Butyl 3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl]pyrazol-1-yl)azetidine-1-carboxylate 1                     N=\ i°\ 339.3 331 tert-Butyl 3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -3-methylpyrazol-1-yl)azetidine-1-carboxylate N=\ —r~°           / 1 , 0     nA a 332 tert-Butyl 4-(4-[5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1 ,2-a]pyridin-7 -yl]-5 -methyl-pyrazol-1 -yl)piperidine-1-carboxylate ° zh z' 0 503.2 333 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-cyclobutylethoxy]py razolo[1,5-a]pyridin-6-yl] -5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate N^\ 1      \ nM—SN / ---\ FN Vn H     | —o  \— / n'n 506.3 334 tert-Butyl (2S,4R)-4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1 -yl)-2-methylpyrrolidine-1-carboxylate N=\ V\ kJCX / 4 Y   N 1     0 437.3 335 tert-Butyl 4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1 -yl)-2,2- dimethylpyrrolidine-1-carboxylate Z / z ,z MJ o r x / z 451.2 3362 tert-Butyl (2R,4R)-4-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1 -yl)-2-methylpyrrolidine-1-carboxylate N=\ 1      \ \ / o xv, vX 1     M    u 437.20 3377 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(2-pyridyl)ethoxy]imid azo[1,2-a]pyridin-7-yl]-5-methyl-triazol- 1-yl]piperidine-1-carboxylate 0 \ /              N=N Il J N.y 504.3 338 tert-Butyl 4-[3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate, Isomer 1 0                     ( 1      p F     W 528.2 339 tert-Butyl 4-[3-(4-[3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate, Isomer 2 N=\ 528.3 340 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-cyclobutylethoxy]py razolo[1,5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)piperidine-1-carboxylate N=\ —§n O           \ Jf 7 __1 N. V n          0 449.2b 3418 tert-Butyl 4-[4-(5-chloroimidazo [1,2-a]pyridin-7-yl)-5-methyl-pyrazol-1 -yl]piperidine-1-carboxylate \ i । 0 / —\  v yy -^-0  \ 416.2 3422 tert-butyl 2-[4-[3-cyano-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imid azo[1,2-a]pyridin-7-yl]-5-methyl-triazol- 1-yl]-7- azaspiro[3.5]nonane -7-carboxylate N"A —M II / ——N A-n \ O / --\ z\ ^-O  \N'        Ns; / F 587.2 3439 tert-Butyl 4-[4-(5-methoxy-3-methyl-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate \ j 7 0    / —\ ^n Vn       | n*n         1 427.2 34410, 11 tert-butyl 2-[4-(3-cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol- 1-yl] - 7- azaspiro[3.5]nonane -7-carboxylate / n^CN n-n        1 478.2 34513 tert-Butyl 4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]-3,3-difluoro-piperidine-1-carboxylate N^\ / \ 0 \           Vn |        I 0 /         F F 473.3 34614 tert-Butyl 4-[4-(4-methoxypyrazolo[1, 5-a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]piperidine-1-carboxylate N=a 1      \ 0 \                                                     I 412.2 34715 tert-Butyl 2-[4-[3-cyano-5-[(1R)-1-(2-pyridyl)ethoxy]imid azo[1,2-a]pyridin-7- yl]-5-methyl-triazol-1-yl]-7- ,z z v-- 569.0 azaspiro[3.5]nonane -7-carboxylate 34813 tert-butyl 4-(4-(3-cyano-4-methoxypyrazolo[1, 5-a]pyridin-6-yl)-5-methyl- 1H-pyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylate N=a /         F F 473.3 34916 tert-Butyl (3S)-3-[3-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]azetidin-1-yl]pyrrolidine-1-carboxylate z Y z VF KJ O X ill z 478.3 3501 tert-Butyl 3-[4-[3-cyano-5-[(1R)-1-(2-pyridyl)ethoxy]imid azo[1,2-a]pyridin-7-yl]-5-methyl-pyrazol-1-yl]azetidine-1-carboxylate 'y^° z Y z Cf 500.1 35117 tert-Butyl 4-[4-(5-methoxyimidazo[1,2 -a]pyridin-7-yl)-5-methyl-triazol-1-yl]azepane-1-carboxylate Y1 t 11 / A ,Yf 1      )—N 1 n'N 1 o c 35218 tert-Butyl (3S)-3-[4-(3-cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate 0          J / Fv pF . / nk k A A K / n^N      1 438.1 35310,21 tert-Butyl 4-[4-(3-cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]azepane-1-carboxylate n K''N^?- 1 0 452.3 35410, 19, 20 tert-Butyl 4-[4-[3-cyano-5-[[(1R)-1-(5-fluoro-2-pyridyl)ethyl]amino] imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate 0 ,z z \--- 546.3 35510, 21, 18 tert-Butyl (3R)-3-[4-(3-cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate “X / n~a V 'n^N          1 438.3 35622, 23 tert-Butyl 4-[4-(3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate °^° Q z IK MJ 0 \ m 431.2 35723 Cis-tert-Butyl 4-[3-[4-(4-methoxy pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]cyclobutyl]pipera zine-1 -carboxylate °^° 0 Y z IK MJ —0 468.3 35824 tert-Butyl 4-[4-(3-cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-3-(2-hydroxyethyl)-5-methyl-pyrazol-1 - Q Z / 8 pf‘ \ ill z 481.3 yl]piperidine-1-carboxylate 35925 tert-Butyl 4-[4-[4-methoxy-3-(trifluoromethyl)pyr azolo [ 1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate N=\ F o kXJ F x                         9 ^-0 \— /          1 424.8 [M+H-C4H8]+ 36026 tert-Butyl (2SR,4RS)-2-cyclopropyl-4-[4-(5 -methoxyimidazo[1,2 -a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate 0^0 ,z —o 453.2 1 Prep-TLC (EtOAc:PE = 1:1).2 Reverse flash chromatography with the following conditions: column, C18; ACN in H2O (0.1% NH4HCO3).3 Reverse flash chromatography with the following conditions: Column, C18, ACN in5   H2O (0.1% FA).4 Reverse flash chromatography with the following conditions: Column, C18; ACN in H2O (0.1% NH3H2O).5 Reverse flash chromatography with the following conditions: Column, C18; ACN in H2O.10   6 Reverse flash chromatography with the following conditions: Column, C18, H2O (0.1%FA).7 Silica gel column chromatography, eluting with a gradient of DCM:MeOH.8 Silica gel column chromatography, eluting with PE:EtOAc (1:2)9 Reverse flash chromatography: Column, C18, 40% to 70% ACN in H2O (0.1% FA).15    10 Catalyst: Pd(DtBPF)Cl2.11 Silica gel column chromatography, eluting with PE:EtOAc (1:1).13 Silica gel column chromatography, eluting with PE:EtOAc (4:1 to 1:2).14 Silica gel flash column chromatography, eluting 10% to 60% EtOAc in PE.15 Prep-TLC (EtOAc).16 Silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1).17 Reverse flash chromatography with the following conditions: column, C18; 10% to 50% ACN in H2O (0.1% NH4HCO3).18 Reverse flash chromatography with the following conditions: column, C18; 50% to 60% ACN in H2O (0.1% NH4HCO3).19 Silica gel column chromatography, eluting with 50% to 100% EtOAc in PE.20 Silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1 to 12:1).21 Cs2CO3 used as base.22 Pd(DtBPF)Cl2 used as catalyst23 Silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1).24 Silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1).25 Silica gel column chromatography, eluting with 0% to 100% EtOAc in heptane.26 Reverse flash chromatography with the following conditions: column, C18; 10% to 50% ACN in H2O.a 1H NMR (300 MHz, Methanol-d4) 8 7.82 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 6.77 (s, 1H), 4.24 (s, 3H), 3.86 -3.73(m, 1H), 3.65-3.37 (m, 4H), 2.62 (s, 3H), 2.09-2.01 (m, 1H), 1.94 -1.81(m, 1H), 1.54 (s, 9H), 1.49 -1.14 (m, 4H).b ES / MS m / z [M+2H-tBu]+.c 1H NMR (300 MHz, d6-DMSO) 8 8.59-8.49 (m, 2H), 8.35 (s, 1H), 7.12 (d, 1H), 5.24-5.11(m, 1H), 4.38-4.28(m, 2H), 4.22-4.12 (m, 2H), 4.06 (s, 3H), 2.41 (s, 3H), 1.42 (s, 9H).Preparation 361tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateA solution of 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.28 mmol), tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (487 mg, 1.41 mmol), K2CO3 (531 mg, 3.84 mmol), Pd(PPh3)4 (148 mg, 0.13 mmol), H2O (2 mL) and dioxane (8 mL) is stirred overnight at 100 °C under N2. The mixture is diluted with H2O (20 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts are washed with brine (2x20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi- flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 60% ACN in H2O (0.1% NH4HCO3) to give the title compound as a brown solid (354 mg, 52.27%). ES / MS m / z 529.3 [M+H]+.Preparation 362 tert-Butyl 2-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylateA stirred mixture of tert-butyl 2-(4-bromo-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200.00 mg, 0.52 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (171.24 mg, 0.57 mmol) in dioxane (4.00 mL) and H2O (1 mL) is treated with K2CO3 (215.77 mg, 1.56 mmol) and Pd(PPh3)4 (120.27 mg, 0.10 mmol) in portions at RT under N2. The mixture is stirred for 2 hrs at 80 °C under N2. The mixture is cooled to RT and concentrated under reduced pressure. The residue is purified by silica gel columnchromatography, eluting with a gradient of PE:EtOAc (3:1 to 2:1), to give the title compound as a yellow solid (110 mg, 44.3%). ES / MS m / z 462.3 [M-tBu+ACN+H]+.The following compounds are prepared essentially as described for tert-butyl 2-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)-7-5 azaspiro[3.5]nonane-7-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 80 °C to 100 °C. Toluene:H2O can also be used as the solvent. Pd(AcO)2, PCy3, XPhos Pd G2, XPhos Pd G4, or Pd(dppf)Cl2 can also be used as the catalyst or no catalyst can be used. K3PO4, KF or CsF can also be used as the base. Pd(DtBPF)Cl2 may also be used as a10 catalyst.Table 37Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 3631 tert-Butyl 4-[4-(3-cyano-4-isopropoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]piperidine-1-carboxylate N=\ 1      \ ° i ryN 4oKY>yy 1 465.3 364 tert-Butyl (1R,3r,5S)-3-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1 H-pyrazol-1 -yl)-8-azabicyclo[3.2.1]octane-8-carboxylate z z yz u O 1 x II z 463.1 365 tert-Butyl (3S)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate N=\ —=N °y ^(3 492.3 366 tert-Butyl (3R)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate / ° ;"’V ? z MT yzj o 1 x III z 392.20 367 tert-Butyl (3R)-3-[3-(4-[3-cyano-4-[(1 R)-1 -(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate o o-X p Y z MT yH / °     1 Z=(       III O z 569.3 368 tert-Butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl] -3-methylpyrazol-1-yl)piperidine-1-carboxylate C mJ O / x ill z 381.1 [M-tBu +H]+ 369 tert-Butyl (2R,4S)-4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl] -5-methylpyrazol- 1-yl)-2-methylpyrrolidine-1-carboxylate N=a V O    NN O^N^ N          O N^ 437.3 370 tert-Butyl (2S,4S)-4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl] -5-methylpyrazol- 1-yl)-2-methylpyrrolidine-1-carboxylate \ Xo 9 Qj o r v Ji 437.3 371 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-cyclopropylethoxy]pyraz olo[1,5-a]pyridin-6 -yl]-5-methyl- 1,2,3-triazol-1-yl)piperidine-1-carboxylate N=\ 1      \ o    \ n 1               N=N 492.3 372 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-cyclopropylethoxy]pyraz olo[1,5-a]pyridin-6 -yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate N=\ —SN O _\ JI N J 4 491.3 373 tert-Butyl 4-(4-[3-cyano- 4-[(1R)-1-phenylethoxy]pyrazolo[1, 5-a]pyridin-6-yl] -5-methyl- 1,2,3-triazol-1-yl)piperidine-1-carboxylate N=\ 1      \ n^~~~s=n 0         \ I / 1 r        n=n kJ 528.3 3742 tert-Butyl (3R)-3-(3-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1 H-pyrazol-1 -yl)azetidin-1-yl)pyrrolidine-1-carboxylate JV o ,z Z V-- O r x / z 478.3 375 tert-Butyl 3-(4-[3-cyano-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl) azetidine-1 -carboxylate \ A N o         \ J! A 1 501.3 3763 tert-Butyl (3S)-3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl) pyrrolidine- 1-carboxylate N=a 0. N V    N=N V 424.2 377 tert-Butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy] imidazo[ 1 ,2-a]pyridin-7 -yl]-5 -methyl-triazol-1 -yl] piperidine- 1-carboxylate \ n -X-C) \— / N'N 3784 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(3-pyridyl)ethoxy] imidazo[ 1 ,2-a]pyridin-7 -yl]-5 -methyl-triazol-1 -yl] piperidine- 1-carboxylate IB rj^N^^N \          kN J       | ^-0     ' N'N 529.2 3795 tert-Butyl 4-[5-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-4-methyl-1,2,4-triazol-3-yl] piperazine- 1-carboxylate N JIA / ~y~ °   — / n-n 439.2 3805 tert-Butyl 4-[2-[4-[3-cyano-5-[(1R)-1-(2-pyridyl)ethoxy] imidazo [1,2-a]pyridin-7 -yl]-5-methyl-triazol- 1-yl] -1,1-dimethyl-ethyl] piperazine- 1-carboxylate '% Z' 0 586.3 3816 tert-butyl (3R,4S)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-fluoro-piperidine-1-carboxylate, Isomer 2 N=\ 1      \ f Al o / -7 ill /            N=N \ 0 Si       <^ f \ 670.3 3827 tert-Butyl (3S,4S)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-fluoro-piperidine-1-carboxylate, Isomer 2 N=\ 1      \ o   ill A o v >n7A^ /     ^-7 N=N \ 0 Si \ 670.3 3838 tert-Butyl (3S,4R)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl) ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-fluoro-piperidine-1-carboxylate, Isomer 2 N=\ 1      \ 0 z-A        \\ 1 / n=n \ o n.A Si     ^^^F A x 670.4 3849 tert-Butyl (3R,4R)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl) ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-fluoro-piperidine-1-carboxylate, Isomer 2 N=\ 1      \ f rNA A o4nN \      N. ! \ Si               f >r \ 670.4 38510 (1r,3r)-3-(4-(3-Chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan- 1-ol 1      \ 7WCI \ X 1 N J, 334.2 38611 tert-Butyl (3S,4S)-4-[4-[4-[2-[tert-butyl (dimethyl) silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy] pyrazolo [1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl] -3-hydroxy-piperidine-1-carboxylate, Isomer 2 N=\ 0     PH 7°      n-n Si       '< / f 7 x 668.3 38712 tert-Butyl (3R,4S)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl) ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl] -3-hydroxy-piperidine-1-carboxylate, Isomer 2 ;......7 W_ / A 7 7 668.4 38812 tert-Butyl (3S,4R)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl] -3-hydroxy-piperidine-1-carboxylate, Isomer 2 N=\ 1      \ 0        fNI / n=n \ Si            F 7 x 668.3 38913 tert-Butyl (3R,4R)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl] -3-hydroxy-piperidine-1-carboxylate, Isomer 2 ^r° z •71 7 / A 7HJ 7 668.4 39014 tert-Butyl (3RS,4RS)-4-[4-[4-[2-[tert-butyl (dimethyl)silyl] oxy-1-(5-fluoro-2-pyridyl) ethoxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl] -3 -methyl-piperidine-1-carboxylate, Isomer 2 N=\ 1       \ N..A o       \ / T /     ^-7  N=N \ 0 nA. Si A x 666.3 3916 tert-butyl (3RS,4SR)-4- [4-[4-[2-[tert-butyl(dimethyl)silyl] oxy-1 -(5-fluoro-2-pyridyl) ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl] -3 -methylpiperidine- 1-carboxylate, Isomer 2 N—\ 1       \ n 0     /  \   / 1 /            N=N \      N. JL Si A x 666.2 39215 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl] oxy-1 -(5-fluoro-2-pyridyl) ethoxy]-3-fluoro- pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-4-methyl-piperidine-1-carboxylate, Isomer 2 N=\ 1      \ / n\A'f o        \ j 7 /        N=N 4'VA V-0 N4\r-\ Si            F >4 \ 684.5 1 ISCO Column, eluting with hexanes:EtOAc (10-100%).2 Purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH(20:1).3 Purified by silica gel column chromatography, eluting with a gradient of 0% to 10%5 MeOH in DCM.4 Purified by Prep-TLC (EA)5 Purified by reverse Combi-flash chromatography with the following conditions: Column, C18; ACN in H2O (0.1% NH4HCO3).6Purified by Prep-TLC PE:EtOAc (1:1).10   7 Purified by Prep-TLC (EA).8 Purified by silica gel column chromatography, eluting with PE:EtOAc (1:3).9 Purified by silica gel column chromatography, eluting with PE:EtOAc (2:3).10 Purified by silica gel column chromatography, eluting with a gradient of 0% to 10% MeOH in DCM.11 Purified by silica gel column chromatography, eluting with PE:EA (2:3).12 Purified by silica gel chromatography, eluting with PE:EA (1:1 to 1:2).13 Purified by reverse phase chromatography: column, C18; eluting with 40% to 50% ACN in H2O (0.1% NH4OH).14 Purified by silica gel column chromatography, eluting with PE:EtOAc (3:1).15 Purified by silica gel column chromatography, eluting with PE:EA (2:1 to 1:1).Preparation 393tert-Butyl (3R)-3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate(Trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (10 mL, 8.32 mmol) is added dropwise over 5 min to a stirred solution of 4-methoxy-6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (400.00 mg, 1.18 mmol) and DIEA (307.36 mg, 2.37 mmol) in DCM (5.00 mL) at -60 °C under N2. The mixture is stirred for 1 hr at RT under N2, washed with H2O (3x20 mL), and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of DCM: MeOH (9:1) to give the title compound as a brown solid (411 mg, 68.36%). ES / MS m / z 506.3 [M+H]+.Preparation 394tert-Butyl (2S,4R)-4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]-2-methylpyrrolidine-1-carboxylateTf2O (420.55 mg, 1.491 mmol) is added dropwise to a stirred solution of tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate(300.00 mg, 1.491 mmol) and DIEA (577.94 mg, 4.472 mmol) in DCM (5.00 mL) at -70 °C under N2 for 1 hr. The solution of tert-butyl (2S,4S)-2-methyl-4-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate is then added dropwise to a stirred solution of 6-[1-(azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.TFA (400.00 mg, 0.95 mmol) and DIEA (367.20 mg, 2.84 mmol) in DCM (20.00 mL) at -70 °C under N2. The solution is stirred overnight at RT, quenched by H2O (50 mL), and extracted with DCM (2x50 mL). The combined organic extracts are washed with brine (2x50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by Prep-TLC (EtOAc) give the title compound as a light-yellow solid (80 mg, 17.18%). ES / MS m / z 492.2 [M+H]+.Preparation 395 tert-Butyl (3S)-3-(4-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)pyrrolidine-1-carboxylateA mixture of 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (300.00 mg, 0.89 mmol), tert-butyl (3R)-3-(methanesulfonyloxy)pyrrolidine-1-carboxylate (2.37g, 8.92 mmol) and K2CO3 (369.75 mg, 2.68 mmol) in toluene (3.00 mL) is stirred for 4 hrs at 150 °C under N2. The mixture is cooled to RT, poured into H2O (20 mL), and extracted with DCM (2 x 20 mL). The combined organic extracts are washed with saturated NaCl aq. (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (95:5-90:10) to give the title compound as a light-yellow solid (260 mg, 57.66%). ES / MS m / z 506.4 [M+H]+.Preparation 396tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylateA mixture of 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazetidin-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (400.00 mg, 0.68 mmol), Boc2O (447.11 mg, 2.05 mmol) and Pd(OH)2 / C (287.69 mg) in MeOH (10.00 mL) is stirred for 12 hours at RT under H2. The mixture is filtered, the filter cake is washed with MeOH (2x30 mL), and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 30% to 33% ACN in H2O (0.1% FA) to give the title compound as a yellow solid (260 mg, 73.27%). ES / MS m / z 520.4 [M+H]+.Preparation 397tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate, Isomer 1andPreparation 398tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate, Isomer 2Isomers of tert-butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate (390.00 mg) are separated by Prep-chiral chromatography with the following conditions: Column,CHIRAL ART Cellulose-SB, 2*25 cm, 5 ^m; eluting with a gradient of 30% iPrOH in hexanes (10 mM NH3 MeOH); flow rate 20 mL / min; 254 / 220 nm; t(R) Isomer 1 is 10.2 min (110 mg, 28.21%) as a yellow solid with 100% ee; t(R) Isomer 2 is 12.7 min (120 mg, 30.77%) as a yellow solid with 99.6% ee. ES / MS m / z 520.4 [M+H]+.Preparation 399tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]azetidine-1-carboxylatetert-Butyl 3-oxoazetidine-1-carboxylate (101.18 mg, 0.59 mmol) in MeOH (4.00 mL) is added to 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100.00 mg, 0.30 mmol) at RT. The solution is stirred for 1 hr at 40 °C. After the solution is cooled to RT, NaBHsCN (37.14 mg, 0.591 mmol) is added and the mixture is stirred for 15 hrs at RT. The mixture is diluted with EtOAc (50 mL) and washed with H2O (2 x 50 mL). The organic extract is dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 60% ACN in H2O (0.1% FA) to give the title compound as a light-yellow solid (130 mg, 89.5%). ES / MS m / z 492.2 [M+H]+.Preparation 400tert-Butyl (3R)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate6-[1-(Azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (241 mg, 0.78 mmol) is added to a stirred solution of tert-butyl (3S)-3-(trifluoromethanesulfonyloxy) pyrrolidine-1-carboxylate (2.3 mL, 0.78 mmol, 3.4 M in DCM) in DCM (5 mL) at -50 °C under N2. After the solution is stirred for 1 hr at -50 °C, additional tert-butyl (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (2.3 mL, 0.78. mmol, 3.4 M in DCM) is added and stirring is continued at -50 °C for an additional hr. The mixture is diluted with EtOAc (100 mL) and washed with H2O (2x20 mL) and brine (20 mL). The combined organic extracts are dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: C18; eluting with a gradient of 35% to 60% ACN in H2O (0.1% NH4HCO3) to give the title compound as a light-yellow solid (80 mg, 20.6%). ES / MS m / z 478.4 [M+H]+.Preparation 401 tert-Butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateA stirred RT solution of tert-butyl 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (500 mg, 1.21 mmol) in DCM (6 mL) is treated with NIS (300 mg, 1.33 mmol) and stirred for 8 hrs at RT. The mixture is diluted with EtOAc (100 mL), washed with H2O (20 mL), and then brine (20 mL). The combined organic extracts are dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (820 mg, crude), which is used directly without further purification. ES / MS m / z 539.2 [M+H]+.The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The compound can also be chlorinated with NCS, or with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione. The reaction can be quenched with Na2SO3, and the mixture can also be extracted with DCM. Temperature is varied from -60 °C to RT.Table 38Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 402 tert-Butyl 4-(4-[3-iodo-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate O        I r'N _______1 —bO  \  }—N II J 629.2 403 tert-Butyl 4-(4-[3-iodo-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate Nx A q    _    \ II r i ~~r°   — / n-n i                                                                                              ii 630.2 404 tert-Butyl 4-(4-[3-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate °        \ ifS^~cl ' N = N h q 538.3 405 tert-Butyl 4-[4-[3-chloro-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy] imidazo[ 1, 2-a]pyridin-7-yl] -5-methyl-triazol-1-yl]piperidine-1-carboxylate z^ci ^o.F 556.2 406 2-[(1R)-1-([7-Chloro-3-iodoimidazo[1,2-a]pyridin-5-yl] oxy)ethyl]pyridine o 400.0 407 tert-Butyl 4-[4-(5-chloro-3-iodo-imidazo[1,2-a]pyridin-7-yl)-5-methyl-pyrazol-1 -yl]piperidine-1 -carboxylate A Ki \ Il 1 o / —\ V aA -y-° x 542.1 408 tert-Butyl 4-[4-(3-iodo-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1 -yl]azepane-1 -carboxylate o °A z '"K °A 553.0 4091 tert-Butyl 4-[4-(3-iodo-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ 1      \ °   / —\ vV n.n      I 538.7 500 tert-Butyl (2SR,4RS)-2-cyclopropyl-4-[4-(3-iodo-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate A Ki o               \ ji r \ Kn -po AA n=n     I 579.0 1 Purified by flash silica gel chromatography eluting with 0% to 100% EtOAc in heptane.Preparation 501tert-Butyl 4-[4-(3-cyclopropyl-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo a solution of tert-butyl 4-[4-(3-iodo-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (500 mg, 0.929 mmol) in toluene:H2O 10:1 (6.6 mL) is added cyclopropylboronic acid (160 mg, 1.86 mmol), K3PO4 (986 mg, 4.64mmol), tricyclohexylphosphane (57.3 mg, 0.204 mmol), and PdOAc2 (22.9 mg, 0.102 mmol) and the mixture is heated at 100 °C for 16 hr. Upon cooling to RT, the reaction is diluted with EtOAc (20 mL) and H2O (20 mL), layers are separated, and the aqueous layer is extracted with EtOAc (3 X 10 mL). The combined organic layers are concentrated in vacuo and the residue is purified by reverse phase chromatography eulting with a gradient of 0% to 100% ACN in H2O to afford the title compound (79 mg, 19 %). ES / MS m / z 452.9 [M+H]+.Preparation 502tert-Butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateA solution of tert-butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (800 mg, crude), DMF (8.00 mL), and CuCN (173.01 mg, 1.93 mmol) is stirred for 2 hrs at 100 °C under N2. The mixture is diluted with DCM (100 mL), washed first with H2O (20 mL), and next washed with brine (20 mL). The combined organic layers are dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 70% ACN in H2O (0.1% FA) to give the title compound (450 mg, 46%%). ES / MS m / z 438.3 [M+H]+.The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The temperature is varied from 80 °C to 100 °C. The reaction can also be quenched with H2O or NH4OH aq., and the mixture can be extracted with EtOAc or DCM.Table 39Prep No. Chemical Name Structure ES / MS m / z [M+H]+ 503 tert-Butyl 4-(4-[3-cyano-5-[(1R)- 1-(pyridin-2-yl)ethoxy] imidazo[1,2-a]pyridin-7-yl]-5-methylpyrazol-1-yl)piperidine-1 -carboxylate 0^0 z MT Z=<        ill O z 528.4 504 tert-Butyl 4-(4-[3-cyano-5-[(1R)- 1-(pyridin-2-yl)ethoxy] imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1 -carboxylate A O / \ |l A 1 An v         9 n-n N^Y 529.3 505 7-Chloro-5-[(1R)-1- (pyridin-2-yl)ethoxy] imidazo[1,2-a]pyridine-3 -carbonitrile c / 'Ao J 299.1 506 tert-Butyl 4-[4-(5-chloro-3-cyano-imidazo [1,2-a]pyridin-7-yl)-5-methyl-pyrazol-1 -yl]piperidine-1 -carboxylate x Yn / o \— / 441.1 507 tert-Butyl 4-[4-(3-cyano-5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1 -yl]azepane-1-carboxylate Y o °A z A z 452.0 5081 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-c]pyrimidin-7-yl]-5-methyl-pyrazol-1 -yl]piperidine-1 -carboxylate 4 / z Z' 0 0^0 -4 547.2 509 tert-Butyl (2SR,4RS)-4-[4-(3-cyano -5-methoxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1 -yl]-2-cyclopropyl-piperidine-1 -carboxylate 0^0 z z - -44 III z 478.2 1 Purified by silica gel chromatography, eluting with 0% to 100% EtOAc in DCM.Preparation 5106-(1-((1r,3r)-3-((tert-Butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloro-4-methoxypyrazolo[1,5-a]pyridineA solution of (1r,3r)-3-(4-(3-Chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol (1.03 g, 3.09 mmol), tertbutyldimethylchlorosilane (930 mg, 6.17 mmol) in DCM (15 mL) and imidazole (420mg, 6.17 mmol) is stirred at RT for 30 min. The reaction is directly loaded onto a silica10 gel column which is eluting with 0% to 100% EtOAc in heptane to afford the title compound (700 mg, 1.56 mmol) as solid. ES / MS m / z 448.2 [M+H]+.Preparation 511tert-Butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateNaOH (50% aq.) (8.23 g, 102.856 mmol) is added dropwise to a stirred solutionof tert-butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (15.00 g, 34.29 mmol) and NDM (10.41 g, 51.43mmol) in DMA (200.00 mL) at RT under N2. The mixture is stirred for 2 hrs at 50 °Cunder N2. The mixture is diluted with H2O (1500 mL) and PE (500 mL) and acidified to pH 4 with FA. The precipitated solids are collected by filtration, washed with H2O (2x50 mL), PE (2x100 mL), and dried under reduced pressure to give the title compound as a white solid (13 g, 89.54%). ES / MS m / z 424.2 [M+H]+.Preparation 512tert-Butyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo tert-butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (900 mg, 2.18 mmol) and NaOH in water (523.60 mg, 6.55 mmol, 50% in water) in DMA (10 mL) is added dodecane-1-thiol (883 mg, 4.36 mmol) at RT under N2. The reaction is stirred at 50 °C for 2 hr. Upon cooling to RT, the reaction is diluted with water (150 mL) and PE (50 mL). The pH of the mixture is acidified to pH 4 with FA. The mixture is stirred for 3 hr at RT under N2. The resultant precipitate is filtered then washed with water (3 x 10 mL) and PE (3 x 10 mL). The solids are concentrated under vacuum to afford the title compound as a light-yellow solid (740 mg, 85.12%). ES / MS m / z 399.2 [M+H]+.The following compounds are prepared essentially as described for tert-butyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. Table 40Prep No. Chemical Name Structure ES / MS m / z [M+H] + 5131 tert -Butyl 4-[4-(5-hydroxy-3-methyl-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate TK \ J! 1 ^-0  \— / N-N 413.3 5142 tert -Butyl 4-[4-(4-hydroxypyrazolo [1,5 -a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]piperidine-1-carboxylate N=\ 398.0 515 tert- Butyl (3S)-3-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate N-a p            ji / N—\   V JI. J / X ( / n^n 424.2 5163 tert -Butyl 4-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]azepane-1-carboxylate J N=n 1 0 438.4 5174 tert -Butyl (3R)-3-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate N-A P             JI pA . / N—\ V Ji X / x ( '-- / N-n 424.2 518 tert -Butyl 4-[4-(3-fluoro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate N=a 1      \ \ AN Vn J, y C> \— / n-n 417.2 519 Cis -tert- butyl 4-[3[4-(4-hydroxypyrazolo [1,5 -a]pyridin-6-yl)-5-methyl-triazol-1-yl]cyclobutyl] piperazine-1-carboxylate 0^0 ¢1 z Ik o T 454.2 5205 tert -Butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate N=\ N z^ci 0 r— \ J I \ Vn \ N / y^^OH 377.2 or [M+2H-tBu]+ 5216 tert -Butyl 4-[4-(3-cyclopropyl-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate N=\ vV n-n 438.8 5229 tert -Butyl 4-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-3-(2-hydroxyethyl)-5-methyl-pyrazol-1 -yl]piperidine-1-carboxylate N'A — M JI A-n \ )L Z^OH ° / —\ k / x An Vn } ^OH 467.1 5237 tert-Butyl (2SR,4RS)-4-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1 -yl] -2-cyclopropyl- o                    \ ii r x AN V-7 n=n 464.3 piperidine-1-carboxylate 524 3-chloro-6-(1- ((1r,3r)-3-hydroxycyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol N=\ / \ N \ Jf J HO"< / —N  । V n^n 320.0 525 tert-Butyl 2-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]-7-azaspiro[3.5] nonane-7-carboxylate N=a 407.2a 526 tert-Butyl 2-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate \ ^N\ KXn N V N'n 464.2 527 tert -Butyl (3S)-3-[3-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1 -yl]azetidin-1-yl]pyrrolidine-1-carboxylate / \ Z\           OH \  )"N    N 0 464.2 5288 tert-Butyl 4-[4-(3-cyano-5-hydroxy-imidazo[1,2-a]pyridin-7-yl)-5-methyl-triazol-1-yl]azepane-1-carboxylate / \ K / ^-QH '     HN KI n^N 1 0 438.2 1 Purified by silica gel chromatography eluting with PE:EtOAc (1:2).2 Purified by flash silica gel chromatography eluting with 10% to 70% EtOAc in PE.3Purified by flash reverse phase chromatography: Column, C18; eluting with 10% to 70%ACN in H2O (0.1% NH4CO3).5   4 Work up: Mixture acidified to pH 6 with FA. Insoluble material collected by filtration.5 Purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM.6 Purified by flash reverse phase chromatography: Column, C18; eluting with 0% to 100% ACN in H2O.7 Purified by reverse phase chromatography: Column, C18; eluting with 10% to 50% ACN in H2O.8 Purified by reverse phase chromatography: Column, C18; eluting with 30% to 70% ACN in H2O (0.1%FA).a [M+H-C4H8]+9 Upon adjusting pH to 4 with FA, the resultant insoluble material is collected by filtration.Preparation 529tert-Butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateNaOH (50% aq.) (36.57 g, 457.14 mmol) is added dropwise to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (40.00 g, 91.43 mmol) and NDM (55.51 g, 274.28 mmol) in DMA (400 mL) at 0 °C. The mixture is stirred for 8 hrs at 50 °C. The mixture is diluted with H2O (400 mL), acidified to pH 6 with FA, filtered, and the filter cake is washed with H2O, and dried under vacuum. The solid is triturated with a mixture of hexanes (200 mL) and Et2O (200 mL), filtered, and stirred in MeOH (400 mL) for 2 hrs at 60 °C. The mixture is filtered, and the filtered cake is concentrated under vacuum to give the title compound as a light-yellow solid (32 g, 82.6%). ES / MS m / z 424.3 [M+H]+.Preparation 530tert-Butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylateNaOH (50% aq.) (10.44 g, 130.58 mmol) is added to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate (19.00 g, 43.53 mmol) and NDM (26.43 g, 130.58 mmol) in DMA (150 mL) under N2 and the mixture is stirred for 3 hrs at 60 °C under N2. The mixture is diluted with H2O (1 L), acidified to pH~4 with FA, and extracted with EtOAc (3x1 L). The combined organic extracts are washed with brine (3x800 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is crystallized with MTBE:DCM:MeOH (1000 mL: 100 mL: 10 mL). The precipitated solids are collected by filtration and washed with hexanes (3x50 mL) to give the title compound as a grey solid (15.03 g, 81.7%). ES / MS m / z 421.30 [M-H]-.The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The extraction / washing / drying / crystallization steps can be omitted. The solids can also be washed with H2O, hexanes, and PE. The solvent can also be 1,4-dioxane. Temperature is varied from 50 °C to 60 °C.Table 41Prep No.Chemical NameStructureES / MS m / z [M+H]+tert-Butyl (3R)-3-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)pyrrolidine-1-carboxylate409.3tert-Butyl (3R)-3-(3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azetidin-1-yl)pyrrolidine-1-carboxylate tert-Butyl (3S)-3-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)pyrrolidine-1-carboxylate464.3409.2Preparation 534tert-Butyl (3S)-3-[3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azetidin-1-yl]pyrrolidine-1-carboxylateTo tert -butyl (S)-3-(3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azetidin-1-yl)pyrrolidine-1-carboxylate (300 mg, 0.64 mmol) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (346 mg, 0.97 mmol) in DCM (10.00 mL) is added TEA (196 mg, 1.94 mmol) and DMAP (7 mg,10   0.06 mmol) at RT under N2. The reaction is stirred for 1 hr at RT under N2 then isconcentrated in vacuo. The residue is purified by Prep-TLC 10% MeOH in DCM to afford the title compound as a light-yellow solid (350 mg, 90%). ES / MS m / z 596.2 [M+H]+.Preparation 53515 tert-Butyl 4-[4-(3-cyano-4-[[(2S)-1,1,1-trifluoropropan-2-yl]oxy]pyrazolo[1,5-a] pyridine-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylateA stirred solution of (2R)-1,1,1-trifluoropropan-2-ol (150.00 mg, 1.32 mmol) and DIEA (509.87 mg, 3.95 mmol) in DCM (5.00 mL) is treated with Tf2O (371.02 mg, 1.32 mmol) at 0°C under N2, and the mixture is stirred for 1 hr at RT under N2. The mixture is added directly to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a] pyridine-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.41 mmol) and K2CO3 (168.46 mg, 1.22 mmol) in CAN (8.00 mL). The mixture is stirred for 5 hrs at 80 °C under N2. The mixture is cooled to RT, the reaction quenched with H2O (50 mL), and extracted with EtOAc (3x50 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by Prep-TLC (PE:EtOAc 2:1) to give the title compound as a light-yellow solid (60 mg, 48.89%). ES / MS m / z 504.3 [M-tBu+H]+.The following compound is prepared essentially as described for tert-butyl 4-[4-(3-cyano-4-[[(2S)-1,1,1-trifluoropropan-2-yl]oxy]pyrazolo[1,5-a]226yridine-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.Table 42Prep No. Chemical Name Structure ES / MS m / z [M+H]+]+ 536 tert -Butyl 4-[4-(3-cyano-4-[[(2R)-1,1,1 -trifluoropropan-2-yl] oxy]pyrazolo[ 1,5-a]226yridine-6-yl)-5-methylpyrazol-1-yl]piperidine-1 -carboxylate N=\ 1       \ 0    / __\   1 1 ycyy F F 519.1 tert-Butyl (3S)-3-[3-[4-[3-cyano-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azetidin-1-yl]pyrrolidine-1-carboxylateTo tert-butyl (3S)-3-[3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azetidin-1-yl]pyrrolidine-1-carboxylate (350 mg, 0.58 mmol) and (1R)-1-(pyridin-2-yl)ethanamine (358 mg, 2.93 mmol) in toluene (10 mL) at RT is added Cs2CO3 (765 mg, 2.35 mmol), XantPhos (68 mg, 0.11 mmol) and Pd2(dba)3 (53 mg, 0.05 mmol). The reaction is stirred overnight at 100 °C under N2. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with DCM;MeOH (20:1 to 10:1) to afford the title compound as a green solid (60 mg, 17%). ES / MS m / z 568.4 [M+H]+.Preparation 538tert-Butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-methyl-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo tert- Butyl 4-(4- {5-hydroxy-3-methylimidazo[1,2-a]pyridin-7-yl}-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (600.0 mg, 1.46 mmol) and (1S)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate (382.66 mg, 1.75 mmol) in DMF (10.0 mL) is added Cs2CO3 (1.42 g, 4.37 mmol) RT under N2. The reaction is stirred at 120 °C for 2 hr. Upon cooling to RT, the mixture is diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by Prep-TLC (DCM / MeOH 20:1) to afford the title compound as a yellow solid (240 mg, 30.8%).ES / MS m / z 536.3 [M+H]+.The following compounds are prepared essentially as described for tert-butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-methyl-imidazo[1,2-a]pyridin-7-yl]-5-methyl-5 triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times and temperature, and adjusting the purification system as appropriate.Table 43Prep No. Chemical Name Structure ES / MS m / z [M+H]+]+ 5391, 2 tert-Butyl 4-[4-[3-cyano-4-[1-(2-methoxycarbonylphenyl) ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ I      \ N. / o OX ' / N )-N /      1 / °        o / / ) 586.3 5403 tert-Butyl 4-[4-[3-cyano-4-[ 1- [2-(dimethylcarbamoyl) phenyl]ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate f JI' yy / x Z'Z / Z / z z z' n 599.3 5413 tert-Butyl 4-[4-[3-cyano-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ 1       \ 0   / —\   \ J J x Vn y o   '—n=n Q F 554.4 5423 tert -Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ i \ 0 —III 9 F 514.2 [M+H-tBu]+ 5434 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-3-(2-hydroxyethyl)-5-methyl-pyrazol-1 -yl]piperidine-1 -carboxylate NA  M 1 / —=N An ^OH 590.1 5445 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-[4-(2,2,2-trifluoroethyl)- 1,2,4-triazol-3-yl]ethoxy] imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate 0         . An := n f N=N   AA. z N-N 601.5 5456 (1s,3r)-3-(4-(4-((S)-2-((tert-Butyldimethylsilyl)oxy)-1 -(5-fluoropyridin-2 -yl)ethoxy)-3-chloropyrazolo [1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan- 1-ol N=\ N^^CI \ 1 Z\ AZ'-Ao HOn< >-N J,       I N-N <V'Z n. !L \ Si             f d 1 573.0 1 Methyl 2-(1-bromoethyl)benzoate used as starting material.2 Purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in H2O.3 Purified by reverse phase chromatography eluting with a gradient of 10% to 100% ACN 5   in H2O.4Purified by Prep-TLC 2:1 EtOAc:PE.5 Purified by Prep-TLC 10:1 DCM:MeOH.6 Purified by silica gel chromatography eluting with a gradient of 0% to 20% MeOH in DCM.Preparation 546tert-Butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo a solution of tert-butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-5 ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (45 mg, 0.08 mmol) in MeOH (5 mL) is added NaBH4 (3.7 mg, 0.098 mmol). The reaction is stirred for 30 min. at RT then concentrated under reduced pressure. The residue is treated with EtOAc and H2O. The organic layer is separated, and the aqueous layer is extracted with EtOAc (2 x 10 mL). The combined organic layers are washed brine, dried over10   Na2SO4, and concentrated to afford the title compound (45 mg, 0.08 mmol,) as a whitesolid. The crude product is used in the next without further purification. ES / MS m / z 556.2 [M+H]+.The following compound is prepared essentially as described for tert-Butyl 4-[4-[3-cyano-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-15 methyl-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction time and temperature, and adjusting the purification system as appropriate.Table 44Prep No. Chemical Name Structure ES / MS m / z [M+H]+]+ 547 tert -Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate 1    \ ,N.,^ 2 °   '— /  N=N        1^°H o F 572.2 tert-Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo a solution of tert- butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-5 ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (200 mg, 0.35 mmol) in THF (10 mL) at RT is added a solution of MeMgBr (3M in Et2O) (50.2 mg, 0.42 mmol ). After stirring at RT for 60 min. the reaction is quenched with sat. NH4Cl, extracted with EtOAc (2X), dried over Na2SO4 and concentrated. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to10 afford the title compound (170 mg, 82.7 %) as a white solid. ES / MS, m / z 586.4 [M+H]+. Preparation 549tert-Butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate15           To a solution of tert-butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (180 mg, 0.33 mmol) in THF (8 mL) at RT is added MeMgBr (3M solution) (58.2 mg, 0.49 mmol) and the reaction is stirred at RT for 30 min. Next, the reaction is quenched withsat. NH4Cl, extracted into EtOAc (2X), dried over Na2SO4 and concentrated. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford the title compound (90 mg, 49 %) as a white solid. ES / MS, m / z 570.4 [M+H]+.Preparation 550tert-Butyl4-(4-{4-[2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethoxy]-3-cyanopyrazolo[1,5-a]pyridin-6-yl}-5-methylpyrazol-1-yl)piperidine-1-carboxylateTo a stirred mixture of PPh3 (9.93 g, 97.87 mmol) in THF (30mL) is added DIAD (7.66 g, 37.87 mmol) dropwise at 0 °C under N2. The reaction is stirred at 0 °C for 0.5 hr under N2. To the mixture is added 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (1.93 g, 7.10 mmol) and tert-butyl 4-(4-{3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl}-5-methylpyrazol-1-yl)piperidine-1-carboxylate (2 g, 4.73 mmol) in THF (20 mL). The resulting mixture is stirred for 2 hr at RT then concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 80% to 100% ACN in H2O (0.1% NH4HCO3) to give the title compound as a white solid (2.7 g, 85.9%). ES / MS, m / z 676.4 [M+H]+.Preparation 551tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateTo PPh3 (789.88 mg, 3.01 mmol) in THF (15 mL) is added DIAD (568.36 mg, 2.811 mmol) dropwise at 0 °C under N2. The reaction is stirred at 0 °C for 0.5 hr. To the mixture is added to tert-butyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (400 mg, 1.00 mmol) and 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (408.68 mg, 1.51 mmol) in THF (10 mL). After stirring 2 hr at RT, the reaction is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 70% to 80% ACN in H2O (0.1% NH4HCO3) to give the title compound as a light-brown oil (450 mg, 68.77%). ES / MS, m / z 652.4 [M+H]+.Preparation 552 tert-Butyl 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylateDEAD (185.1 mg, 1.06 mmol) is added to a stirred solution of PPh3 (278.7 mg,1.06 mmol) in THF (5.0 mL) at 0 °C under N2 After the mixture is stirred for 30 min at 0°C under N2, a solution of tert-butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (150.0 mg, 0.35 mmol) and (1S)-1-(5-fluoropyridin-2-yl)ethanol (60.0 mg, 0.425 mmol) in THF (5.0 mL) is added to the mixture at RT under N2 and stirred overnight at RT. The mixture is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography withthe following conditions: Column, C18; eluting with a gradient of 50% to 70% ACN in H2O (0.1% NH4HCO3) to give the title compound as a yellow solid (80.0 mg, 41.3%). ES / MS m / z 547.2 [M+H]+.Preparation 553tert-Butyl 4-[4-[3-cyano-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateDIAD (334.25 mg, 1.65 mmol) is added dropwise to a stirred mixture of PPh3(464.52 mg, 1.77 mmol) in THF (10 mL) at 0 °C under N2 and the mixture is stirred for30 min. at 0 °C under N2. To the mixture is added to 1-[5-(trifluoromethyl)pyridin-3-yl]ethanol (135.42 mg, 0.71 mmol) and tert -butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (250.00 mg, 0.59 mmol) in THF (20 mL). The mixture is stirred overnight at RT and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18; eluting with 0 to 100% ACN in H2O (0.1% FA) give the title compound (150 mg, 42.59%) as an off-white solid. ES+H, m / z 596.9 [M+H]+Preparation 554tert-Butyl 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateDIAD (171.90 mg, 0.85 mmol) is added dropwise to a stirred mixture of PPh3 (241.55 mg, 0.92 mmol) in THF (10.00 mL) at 0 °C under N2. The mixture is stirred for 30 min. at 0 °C under N2, then the mixture is added to 1-(5-fluoropyridin-2-yl)-2-methoxyethanol (133.39 mg, 0.78 mmol) and tert -butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (300.00 mg, 0.71 mmol) in THF (10 mL). The mixture is stirred for 2 hr at RT under N2 and concentrated under vacuum. The residue is purified by reversed Combi-flash chromatography with the following conditions: Eluting with 55% to 60% ACN in H2O (0.1% NH4HCO3) to give the title compound (160 mg, 39.17%) as an off-white solid. ES / MS, m / z 577.3 [M+H]+.Preparation 555 tert-Butyl 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateDIAD (171.90 mg, 0.85 mmol) is added dropwise to a stirred mixture of PPh3 (241.55 mg, 0.92 mmol) in THF (10.0 mL) at 0 °C under N2 and the mixture is stirred for 30 min at 0 °C under N2. The mixture is added to 1-(5-fluoropyridin-2-yl)propan-1-ol (120.92 mg, 0.78 mmol) and tert-butyl-4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (300.00 mg, 0.71 mmol) in THF (10 mL). The mixture is stirred for 2 hr at RT under N2. The mixture is concentrated under reduced pressure and the residue is purified by reversed Combi-flash chromatography with the following conditions: Eluting with 55% to 60% ACN in H2O (0.1% NH4HCO3) to give the title compound (210 mg, 52.87%) as a grey solid. ES / MS m / z 561.5 [M+H]+.Preparation 556 tert-Butyl 4-[4-[3-cyano-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylateDIAD (143.25 mg, 0.71 mmol) is added dropwise to a stirred mixture of PPh3 (201.29 mg, 0.77 mmol) in THF (15.00 mL) at 0 °C under N2 and the mixture is stirred for 30 min at 0 °C under N2. To the mixture is added to 1-(5-fluoropyridin-2-yl)-5   2-methoxyethanol(111.16 mg, 0.65 mmol) and tert -butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (250.00 mg, 0.59 mmol) in THF (15 mL). The mixture is stirred for 2 hr at RT under N2 and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Eluting with 55% to 60% ACN in10   H2O (0.1% NH4HCO3) to give the title compound (200 mg, 58.75%) as an off-whitesolid. ES / MS m / z 577.1+.The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the15 reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. DIAD, DIEA and DMAP can also be used in lieu of DEAD.Temperature is varied from 0 °C to 80 °C. Polymer supported PPh3 can be used in place of PPh3.Table 45Prep No. Chemical Name Structure ES / MS m / z [[M+H]+ 5571 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-(oxan-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 -methylpyrazol-1-yl)piperidine-1 -carboxylate N=x O ____       \ H 1 4oKnOnV^? 535.3 5581 tert-Butyl 4-(4-[3-cyano-4-[(3-fluoropyridin-2-yl)methoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 -methylpyrazol-1-yl)piperidine-1 -carboxylate N=\ 0       \ X J N F        N 532.3 559 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-(3-fluoropyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 -methylpyrazol-1-yl)piperidine-1 -carboxylate N=\ 0           \ 1] X NX 546.2 5601 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1 -(pyrazin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 -methylpyrazol-1-yl)piperidine-1 -carboxylate N=\ n4^sn O ____      \ H I i —F-o   \ / J       1 r NX 529.3 5611 tert-Butyl 4-(4-[3-cyano-4-[(1R)- 1-(2-methylpyrazol-3-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 -methylpyrazol-1-yl)piperidine-1 -carboxylate N=\ 1     \ N 4—SN O ,s \ f X । 4-444^45 4° zN-N 531.3 562 tert-Butyl 4-(4-[3-cyano-4-[(1R)- 1-(pyridin-2-yl)propoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 -methylpyrazol-1-yl)piperidine-1 -carboxylate N=\ ,N / —SN o          \ Ji JL N\Z Xni 40 v> nj 542.3 563 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-(1-methylpyrazol-3-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5 - N=\ 1      \ N —SN 0 __\ f J -r° 531.4 methylpyrazol-1-yl)piperidine-1 -carboxylate 564 tert-Butyl 4-(4-(3-cyano-4-(((7R)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl- 1H-1,2,3-triazol-1- yl)piperidine-1 -carboxylate N=\ 1     \ N #—SN 0    __\ —p°  \ /         \ 541.3 5652 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-cyclohexylethoxy]pyrazo lo[ 1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1 -yl)piperidine-1 -carboxylate N=x 0     ____ \ f I 4oKnC>nV^o 1               N=N 534.5 5661 tert-Butyl 4-[4-(3-cyano-4-[[2-(pyridin-2-yl)propan-2-yl] oxy]pyrazolo [1,5-a]pyridin-6-yl)-5 -methylpyrazol-1- yl]piperidine-1 -carboxylate 0 ,z ia 7=7         III z 542.4 567 tert-Butyl 4-[4-[3-cyano-4-[2-methoxy-1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate N=\ o / \ j T \ 1-N                       F F / ° n=n o      J 627.2 568 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-pyrazol-1 -yl]piperidine-1 -carboxylate o    / —\ \     n Vn'^I       I #-0  \- / 546.4 569 tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-cyano-imidazo[1,2-a]pyridin-7-yl]-5-methyl-pyrazol-1 -yl]piperidine-1 -carboxylate J-A n^"^n \       N7 / N^ -V O     N N A## 7           . . OO X 1 Si--      '<-"^f 677.5 5705 tert-Butyl 4-[4-[4-[3-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)propoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate 1    \ i \ A 691.4 571 tert-Butyl 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5 -a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ 1      \ ,na \ > n J AA ^^ -Ao VJ N-N 522.4 5726 tert-Butyl 4-[4-[3-cyano-4-[ 1 -(5-methylpyridazin-3-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ 1 \ N / 544.3 5731 tert-Butyl 4-[4-[3-cyano-5-[[(7R)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl] oxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate • z z 541.3 5747 tert-Butyl 4-[4-[3-cyano-4-[1-(4-isoquinolyl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate - Xx / / / ° \ Xi z’ t / j 579.3 5756 tert-Butyl 4-[4-[3-cyano-4-[1-(7-fluoro-4-isoquinolyl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate ANANbAAXlF 596.3 5767 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(4-isoquinolyl)ethoxy]-3-cyano-pyrazolo [1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=a AA^n V        1     O a.oKANNJ AJ /                 \ _O L JI \ Si       N^ d 1 709.3 5775 tert-Butyl 4-[4-[3-cyano-4-[ 1-(5-methylthiazol-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate AAXA 549.3 5788 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(2-pyridyl)propoxy] imidazo [ 1, 2-a]pyridin-7 -yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate, Isomer 2 / ''N   '-N 0 VN J      1 A N= A) 543.3 5799 tert-Butyl 4-[4-[3-cyano-4-[2-fluoro-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5 -a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate 1    \ °v x-\ lWo /            F FAf 508.7 [M+H-C4H9]+ 5807 tert-butyl 4-[4-[3-cyano-4-[cyclopropyl-(5-fluoro-2-pyridyl)methoxy]pyrazolo[ 1 ,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ V n^f 572.8 5817 tert-Butyl 4-[4-[3-cyano-4-[(1 -fluorocyclopropyl)-(5 -fluoro-2- pyridyl)methoxy]pyrazolo[ 1 ,5-a]pyridin-6-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate 590.8 58210 tert-Butyl 4-[4-[3-cyano-4-[(5-fluoro-2-pyridyl)-[1 -(trifluoromethyl)cyclopropyl ]methoxy]pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ o aXXX \                    a i -4-o  — / n'n AA\^\ /           A FjF     F F 641.3 58315 tert-Butyl 2-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-pyrazol-1-yl]-7- ,z z ____ x A —w     / A F 716.5 azaspiro[3.5]nonane-7-carboxylate 5847 tert-Butyl 4-[4-[3-cyano-4-[1-(2-methyltriazol-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ ° k,X4o n-n \ 533.2 5857 tert-Butyl 4-[4-[3-cyano-4-[ 1-(1-isopropyltriazol-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate z i 533.2 5864 tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-[5-(trifluoromethyl)-3-pyridyl]ethoxy] -3-cyano-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate n Xo vV n'n 3'^ \ Si 1       F^F 727.4 5874 tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(3,5-difluoro-2-pyridyl)ethoxy] -3-cyano-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate / \ 333^0 F \            VN J         I    1 4-0   - / N'N d 1 695.4 58811 tert-Butyl 2-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-cyano-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate z 717.4 58912 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl] -5-methyl-triazol-1 -yl]piperidine-1 -carboxylate N=\ ° / —\ \ ^N\ 3N Fl A —0  \- / N'N \ Si       ;'^ F d 1 677.4 59013 tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-chloro-2-pyridyl)ethoxy]-3-cyano-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate O   / — )—N I            1 ' n-n -sr° N^ci 1 693.6 5915 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-[5-(trifluoromethyl)-3-pyridyl]ethoxy] -3-cyano-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate 0 / — \ M \ Jl I / Nn^n V 1       F^F 727.4 59214 tert-Butyl 4-[4-[5-[3-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)propoxy]-3-cyano-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1 -carboxylate o   / — \ ^N\ 2 —cp       \__ 691.5 5938 tert-Butyl 4-[4-[3-cyano-5-[2-methoxy-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylate, Isomer 1 o / — z IZ" xo~. 559.3 5948 tert-Butyl 4-[4-[3-cyano-5-[3-methyl-1-(2-pyridyl)butoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1 -yl]piperidine-1 -carboxylat...

Claims

CLAIMS1. A compound of the formula:whereinA is pyrazole, triazole, thiadiazole or oxadiazole, substituted with R1 and R1A;R1 is hydrogen or C1-C3 alkyl;R1A is hydrogen, halo, CN, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3;X1 and X2 are independently selected from N and C, wherein when one of X1 or X2 is N the other is C;X3 is N or CH;X4 is N or C-R9;Y is NH, O, S or a bond;Y1 is a bond, CHR7, CH2-CHR7, CHR7-CH2, CF2, CH2-CF2 or CF2-CH2;Y2 is a bond, CHR3, CH2-CHR3, CHR3-CH2, CF2, CH2-CF2 or CF2-CH2;Y3 is CR4R5 or CF2;Y4 is CR3R4, or CF2;Z is a bond, CHR9A, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine;Z1 is a bond when Z is a bond, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine, or Z1 is CH2 or CH2-CH2 when Z is CHR9A;Z2 is a bond, C(O), SO2 or -NR4C(O);Z3 is a bond, C(O), SO2 or -NR4C(O);R2 is 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-R11 and 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;R3 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R3 is fused with R5 or R7 to form CH2, CH2-CH2 or CH2OCH2;R4 is hydrogen or C1-C3 alkyl;R4A is hydrogen, halo, OH, or C1-C3 alkyl;R5 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2;R6 is 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;R7 is hydrogen, F, OH, OCH3, C1-C3 alkyl or is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2;R8 is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R8A is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R9 is hydrogen, C1-C3 alkyl, or is fused with R9A to form CH2 or CH2-CH2;R10 is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R11 is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-C3 alkyl)2, wherein C1-C4 alkyl, C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with oneor more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN;R12 is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-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, R10 and R8A are optionally substituted with one or more substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R12 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;or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein X1 is C, and X2 is N; or X1 is N, and X2 is C.

3. The compound according to claim 1 of the formula:or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 of the formula:or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-4, wherein X3 is CH, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-5, wherein R1A is hydrogen or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1-5, wherein R1A is hydrogen or CH3, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1-5, wherein R1A is hydrogen, or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1-8, wherein R9 is hydrogen or is fused with R9A to form CH2 or CH2-CH2, or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1-9, wherein R6 is CN, F, Cl, CH3, CF3 or cyclopropyl, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein R6 is CN, F or Cl, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1-11 wherein A is pyrazole or triazole, substituted with R1and R1A, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12, wherein A is triazole, substituted with R1and R1A, or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1-13, wherein Z is a bond, cyclobutyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14, wherein Z is a bond, cyclobutyl, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1-15, wherein R2 is 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-R11 and 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 1-15, wherein R2 is selected from:optionally substituted with one, two, three or four substituents independently selectedfrom halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10, whereinC1-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 thereof.10   18. The compound according to claim 17, wherein R2 is selected from:optionally substituted with one, two, three or four substituents independently selectedfrom halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11 and R10, wherein15   C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituentsindependently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN,wherein * indicates the connection point to Y, or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 17-18, wherein R2 is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl, or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1-19, wherein R10 is 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally fused with R8A, or a pharmaceutically acceptable salt thereof.

21. The compound according to any one of claims 1-19, wherein R10 is 5-6 membered heteroaryl, optionally fused with R8A, or a pharmaceutically acceptable salt thereof.

22. The compound according to any one of claims 1-21, wherein R10 and R8A are optionally substituted with one, two or three substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R12 wherein 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.

23. The compound according to any one of claims 1-21, wherein R10 and R8A are optionally substituted with one, two or three substituents independently selected from F, Cl, CN, CH3, CH2F, CHF2, CF3, -OCH3, -C(O)NH2 and -S(O)2CH3, or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1-23, wherein Y1 is a bond, CHR7, CH2-CHR7 or CHR7-CH2, wherein R7 is selected from hydrogen, F, OH and CH3, or a pharmaceutically acceptable salt thereof.

25. The compound according to any one of claims 1-24, wherein Y2 is a bond, CHR3, CH2-CHR3 or CHR3-CH2, wherein R3 is selected from hydrogen, F, OH and CH3, or a pharmaceutically acceptable salt thereof.

26. The compound according to any one of claims 1-25, wherein Y3 is CR4R5 or CF2 wherein R4 is hydrogen or CH3 and R5 is hydrogen, F, OH or CH3, or a pharmaceutically acceptable salt thereof.

27. The compound according to any one of claims 1-25, wherein Y3 is CR4R5 wherein R4 is hydrogen and R5 is fused with one R3 to form CH2, CH2-CH2 or CH2OCH2, or a pharmaceutically acceptable salt thereof.

28. The compound according to any one of claims 1-27, wherein Y4 is CR3R4 or CF2 wherein R4 is hydrogen or CH3 and R3 is hydrogen, F, OH or CH3, or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1 of the formula:whereinA is pyrazole, triazole, thiadiazole or oxadiazole, optionally substituted with R1;R1 is C1-C3 alkyl;X1 and X2 are independently selected from N and C, wherein when one of X1 or X2 is N the other is C;Y is NH, O, or a bond;Y1 is a bond, CHR7, CH2-CHR7 or CHR7-CH2;Y2 is a bond, CH2, CF2, CHR3, CH2-CHR3 or CHR3-CH2;Z is a bond, CHR9A, azetidine, pyrrolidine or piperidine;Z1 is a bond when Z is a bond, azetidine, pyrrolidine or piperidine, or Z1 is CH2 or CH2-CH2 when Z is CHR9A;R2 is C1-C5 alkyl or R8, wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R10;R3 is hydrogen, C1-C3 alkyl, or one R3 is fused with R5 or R7 to form CH2 or CH2-CH2;R4 is hydrogen, or C1-C3 alkyl;R5 is hydrogen, or is fused with one R3 to form CH2 or CH2-CH2;R6 is hydrogen, CH3, CN, Cl or F;R7 is hydrogen, or is fused with one R3 to form CH2 or CH2-CH2;R8 is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R8A is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R9 is hydrogen or is fused with R9A to form CH2 or CH2-CH2;R10 is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A; andR8, R10 and R8A are optionally substituted with one or more substituents independently selected from halo, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)2CH3, C(O)NH2, N,N-dimethylamine and C(O)N,N-dimethylamine;or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 29 wherein X1 is C, and X2 is N; or X1 is N, and X2 is C.

31. The compound according to claim 29 of the formula:or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 29 of the formula:or a pharmaceutically acceptable salt thereof.

33. The compound according to any one of claims 29-32, wherein A is pyrazole or triazole, optionally substituted with R1, or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 33, wherein A is triazole, optionally substituted with R1, or a pharmaceutically acceptable salt thereof.

35. The compound according to any one of claims 1-34, wherein R1 is methyl, or a pharmaceutically acceptable salt thereof.

36. The compound according to any one of claims 1-35, wherein Y is NH or O, or a pharmaceutically acceptable salt thereof.

37. The compound according to claim 36, wherein Y is O, or a pharmaceutically acceptable salt thereof.

38. The compound according to any one of claims 29-37, wherein R2 is C1-C3 alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R10, or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 37, wherein R2 is selected from:optionally substituted with one or two substituents independently selected from OH, CF3and methoxy, wherein * indicates the connection point to Y, or a pharmaceutically acceptable salt thereof.

40. The compound according to any one of claims 29-39, wherein R10 is 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally fused with R8A, or a pharmaceutically acceptable salt thereof.

41. The compound according to claim 40, wherein R10 is 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, or a pharmaceutically acceptable salt thereof.

42. The compound according to claim 40, wherein R10 is 5-6 membered heteroaryl, or a pharmaceutically acceptable salt thereof.

43. The compound according to any one of claims 1-42, wherein R6 is CN or Cl, or a pharmaceutically acceptable salt thereof.

44. The compound according to claim 43, wherein R6 is CN, or a pharmaceutically acceptable salt thereof.

45. The compound according to claim 43, wherein R6 is Cl, or a pharmaceutically acceptable salt thereof.

46. The compound according to any one of claims 1-45, wherein Z is a bond, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.

47. The compound according to any one of claims 1-46, wherein Z1 is a bond, or a pharmaceutically acceptable salt thereof.5   48. The compound according to any one of claims 1-45, wherein Z is CHR9A, Z1 isCH2 and R9 is fused with R9A to form CH2, or a pharmaceutically acceptable salt thereof.

49.    The compound according to any one of claims 29-48, wherein R3 and R4 arehydrogen or CH3, or a pharmaceutically acceptable salt thereof.

50.    The compound according to any one of claims 29-49, wherein R5 is hydrogen, or a10 pharmaceutically acceptable salt thereof.

51.    The compound according to any one of claims 29-49, wherein R5 is fused withone R3 to form CH2-CH2, or a pharmaceutically acceptable salt thereof.

52. The compound according to any one of claims 29-51, wherein Y1 is a bond or CH2, or a pharmaceutically acceptable salt thereof.15   53.    The compound according to any one of claims 29-52, wherein Y2 is a bond orCH2, or a pharmaceutically acceptable salt thereof.

54. The compound according to claim 1, selected from the group consisting of:For a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claim 1-54, and a pharmaceutically acceptable carrier, diluent or excipient.

56. Use of a compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.

57. The use of claim 56 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, non-muscle 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.

58. The use of claim 57 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, non-muscle invasive bladder cancer, muscle invasive bladder cancer upper tract cancer, urothelialupper tract cancer, and glioblastoma.

59. The use of claim 58, wherein the cancer is selected from the group consisting of bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer and muscleinvasive bladder cancer.

60. The use according to any one of claims 56-59, wherein the cancer is FGFR3-associated cancer.

61. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-54, for use in therapy.

62. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-54, for use in the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.

63. The compound, or a pharmaceutically acceptable salt thereof, according to claim 62, 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, non-muscle 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.

64. The compound, or a pharmaceutically acceptable salt thereof, according to claim 62, 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, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer and glioblastoma.

65. The compound, or a pharmaceutically acceptable salt thereof, according to claim 62, 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.

66. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 61-65, wherein the cancer is FGFR3-associated cancer.

67. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 54 and 61 to 66 substantially as herein described with reference to any example thereof.

68. A pharmaceutical composition according to claim 55 substantially as herein5 described with reference to any example thereof.

69. Use according to any one of claims 56 to 60 substantially as herein described with reference to any example thereof.

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