FGFR inhibitor compounds

Abstract

A compound having the structure of formula (I) below, or a stereoisomer, salt, or tautomer thereof, wherein R 1 , R 2 , R 5 , A, B, X, and Y are as defined herein. Pharmaceutical compositions containing the compounds and their use in methods of treating diseases are also described. The present disclosure relates to substituted pyrazolopyridine compounds that act as fibroblast growth factor receptor tyrosine kinase (FGFR) inhibitors. The present disclosure also provides compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as the use of the compounds for the treatment of abnormal cell growth (e.g., cancer) in a subject. TIFF2026501820000868.tif59165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 63 / 479,292, filed January 10, 2023, and 63 / 516,701, filed July 31, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to substituted pyrazolopyridine compounds that act as fibroblast growth factor receptor tyrosine kinase (FGFR) inhibitors. The present disclosure also provides compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as uses of the compounds for treating abnormal cell growth (e.g., cancer) in a subject. [Background technology]

[0003] Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate a wide range of physiological cellular processes, such as embryonic development, differentiation, growth, survival, migration, and angiogenesis. There are five FGFRs, four of which (FGFR1-4) are highly conserved single-transmembrane tyrosine kinase receptors. Binding of FGFs to FGFRs results in receptor dimerization and transphosphorylation of the tyrosine kinase domain. Dysregulation of the FGF signaling pathway underlies various diseases associated with increased FGF expression.

[0004] There remains a need to discover FGFR inhibitors with enhanced activity profiles that may be useful in the treatment of FGFR-mutated cancers or other proliferative diseases or conditions. Summary of the Invention [Means for solving the problem]

[0005] Briefly, the disclosure provides compounds (eg, stereoisomers, pharmaceutically acceptable salts, or tautomers) that can be used alone or in combination with other therapeutic agents.

[0006] In one embodiment, a compound having the structure of Formula (I): [ka] or a stereoisomer, salt, or tautomer thereof is provided, wherein R 1 , R 2 , R 5 , A, B, X, and Y are as defined herein.

[0007] Pharmaceutical compositions comprising one or more of the compounds of formula (I) above and a therapeutic agent are also provided.

[0008] In another embodiment, there is provided a method of treatment by administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) as described above to treat a disease.

[0009] Various aspects and embodiments will be described in further detail below. Such aspects and embodiments may take many different forms, and the illustrative examples disclosed herein are not intended to be limiting; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. DETAILED DESCRIPTION OF THE INVENTION

[0010] I. Definition For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0011] Where a range of values ​​is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is intended to be encompassed within the scope of the disclosure. For example, if a range of 1 mm to 8 mm is stated, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, and 7 mm are also expressly disclosed, and ranges of values ​​above 1 mm and below 8 mm are also expressly intended to be disclosed.

[0012] The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and so forth.

[0013] The term "about" is specifically intended to encompass a deviation of plus or minus 5 percent with respect to a given quantity.

[0014] The compositions of the present disclosure can comprise, consist essentially of, or consist of the disclosed components.

[0015] All percentages, parts, and ratios are based on the total weight of the composition and all measurements are taken at about 25 degrees unless otherwise specified.

[0016] As used in this specification and the appended claims, unless specifically stated to the contrary, the following meanings shall be used: "Amino" refers to the radical -NH2, -NHR, or -NR2. "Cyano" refers to the -CN radical. "Hydroxyl" refers to the --OH radical. "Imino" refers to a =NH or =NR substituent. "Nitro" refers to the -NO2 radical. "Oxo" refers to the =O substituent. "Thio" refers to the ═S substituent. "Trifluoromethyl" refers to the -CF3 radical. Hydrazide or hydrazino refers to an N-N substituent. Each R is a compatible substituent as described herein. When an R group is chiral, isomers are contemplated and included herein.

[0017] "Alkyl" refers to a linear saturated acyclic monovalent hydrocarbon radical or a branched saturated acyclic monovalent hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms or 1 to 6 carbon atoms, attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Optionally substituted alkyl radicals, valence permitting, can independently include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, -OR, -OR- ... ’ , -OC(O)-R ’ , -N(R ’ )2, -C(O)R'', -C(O)OR ’ , -C(O)N(R ’ )2, -N(R ’ )C(O)OR''', -N(R ’ )C(O)R''', -N(R ’ )S(O) t R''' (t is 1 or 2), -S(O) t OR'''(t is 1 or 2), -S(O) p R''' (p is 0, 1, or 2), and -S(O) t N(R ’ )2 (t is 1 or 2), and each R ’is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl; each R" is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl; and each R'" is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0018] "Alkoxy" means a group of the formula -OR a refers to the radical of R a is an alkyl radical as defined above containing 1 to 12 carbon atoms. The alkyl portion of an optionally substituted alkoxy radical is optionally substituted as defined above for an alkyl radical.

[0019] "Alkoxyalkyl" refers to a group of the formula -R a -OR b refers to the radical of R a is alkylene, and R b is alkyl as defined above. The alkyl and alkylene portions of an optionally substituted alkoxyalkyl radical are optionally substituted as defined above for the alkyl radical and alkylene chain, respectively.

[0020] "Aralkyl" is a group of the formula -R a -R b refers to the radical of R a is alkylene, and R b is aryl as described herein. The alkylene and aryl portions of an optionally substituted aralkyl are optionally substituted as described herein for alkylene and aryl, respectively.

[0021] "Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system radical containing 6 to 18 carbon atoms, with polycyclic aryl ring systems being bicyclic, tricyclic, or tetracyclic ring systems. Aryl radicals include, but are not limited to, groups such as fluorenyl, phenyl, naphthyl, and the like. Optionally substituted aryl is independently alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl, -R"-OR. ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (t is 1 or 2), -R''-S(O) t OR'''(t is 1 or 2), -R''-S(O) p R''' (p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (t is 1 or 2), and each R ’ are independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R" is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R'" is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, or heteroaryl.

[0022] "Arylalkoxy" refers to a group of formula -OR, where R is aralkyl. An optionally substituted arylalkoxy is an arylalkoxy optionally substituted as described herein for aralkyl. In some embodiments, the arylalkoxy is benzyloxy.

[0023] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the rest of the molecule by a single bond. Polycyclic hydrocarbon radicals are bicyclic, tricyclic, or tetracyclic ring systems. Unsaturated cycloalkyls contain one, two, or three carbon-carbon double bonds and / or one carbon-carbon triple bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. Optionally substituted cycloalkyls are independently alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R"-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (t is 1 or 2), -R''-S(O) t OR'''(t is 1 or 2), -R''-S(O) p R''' (p is 0, 1, or 2), and -R''-S(O) t N(R ’)2 (where t is 1 or 2), and is a cycloalkyl radical; ’ are independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R" is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R'" is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl.

[0024] A "deuterated compound" is a compound in which one or more hydrogen atoms have been replaced with deuterium atoms. A deuterated drug may be a derivative of an active compound. A deuterated drug may be a prodrug. Deuteration may alter the physical properties, metabolic properties, activity, or safety of the drug.

[0025] "Derivatives" are related chemical species that can be derived from similar compounds by chemical reaction. They may include slight chemical modifications, replacement of atoms with deuterated atoms, replacement of atoms with stable or radioactive isotopes, or other modifications that impart desirable properties to the compound.

[0026] "Fused" refers to any ring system described herein that is fused to an existing ring structure in the compounds of the present invention. When the fused ring system is a heterocyclyl or heteroaryl, any carbon atom on the existing ring structure that becomes part of the fused ring system may be replaced with a nitrogen atom.

[0027] "Halo" refers to a halogen substituent (bromo, chloro, fluoro, and iodo).

[0028] "Haloalkyl" refers to an alkyl radical as defined above that is further substituted with one or more halogen substituents. The number of halo substituents contained in a haloalkyl ranges from 1 to the total number of hydrogen atoms that can be replaced by halo substituents (e.g., perfluoroalkyl). Non-limiting examples of haloalkyl include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. In the case of an optionally substituted haloalkyl, a hydrogen atom bonded to a carbon atom of the alkyl portion of the haloalkyl radical can be optionally substituted with a substituent as defined above for an optionally substituted alkyl.

[0029] "Haloalkenyl" refers to an alkenyl radical, as defined above, further substituted with one or more halo substituents. The number of halo substituents contained in a haloalkenyl ranges from 1 to the total number of hydrogen atoms replaceable with halo substituents (e.g., perfluoroalkenyl). Non-limiting examples of haloalkenyls include 2,2-difluoroethenyl, 3-chloroprop-1-enyl, and the like. In the case of an optionally substituted haloalkenyl, a hydrogen atom bonded to a carbon atom of the alkenyl portion of the haloalkenyl radical can be optionally substituted with a substituent as defined above for an optionally substituted alkenyl group.

[0030] "Haloalkynyl" refers to an alkynyl radical, as defined above, further substituted with one or more halo substituents. The number of halo substituents contained in the haloalkynyl ranges from 1 to the total number of hydrogen atoms replaceable with halo substituents (e.g., perfluoroalkynyl). Non-limiting examples of haloalkynyl include 3-chloroprop-1-ynyl and the like. The alkynyl portion of the haloalkynyl radical may be further optionally substituted as defined above for an alkynyl group.

[0031] "Heteroarylalkyl" refers to a group of the formula -R a -R b refers to the radical of R ais alkylene, and R b is heteroaryl as described herein. The alkylene and heteroaryl portions of an optionally substituted heteroarylalkyl are optionally substituted as described herein for alkylene and heteroaryl, respectively.

[0032] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring system radical having 2 to 12 carbon atoms and a total of 1 to 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Heterocyclic radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems. Bicyclic, tricyclic, or tetracyclic heterocycles are fused, spirocyclic, and / or bridged ring systems. Heterocyclyl radicals can be saturated or unsaturated. Unsaturated heterocyclyls contain one, two, or three carbon-carbon double bonds and / or one carbon-carbon triple bond. Optionally substituted heterocyclyls are independently alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R"-OR. ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (t is 1 or 2), -R''-S(O) t OR'''(t is 1 or 2), -R''-S(O) p R''' (p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (t is 1 or 2), and each R’ are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R''' is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R''' is independently alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atom within a heterocyclyl radical can be optionally oxidized (when the substituent is oxo and present on the heteroatom); the nitrogen atom can be optionally oxidized (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (t is 1 or 2), -R''-S(O) t OR'''(t is 1 or 2), -R''-S(O) p R''' (p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (t is 1 or 2), R″ is a straight or branched alkylene or alkenylene chain, R ’and R'" where as defined above may be optionally quaternized. Examples of optionally substituted heterocyclic radicals include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0033] "Heterocyclylene" refers to a heterocyclyl in which one hydrogen atom is replaced by a valence. An optionally substituted heterocyclylene is optionally substituted as described herein for heterocyclyl.

[0034] "Heteroaryl" refers to a 5- to 18-membered ring system radical containing at least one aromatic ring, having 1 to 17 carbon atoms, and a total of 1 to 10 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heteroaryl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems. Bicyclic, tricyclic, or tetracyclic heteroaryl radicals are fused and / or bridged ring systems. Optionally substituted heteroaryl is independently alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, -R"-OR. ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’)2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (t is 1 or 2), -R''-S(O) t OR'''(t is 1 or 2), -R''-S(O) t R''' (p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (t is 1 or 2), and each R ’ are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl radicals; each R''' is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R''' is alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atom in a heterocyclyl radical may be optionally oxidized (if the substituent is oxo and present on the heteroatom), provided that at least one ring in the heteroaryl remains aromatic, and the nitrogen atom may be oxidized (if the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (t is 1 or 2), -R''-S(O) t OR'''(t is 1 or 2), -R''-S(O) pR''' (p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (t is 1 or 2), R″ is a linear or branched alkylene or alkenylene chain, R ’ and R'" are as defined above), may be optionally quaternized, provided that at least one ring within the heteroaryl remains aromatic. Examples of optionally substituted heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl ... Lanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0035] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, salts, compositions, dosage forms, etc. that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and / or other mammals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a federal or state regulatory agency, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia, for use in mammals (e.g., animals), and more particularly, humans.

[0036] A "prodrug" is a compound that is metabolized or otherwise chemically converted into an active moiety after administration. A prodrug can be a derivative of an active compound. A prodrug may or may not be active before being converted to its active form in vivo.

[0037] The term "treating" is used herein with reference to, for example, methods of treating an inflammatory disease or gastrointestinal disease, and generally includes the administration of a compound or composition that reduces the frequency of or delays the onset of symptoms of a medical condition (e.g., an autoimmune disease, an inflammatory disease, a gastrointestinal disease) in a subject compared to a subject not receiving the compound or composition. This can include reversing, reducing, or preventing symptoms, clinical signs, and the underlying pathology of a condition in a manner that improves or stabilizes the subject's condition (e.g., regression of symptoms of an autoimmune disease or inflammatory disease, e.g., improvement in MAYO score in the treatment of ulcerative colitis).

[0038] The embodiments disclosed herein include all pharmaceutically acceptable compounds of compounds (I)-(IL) that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 11 2 H, 3 H, 11 C.13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I). These radiolabeled compounds may be useful, for example, to determine or measure the efficacy of compounds by characterizing the site and mode of action, or binding affinity to pharmacologically important sites of action. Certain isotopically labeled (I)-(IL) compounds (e.g., those incorporating a radioisotope) are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) is particularly useful for this purpose given its ease of incorporation and simple means of detection.

[0039] Heavy isotopes (e.g., deuterium, i.e., 2 H) may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances.

[0040] Substitution with positron-emitting isotopes, such as C, F, O, and N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds (I)-(IL) can generally be prepared by conventional techniques known to those skilled in the art, or by analogy with the processes described in the preparations and examples set forth below, using an appropriate isotopically labeled reagent in place of the previously employed non-labeled reagent.

[0041] Embodiments disclosed herein include in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like, primarily by enzymatic processes, of the administered compound. Accordingly, the present disclosure includes compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a detectable amount of a radiolabeled compound of the present disclosure to an animal (e.g., rat, mouse, guinea pig, monkey) or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0042] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0043] "Pharmaceutically acceptable acid addition salts" refer to those acids which retain the biological effectiveness and properties of the free base and which are biologically or otherwise undesirable, such as inorganic acids (e.g., but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, etc.). , gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid (TFA), undecylenic acid, etc.

[0044] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and that are biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines (e.g., naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0045] A "pharmaceutical composition" refers to a combination of a compound of the present disclosure with a vehicle generally accepted in the art for delivery of a biologically active compound to a mammal (e.g., a human). Such vehicles include all pharmaceutically acceptable carriers, diluents, and excipients.

[0046] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound of the present disclosure that, when administered to a mammal (preferably a human), is sufficient to effect treatment in the mammal (preferably a human). The amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the method of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0047] "Stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. The present disclosure also contemplates "diastereomers," which refer to non-mirror images of non-identical stereoisomers. Diastereomers occur when two or more stereoisomers of a compound have different configurations at one or more equivalent stereocenters and are not mirror images of one another.

[0048] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any such compounds.

[0049] As used herein, unless otherwise indicated, "abnormal cell growth" means cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous).

[0050] Less than the maximum of the disclosure may be claimed for any reason, by reserving the right to exclude or exclude any individual member of any such group (e.g., sub-category or combination of sub-ranges within a group), which may be claimed according to ranges or in any similar manner. Further, less than the maximum of the disclosure may be claimed for any reason, by reserving the right to exclude or exclude any individual substituent, analog, compound, ligand, structure, or group thereof, or any member of a claimed group.

[0051] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure will control.

[0052] II. Compounds The compounds described herein are FGFR inhibitor compounds. In one embodiment, the compounds have the structure of formula (I): [ka] or a stereoisomer, salt, or tautomer thereof, wherein R 1 is -CN, -Cl, -Br, -CF2H, or -CF3; R 2 is C1-C6 alkyl, C1-C6 heteroalkyl, aryl, heteroaryl, fused bicyclic, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, or -NR 3 R 4 and;R 3 and R 4 are each independently H or C1-C4 alkyl; R 5 is -H, -OH, -CN, -F, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, 5- to 6-membered heteroaryl, C3-C8 heterocycloalkyl, -C(=O)R 6, -OC(=O)R 6 , -CH2C(=O)OR 6 , -NR 7 R 8 , -NR 7 C(=O)R 6 , -NR 7 C(=O)OR 6 , -CH2C(=O)NR 7 N 8 , -NR 7 R 8 CH2C(=O)NR 7 N 8 , -CH2NR 7 C(=O)R 6 , sulfonylmethane, oxo, phosphate, or a combination thereof; R 5 C1-C6 alkyl or C1-C6 heteroalkyl is [ka] or optionally substituted with -OH; R 6 is hydrogen, C1-C4 alkyl, C1-C5 heteroalkyl, or C4-C6 heterocycloalkyl, and C4-C6 heterocycloalkyl is [ka] or halo-substituted; R 7 and R 8 are each independently H, C1-C6 alkyl, C1-C6 alkyl alcohol, sulfonylmethane, C3-C6 cycloalkyl, or 5-6 membered heteroaryl; the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with fluoro, C3-C6 cycloalkyl, or 5-6 membered heteroaryl; X is -(CH2)n-, -(CH2)nO-, -(CHCH3)n-, -(CHCH3)n-(CH2)m-, -(CHCH3)n-(CH2)mO-, or a direct bond; Y is -CH2-, -CHCH3-, -C(CH3)2-, -(CH2) pn is an integer from 1 to 4; m is an integer from 1 to 4; p is an integer from 0 to 4; A is aryl, 5- to 6-membered heteroaryl, halo, or fused heterocycle; and B is C-C cycloalkyl, C-C heterocycloalkyl, fused bicyclic, bridged bicyclic, spirocyclic, or absent.

[0053] In one embodiment, R 1 is -CN, -Cl, -Br, -CFH, or -CF. In some embodiments, R 1 has one of the following structures: [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0054] In one embodiment, the compound has the structure of formula (IA): [ka] or a stereoisomer, salt, or tautomer thereof.

[0055] In one embodiment, X is -(CH2)n-, -(CH2)nO-, -(CHCH3)n-, -(CHCH3)n-(CH2)m-, -(CHCH3)n-(CH2)mO-, or a direct bond. In some embodiments, X is -(CH2)n-. In some embodiments, X is -(CH2)nO-. In some embodiments, X is -(CHCH3)n-. In some embodiments, X is -(CHCH3)n-(CH2)m-. In some embodiments, X is -(CHCH3)n-(CH2)m-. In some embodiments, X is -(CHCH3)n-(CH2)mO-. In some embodiments, X is a direct bond.

[0056] In one embodiment, n is an integer from 1 to 4. In some embodiments, n is an integer from 1 to 2. In some embodiments, n is an integer of 1 or 2. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2.

[0057] In one embodiment, m is an integer from 1 to 4. In some embodiments, m is an integer from 1 to 2. In some embodiments, m is an integer of 1 or 2. In some embodiments, m is an integer of 1. In some embodiments, m is an integer of 2.

[0058] In one embodiment, the compound has the structure of formula (IB): [ka] or a stereoisomer, salt, or tautomer thereof.

[0059] In some embodiments, A is aryl, 5-6 membered heteroaryl, halo, or a fused heterocycle.

[0060] In some embodiments, A is aryl. In some embodiments, A is aryl. In certain embodiments, the aryl of A is phenyl.

[0061] In some embodiments, A is halo. In certain embodiments, the halo of A is -F, -Cl, or -Br. In some embodiments, A is -F. In some embodiments, A is -Cl. In some embodiments, A is -Br.

[0062] In some embodiments, A is a fused heterocycle. In certain embodiments, the fused heterocycle of A is indole, isoindole, benzimidazole, purine, indazole, benzoxazole, benzisoxazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phthalazine, 5H-pyrrolo[2,3-b]pyrazine, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine. In some embodiments, the fused heterocycle of A is indole. In some embodiments, the fused heterocycle of A is isoindole. In some embodiments, the fused heterocycle of A is benzimidazole. In some embodiments, the fused heterocycle of A is a purine. In some embodiments, the fused heterocycle of A is indazole. In some embodiments, the fused heterocycle of A is benzoxazole. In some embodiments, the fused heterocycle of A is benzisoxazole. In some embodiments, the fused heterocycle of A is quinoline. In some embodiments, the fused heterocycle of A is isoquinoline. In some embodiments, the fused heterocycle of A is quinoxaline. In some embodiments, the fused heterocycle of A is quinazoline. In some embodiments, the fused heterocycle of A is cinnoline. In some embodiments, the fused heterocycle of A is phthalazine. In some embodiments, the fused heterocycle of A is 5H-pyrrolo[2,3-b]pyrazine. In some embodiments, the fused heterocycle of A is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine. In some embodiments, the fused heterocycle of A is 5H-pyrrolo[2,3-b]pyrazine or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0063] In some embodiments, A is a 5-6 membered heteroaryl. In some embodiments, A's 5-6 membered heteroaryl is a 5 membered heteroaryl. In certain embodiments, A's 5-6 membered heteroaryl is pyrazole or triazole. In some embodiments, A's 5-6 membered heteroaryl is a 6 membered heteroaryl. In certain embodiments, A's 6 membered heteroaryl is pyridine. In some embodiments, A's 5-6 membered heteroaryl is optionally substituted with C1-C4 alkyl, C1-C4 heteroalkyl, or halo. In some embodiments, A's 5-6 membered heteroaryl is optionally substituted with methyl (C1 alkyl), cyano (C1 heteroalkyl), methoxyethyl (C3 heteroalkyl), fluoro (halo), or chloro (halo). In certain embodiments, A's 5-6 membered heteroaryl is 5-methylpyrazole.

[0064] In some embodiments, the aryl, 5- to 6-membered heteroaryl, or fused heterocycle of A is mono- or di-substituted with -CH, -F, -Cl, -CN, -NH, -CHOCH, or combinations thereof. In some embodiments, the aryl, 5- to 6-membered heteroaryl, or fused heterocycle of A is mono-substituted with -CH, -F, -Cl, -CN, -NH, or -CHOCH. In some embodiments, the aryl, 5- to 6-membered heteroaryl, or fused heterocycle of A is di-substituted with -CH, -F, -Cl, -CN, -NH, -CHOCH, or combinations thereof.

[0065] In one embodiment, A has one of the following structures: [ka] wherein * indicates the position of the bond to Y. In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0066] In some embodiments, A has one of the following structures: [ka] where * indicates the position of the bond to Y. In some embodiments, A has one of the following structures: [ka] (wherein * indicates the position of the bond to Y).

[0067] In one embodiment, the compound has the structure of any of the following formulas (IC)-(IG): [ka] [ka] or a stereoisomer, salt, or tautomer thereof.

[0068] In one embodiment, Y is -CH2-, -CHCH3-, -C(CH3)2-, -(CH2) p In some embodiments, Y is -C(=O)-, -NCH3-, or a direct bond. In some embodiments, Y is -CH2-. In some embodiments, Y is -CHCH3-. In some embodiments, Y is C(CH3)2-. In some embodiments, Y is a direct bond. In some embodiments, Y is -(CH2) p In some embodiments, Y is -C(=O)-. In some embodiments, Y is -(CH) p C(=O)-, and p is an integer from 0 to 2. In some embodiments, Y is -NCH3-.

[0069] In one embodiment, p is an integer from 0 to 4. In some embodiments, p is an integer of 0. In some embodiments, p is an integer of 1. In some embodiments, p is an integer of 2. In some embodiments, p is an integer of 3. In some embodiments, p is an integer of 4. In some embodiments, p is an integer of 0 to 2.

[0070] In one embodiment, the compound has one of the following structures of formulas (IH)-(IL): [ka] [ka] or a stereoisomer, salt, or tautomer thereof.

[0071] In one embodiment, R 2 is C1-C6 alkyl, C1-C6 heteroalkyl, aryl, heteroaryl, fused bicyclic, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, or -NR 3 R 4 In some embodiments, R 2 The aryl, heteroaryl, or fused bicyclic of is further substituted with fluoro, chloro, cyano, methyl, amine, —CFH, —CF, C-C alkyl alcohol, C-C alkoxyl, or combinations thereof. 2 The aryl, heteroaryl, or fused bicyclic of is mono-, di-, or tri-substituted with fluoro, chloro, cyano, methyl, amine, -CFH, -CF, C-C alkyl alcohol, C-C alkoxyl, or combinations thereof. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with two fluoro substituents. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with two fluoro substituents and one methyl substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one fluoro and one cyano substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one methyl substituent, one cyano substituent, and one fluoro substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one fluoro and one methyl substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one chloro and one cyano substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with two methyl substituents. In some embodiments, for example, R2 The aryl, heteroaryl, or fused bicyclic of is substituted with one fluoro and one amino substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one fluoro substituent and one deuterium substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic of is substituted with one fluoro and one methoxy substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with two fluoro and one methoxy substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic of is substituted with one fluoro, one chloro, and one methyl substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with two methyl substituents and one fluoro substituent. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one fluoro group, one methoxyl group, and one methyl group. In some embodiments, for example, R 2 The aryl, heteroaryl, or fused bicyclic ring of is substituted with one cyano substituent and one methoxy substituent. In some embodiments, for example, R 2 is substituted with one cyano substituent, one methoxyl substituent, and one methyl substituent.

[0072] In one embodiment, R 2 The fused bicyclic ring system has one of the following structures: [ka] In some embodiments, R 2 The fused bicyclic ring system has one of the following structures: [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] In some embodiments, R 2 The fused bicyclic ring system is [ka] is.

[0073] In one embodiment, R 2 The aryl in has one of the following structures: [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] In some embodiments, R2 The aryl of [ka] In some embodiments, R 2 The aryl of [ka] is.

[0074] In one embodiment, R 2 The heteroaryl of the formula has one of the following structures: [ka] [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] In some embodiments, R 2 The heteroaryl of [ka] is.

[0075] In one embodiment, R 2 The C3-C8 cycloalkyl or C3-C8 heterocycloalkyl has any of the following structures: [ka] In some embodiments, R 2 C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is [ka] In some embodiments, R 2 C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is [ka] is.

[0076] In one embodiment, R 2 has one of the following structures: [ka] [ka] [ka]

[0077] In one embodiment, R 3 and R 4are each independently H or C1-C4 alkyl. In some embodiments, R 3 and R 4 are each independently H or C alkyl. In some embodiments, R 3 and R 4 are each H. In some embodiments, R 3 and R 4 are each C alkyl. In some embodiments, R 3 or R 4 One of the is H and R 3 or R 4 and the other of R is C alkyl. 3 and R 4 The C1 alkyl is methyl.

[0078] In one embodiment, B is C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused bicyclic, bridged bicyclic, spirocyclic, or absent. In some embodiments, the C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused bicyclic, bridged bicyclic, or spirocyclic of B is further substituted with fluoro, —OH, or methyl. In certain embodiments, the C3-C8 heterocycloalkyl of B is sulfoximine or sulfone. In certain embodiments, the C3-C8 heterocycloalkyl of B is sulfoximine. In certain embodiments, the C3-C8 heterocycloalkyl of B is sulfone. In some specific embodiments, the C3-C8 heterocycloalkyl of B is [ka] In some particular embodiments, the C3-C8 heterocycloalkyl of B is: [ka] In some particular embodiments, the C3-C8 heterocycloalkyl of B is: [ka] In some embodiments, B is a C6-C7 cycloalkyl, a C4-C6 heterocycloalkyl, a fused bicyclic, a bridged bicyclic, or a spirocyclic. In certain embodiments, B is a C6 cycloalkyl, a C4-C5 heterocycloalkyl, a fused bicyclic, a bridged bicyclic, or a spirocyclic. In some embodiments, the fused bicyclic of B is octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3.2.0]heptane, or 3-azabicyclo[3.1.0]hexane. In some embodiments, the bridged bicyclic of B is 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, or 2-azabicyclo[2.2.1]heptane. In some embodiments, the spiro ring of B is 1-azaspiro[4.5]decane, 2-azaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 1-azaspiro[3.3]heptane, or spiro[3.3]heptane. In some embodiments, B has one of the following structures: [ka] (where * represents R 5 In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0079] In some embodiments, B is one or more R 5 In some embodiments, B is substituted with 1, 2, or 3 R 5 In some embodiments, B is absent. When B is absent, Y is substituted with R 5 If B is absent and Y is directly bonded, A is 5 is bonded to.

[0080] In some embodiments, R 5 is -H, -OH, -CN, -F, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 heteroalkyl, 6-membered heteroaryl, C4-C6 heterocycloalkyl-OC(=O)R 6 , -CH2C(=O)OR 6 , -NR 7 R 8 , -NR 7 C(=O)R 6 , -NR 7 C(=O)OR 6 , -CH2C(=O)NR 7 N 8 , -NR 7 R 8 CH2C(=O)NR 7 N 8 , -CH2NR 7 C(=O)R 6 , sulfonylmethane, oxo, phosphate, or combinations thereof.

[0081] In some embodiments, R 5 is —H. In some embodiments, R 5 is —OH. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -F. In some embodiments, R 5 is C1-C4 alkyl. In some embodiments, R 5is C-C cycloalkyl. In some embodiments, R 5 is C1-C4 heteroalkyl. In some embodiments, R 5 is a 6-membered heteroaryl. In some embodiments, R 5 is C4-C6 heterocycloalkyl-OC(=O)R 6 In some embodiments, R 5 is -CH2C(=O)OR 6 In some embodiments, R 5 is -NR 7 R 8 In some embodiments, R 5 is -NR 7 C(=O)R 6 In some embodiments, R 5 is -NR 7 C(=O)OR 6 In some embodiments, R 5 is -CH2C(=O)NR 7 N 8 In some embodiments, R 5 is -NR 7 R 8 CH2C(=O)NR 7 N 8 In some embodiments, R 5 is -CH2NR 7 C(=O)R 6 In some embodiments, R 5 is a sulfonylmethane. In some embodiments, R 5 is oxo. In some embodiments, R 5 is a phosphate.

[0082] In some embodiments, R 5 The C1-C6 heteroalkyl in R is C1-C6 deuterium alkyl. 5 The C1-C6 heteroalkyl in R is C1 deuterium alkyl. 5 In some embodiments, the C1-C6 heteroalkyl in R is C2 deuterium alkyl.5 The C1-C6 heteroalkyl in R is a C3 deuterium alkyl. 5 The C1-C6 heteroalkyl in R is a C4 deuterium alkyl. 5 The C1-C6 heteroalkyl in R is a C5 deuterium alkyl. 5 The C1-C6 heteroalkyl is a C6 deuteroalkyl.

[0083] In one embodiment, R 6 is hydrogen, C1-C4 alkyl, C1-C5 heteroalkyl, or C4-C6 heterocycloalkyl, and C4-C6 heterocycloalkyl is [ka] or halo. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C1-C4 alkyl. In some embodiments, R 6 is C1-C5 heteroalkyl. In some embodiments, R 6 is a C4-C6 heterocycloalkyl. In some particular embodiments, a C4-C6 heterocycloalkyl is [ka] is replaced by .

[0084] In certain embodiments, the C4-C6 heterocycloalkyl is substituted with halo. 6 is C1-C3 alkyl, C1-C4 heteroalkyl, or C4-C5 heterocycloalkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is C1-C4 heteroalkyl. In some embodiments, R 6 is C-C heterocycloalkyl. In some embodiments, R 6In some embodiments, the C1-C4 heteroalkyl in R is C1-C4 fluoroalkyl. 6 In some embodiments, the C1-C4 heteroalkyl in R is C1 fluoroalkyl. 6 In some embodiments, the C1-C4 heteroalkyl in R is C2 fluoroalkyl. 6 In some embodiments, the C1-C4 heteroalkyl in R is C3 fluoroalkyl. 6 The C1-C4 heteroalkyl is a C4 fluoroalkyl.

[0085] In certain embodiments, R 6 The C4-C6 heterocycloalkyl in R is pyrrolidine or 1-methylpyrrolidine. 6 The C4-C6 heterocycloalkyl in R is pyrrolidine. 6 The C4-C6 heterocycloalkyl is 1-methylpyrrolidine.

[0086] In some embodiments, R 6 The C4-C6 heterocycloalkyl of R is substituted with halo. 6 In some embodiments, the C4-C6 heterocycloalkyl of R is substituted with fluoro. 6 The C4-C6 heterocycloalkyl is [ka] In some embodiments, [ka] R is replaced by 6 The C4-C6 heterocycloalkyl is [ka] In some embodiments, [ka] R is replaced by 6 The C4-C6 heterocycloalkyl is [ka] In some embodiments, [ka] R is replaced by 6 The C4-C6 heterocycloalkyl is [ka] In some embodiments, R substituted with fluoro is 6 The C4-C6 heterocycloalkyl is [ka] In some embodiments, R substituted with fluoro is 6 The C4-C6 heterocycloalkyl is [ka] In some embodiments, R substituted with fluoro is 6 The C4-C6 heterocycloalkyl is [ka] is.

[0087] In some embodiments, R 7 and R 8 are each independently H, C1-C3 alkyl, C1-C3 alkylalcohol, sulfonylmethane, C3-C4 cycloalkyl, or 6-membered heteroaryl, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally substituted with fluoro or C3-C4 cycloalkyl.

[0088] In some embodiments, R 5 The 5- to 6-membered heteroaryl is [ka] R 5 The 5- to 6-membered heteroaryl is [ka] R 5 The 5- to 6-membered heteroaryl is [ka] In some embodiments, R 5 The C3-C8 heterocycloalkyl is [ka] In some embodiments, R 5 The C3-C8 cycloalkyl is [ka] In some embodiments, R 5 The oxo of [ka] In some embodiments, R 5 The phosphate of [ka] In some embodiments, R 5 The phosphate of [ka] In some embodiments, R 5 The phosphate of [ka] In some embodiments, R 5 has one of the following structures: [ka] [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0089] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0090] In one embodiment, the compound of Formula (I)-(IL) has one of the structures shown in Table B below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16] Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25 Table 4-26 Table 4-27 Table 4-28 Table 4-29 Table 4-30 Table 4-31 Table 4-32 Table 4-33 Table 4-34 Table 4-35 Table 4-36 Table 4-37 Table 4-38 Table 4-39 Table 4-40 Table 4-41 Table 4-42 Table 4-43 Table 4-44 Table 4-45 Table 4-46 Table 4-47 Table 4-48 Table 4-49 Table 4-50 Table 4-51 Table 4-52 Table 4-53 Table 4-54 Table 4-55 Table 4-56 Table 4-57 Table 4-58 Table 4-59 Table 4-60 Table 4-61 Table 4-62 Table 4-63 Table 4-64 Table 4-65 Table 4-66 Table 4-67 Table 4-68 Table 4-69 Table 4-70 Table 4-71 Table 4-72 Table 4-73 Table 4-74 Table 4-75 Table 4-76 Table 4-77 Table 4-78 Table 4-79 Table 4-80 Table 4-81 Table 4-82 Table 4-83 Table 4-84 Table 4-85 Table 4-86 Table 4-87 Table 4-88 Table 4-89 Table 4-90 Table 4-91 Table 4-92 Table 4-93 Table 4-94 Table 4-95 Table 4-96 Table 4-97 Table 4-98 Table 4-99

Table 4-100

[0091] As can be seen, the ionizable lipids described herein enable the development of new treatments for disease without the need for exotic chemicals or specialized reagents or manufacturing techniques.

[0092] III. Pharmaceutical Compositions Other embodiments relate to pharmaceutical compositions. In one embodiment, the pharmaceutical composition comprises any one (or more) of the compounds described above and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still other embodiments, the pharmaceutical composition comprises a compound disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such additional therapeutic agents are described herein below.

[0093] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, intraocular, pulmonary, transmucosal, transdermal, intravaginal, ocular, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0094] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, by injecting the compound directly into an organ, often as a depot preparation or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the compounds are delivered in targeted drug delivery systems, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target and are selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0095] In methods of treatment according to embodiments of the present disclosure, an effective amount of at least one compound of Formula (I)-(IL) is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. An effective amount or dose can be ascertained by methods such as modeling, dose escalation studies, or clinical trials (e.g., mode or route of administration, drug delivery, drug pharmacokinetics, severity and course of the disease, disorder, or condition, previous or ongoing treatments of the subject, the subject's health status and response to the drug, and the judgment of the treating physician).

[0096] The compounds of the present disclosure are effective over a wide dosage range. For example, in treating adult humans, dosages of about 0.001-0.1 mg, 0.01-0.1 mg, 0.5-5 mg, 0.5-10 mg, 0.01-10 mg, 0.1-10 mg, 10-5000 mg, 100-5000 mg, 1000-4000 mg, or 1000-3000 mg per day are exemplary dosages used in some embodiments. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the subject's weight, and the preference and experience of the attending physician.

[0097] In some embodiments, the compound of the present disclosure is administered in a single dose. In one embodiment, the single dose is administered orally. In another embodiment, the single dose is administered topically. However, other routes may be used as needed. In some embodiments, the compound of the present disclosure is administered multiple times. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present disclosure and another agent (e.g., an anticancer agent) are administered together about once per day to about six times per day. In another embodiment, administration of the compound of the present disclosure and the agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0098] The administration of the disclosed compound may be continued as long as necessary. In some embodiments, the disclosed compound is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the disclosed compound is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the disclosed compound is administered continuously and chronically, for example, to treat chronic effects.

[0099] In some embodiments, the compounds of the present disclosure are administered in individual dosage forms. It is known in the art that optimal therapy requires individualization of dosing regimens due to subject-to-subject variability in the pharmacokinetics of compounds.

[0100] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions.In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of the disclosed compounds into preparations that can be used as pharmaceuticals.Appropriate formulations depend on the selected route of administration. Any pharmaceutically acceptable means, carriers, and excipients may be used as suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0101] Provided herein are pharmaceutical compositions comprising one or more compounds of Formula (I)-(IL) and a pharmaceutically acceptable carrier. Also provided herein are pharmaceutical compositions comprising one or more compounds selected from the compounds of Formula (I)-(IL) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the described compounds are administered as pharmaceutical compositions in which one or more compounds selected from the compounds of Formula (I)-(IL) are mixed with other active ingredients, such as in combination therapy. All combinations of active agents described in the combination therapy section below and throughout this disclosure are encompassed herein. In certain embodiments, the pharmaceutical composition comprises one or more compounds of Formula (I)-(IL).

[0102] As used herein, a pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of Formulae (I)-(IL) and other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of Formulae (I)-(IL) provided herein is administered in a pharmaceutical composition to a mammal having a target disease, disorder, or condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0103] In one embodiment, one or more compounds selected from the compounds of Formulae (I)-(IF) are formulated as an aqueous solution. In certain embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer (e.g., Hank's solution, Ringer's solution, or saline buffer). In other embodiments, one or more compounds selected from the compounds of Formulae (I)-(IL) are formulated for transmucosal administration. In certain embodiments, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated. In still other embodiments, where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0104] In another embodiment, the compound described herein is formulated for oral administration.The compound described herein is formulated by combining active compound with, for example, pharmaceutically acceptable carrier or excipient.In various embodiments, the compound described herein is formulated into oral dosage forms, including, for example, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0105] In certain embodiments, oral pharmaceutical preparations are prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then adding suitable auxiliary agents as needed, followed by processing the granulated mixture to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers, such as sugars (e.g., lactose, sucrose, mannitol, sorbitol); cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose); or others (e.g., polyvinylpyrrolidone (PVP or povidone) or calcium phosphate).In certain embodiments, disintegrants are optionally added.Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts (e.g., sodium alginate).

[0106] In one embodiment, the oral dosage form (e.g., pill, capsule, or tablet) comprises one or more suitable layers or coatings. In certain embodiments, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients (e.g., by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture). Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0107] In certain embodiments, at least one therapeutically effective amount of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (e.g., glycerol and sorbitol). In certain embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, lactose, binders (e.g., starch), and / or lubricants (e.g., talc and magnesium stearate), and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0108] In still other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the injectable formulations are presented in unit dosage form (e.g., ampoules) or multi-dose containers. A preservative is optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains formulating agents (e.g., suspending agents, stabilizers, and / or dispersing agents). In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in water-soluble form. In additional embodiments, a suspension of one or more compounds selected from the compounds of Formulae (I)-(IL) is prepared as a suitable oily injection suspension. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension (e.g., sodium carboxymethylcellulose, sorbitol, or dextran). Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0109] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and one or more compounds selected from the compounds of Formulae (I)-(IL) as an active ingredient. The active ingredient may be in the form of a free acid or free base or a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also called polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds described herein. Furthermore, the compounds described herein encompass unsolvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, carriers, adjuvants (e.g., preservatives, stabilizers, wetting agents, or emulsifiers), solubility enhancers, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0110] Methods for preparing compositions containing the compounds described herein include formulating the compound(s) with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid compositions. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, ointments, suspensions, and creams. The forms of the pharmaceutical compositions described herein include solutions or suspensions, solid forms suitable for dissolution or suspension in liquid before use, or emulsions. These compositions optionally also contain minor amounts of non-toxic auxiliary substances (e.g., wetting agents, emulsifying agents, and pH buffering agents).

[0111] In some embodiments, pharmaceutical compositions comprising one or more compounds selected from the compounds of Formulae (I)-(IL) are illustratively in the form of a liquid in which the drug is present in solution, suspension, or both. Typically, when the composition is administered as a suspension, a first portion of the drug is present in solution and a second portion of the drug is present in the form of particles suspended in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0112] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-insoluble polymers (e.g., cellulose polymers, e.g., hydroxypropylmethylcellulose) and water-soluble polymers (e.g., cross-linked carboxyl-containing polymers). Certain pharmaceutical compositions described herein include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0113] The pharmaceutical composition optionally also includes a solubilizing agent to aid in the dissolution of one or more compounds selected from the compounds of Formulae (I)-(IL). The term "solubilizing agent" generally includes agents that result in the formation of a micellar solution or a true solution of the drug. Certain acceptable nonionic surfactants (e.g., polysorbate 80) are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers.

[0114] Additionally, the pharmaceutical compositions optionally include one or more pH adjusting or buffering agents (e.g., acids (e.g., acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid); bases (e.g., sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane); and buffers (e.g., citric acid / dextrose, sodium bicarbonate, and ammonium chloride)). Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0115] The composition optionally also contains one or more salts in an amount necessary to bring the composition to an acceptable osmolality. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0116] Other pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances (e.g., merfen and thiomersal); stabilized chlorine dioxide; and quaternary ammonium compounds (e.g., benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride).

[0117] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkylphenyl ethers (e.g., Octoxynol 10, Octoxynol 40).

[0118] The compositions may optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0119] In certain embodiments, aqueous suspension compositions are packaged in non-reclosable, single-dose containers. Alternatively, multi-dose, reclosable containers are used, in which case a preservative is typically included in the composition.

[0120] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described herein are delivered using sustained-release systems (e.g., semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent). A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound for weeks up to 100 days or more. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0121] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations (e.g., magnesium and zinc); or (n) combinations thereof.

[0122] In some embodiments, the concentration of one or more compounds selected from compounds of Formulae (I)-(IL) provided in the pharmaceutical composition is 90%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16.25%, 16.75%, 16.50 ... 5%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25 %,8%,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,1.25%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07% , 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or greater than 0.0001% w / w, %w / v, or %v / v. In another embodiment, the amount of the compound selected from the compounds of Formulae (I) to (IL) in the pharmaceutical composition is an amount between about any two of the values ​​recited in the preceding sentence (e.g., about 2-70 w / w%, 3.5-80 w / w%, 1-30 w / w%, etc.).

[0123] In some embodiments, the concentration of one or more compounds selected from the compounds of Formulae (I) to (IL) provided in the pharmaceutical composition of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about The range is from 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% w / w, w / v, or v / v.

[0124] In some embodiments, the amount of one or more compounds selected from compounds of Formula (I)-(IL) provided in the pharmaceutical composition of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g , 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g or less.

[0125] In some embodiments, the amount of one or more compounds selected from the compounds of Formulae (I)-(IL) provided in the pharmaceutical composition of the present disclosure ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0126] Packaging materials used to package the pharmaceutical compositions described herein include those found, for example, in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material appropriate for the selected formulation and mode of administration and treatment. For example, the container(s) optionally contain one or more compounds described herein in a composition or in combination with another agent disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper pierceable by a hypodermic needle). Such kits optionally contain the compounds with an identifying description or label or instructions related to their use in the methods described herein.

[0127] For example, kits typically include one or more additional containers, each containing one or more of various materials (e.g., reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels for the carrier, packaging, container, vial, and / or tube that describe the contents and / or instructions for use, and package inserts containing the instructions. A set of instructions for use is also typically included. A label is optionally on or associated with a container. For example, a label is on a container when letters, numbers, or other symbols forming the label are affixed to, molded into, or etched into the container itself; a label is associated with a container when present within the container or in a carrier that also holds the container, e.g., as a package insert. Additionally, labels are used to indicate that the contents are to be used for a particular therapeutic application. Furthermore, the label indicates instructions for use of the contents, e.g., in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms comprising a compound provided herein. For example, the pack contains metal or plastic foil (e.g., a blister pack). Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser is accompanied by instructions for use associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which instructions reflect the agency's approval of the drug form for human or veterinary administration. Such instructions are, for example, labels approved by the U.S. Food and Drug Administration for prescription drugs or approved product inserts. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0128] As noted above, the compounds and compositions of the present disclosure will find utility in a wide range of protein kinase-mediated diseases and conditions (e.g., kinase-mediated diseases and conditions). Such diseases may include, by way of example and not limitation, cancer, such as lung cancer, NSCLC (non-small cell lung cancer), oat cell carcinoma, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, endocrine system cancer (e.g., thyroid cancer, pancreatic cancer, parathyroid cancer, or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer (particularly hormone-resistant cancer), chronic or acute leukemia, childhood solid tumors, hypereosinophilia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer (e.g., renal cell carcinoma, renal pelvis cancer), childhood malignancies, neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brain stem glioma, or pituitary adenoma), Barrett's esophagus (precancerous syndrome), neoplastic skin diseases, psoriasis, mycosis fungoides, and benign prostatic hyperplasia, diabetes-related diseases (e.g., diabetic retinopathy, retinal ischemia, and retinal neovascularization), liver cirrhosis, angiogenesis (e.g., cardiovascular disease, arteriosclerosis), immune diseases (e.g., autoimmune diseases), and kidney disease.

[0129] In some embodiments, a pharmaceutical composition comprises the compound described above and a pharmaceutically acceptable carrier, including, for example, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier, which has been approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use. In some embodiments, a pharmaceutical composition of the compound is provided for use in treating diseases associated with mutations in fibroblast growth factor receptor 2 (FGFR2) or fibroblast growth factor receptor 3 (FGFR3).

[0130] In some embodiments, the method for treating a disease associated with a mutation in FGFR2 or FGFR3 comprises administering a compound or pharmaceutical composition to a subject in need thereof. In some embodiments, the subject is an animal. In some embodiments, the subject is a human. In some embodiments, the disease associated with a mutation in FGFR2 is cancer or craniosynostosis syndrome. In certain embodiments, the cancer is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, ovarian cancer, endometrial cancer, non-small cell lung cancer, urothelial carcinoma, colorectal cancer, colon cancer, metastatic cholangiocarcinoma, cholangiocarcinoma, osteosarcoma, gastroesophageal junction adenocarcinoma, biliary tract cancer, anaplastic thyroid carcinoma, ganglioglioma, intraductal tubulopapillary neoplasm of the pancreas, gallbladder carcinoma, renal cell carcinoma, mucinous lipocarcinoma, triple-negative breast cancer, or rectal cancer. In certain embodiments, the craniosynostosis syndrome is craniosynostosis, kyphotic dysplasia, Crouzon syndrome, Apert syndrome, Pfeiffer syndrome, Antley-Bixler syndrome, Bear-Stevenson syndrome, Jackson-Weiss syndrome, or Säthle-Hochzen-like syndrome. In some embodiments, the disease associated with mutations in FGFR3 is systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal skeletal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN syndrome), Muenke syndrome, FGFR3-associated cancer, hypochondroplasia, FGFR3-associated craniosynostosis, LADD syndrome, or Alzheimer's disease.

[0131] IV. Preparation method Methods of preparation for the above compounds and compositions are described below and / or are known in the art.

[0132] Those skilled in the art will appreciate that in the processes described herein, functional groups of intermediate compounds may need to be protected with suitable protecting groups. Such functional groups include hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed according to standard procedures known to those skilled in the art and described herein. The use of protecting groups is discussed in detail in Green, T W and P G M Hutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, the protecting group may be a polymer resin (e.g., Wang resin, Rink resin, or 2-chlorotrityl chloride resin).

[0133] Those skilled in the art will also appreciate that such protected derivatives of the compounds of the present invention may not themselves have pharmacological activity, but may be administered to a mammal and then metabolized in the body to form the pharmacologically active compounds of the present invention. Thus, such derivatives may be referred to as "prodrugs." All prodrugs of the compounds of the present invention are within the scope of the present invention.

[0134] Furthermore, all compounds of the present invention that exist in a free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of the compounds of the present invention can be converted into their free base or acid forms by standard techniques.

[0135] The synthesis of compounds of formula (I) is described below.

[0136] General Scheme 1 [ka] General Scheme 2 [ka] [ka] tert-Butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate [ka] Step A. tert-Butyl 3-methylsulfonyloxypiperidine-1-carboxylate. To a 40 mL vial flask equipped with a magnetic stir bar, tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (0.50 g, 2.5 mmol) was added, followed by DCM (12 mL). Triethylamine (0.69 mL, 5.0 mmol) was added to the mixture. The solution was cooled to 0 °C, and methanesulfonic anhydride (0.86 g, 5.0 mmol) was added. The mixture was warmed to 25 °C and stirred for 1 h. Water (10 mL) was added to the reaction, the mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (0.90 g, 99% yield) as a yellow solid, which was used in the next step without further purification.

[0137] Step B: tert-Butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial flask equipped with a magnetic stirrer and reflux condenser, tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (0.65 g, 2.3 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.45 g, 2.3 mmol) were added, followed by DMF (12 mL) and CsCO (1.5 g, 4.7 mmol). The mixture was heated to 90 °C and stirred for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate 50 / 1 to 30 / 1) to give the desired product, tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.80 g, 76% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 378.1 (M+H).

[0138] [ka] tert-Butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate [ka] Step A. tert-Butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 250 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser were added 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (6.0 g, 25.2 mmol) and tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (12 g, 30 mmol), followed by dioxane (60 mL) and HO (12 mL). Pd(dba) (0.46 mg, 2.5 mmol), XPhos (0.60 g, 1.3 mmol), and KCO (7.0 g, 50 mmol) were added. The flask was evacuated and backfilled with nitrogen three times, and the reaction was stirred under a nitrogen atmosphere at 90 °C for 1 h. Water (100 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid. The solid was purified by silica gel column chromatography (30–100% ethyl acetate / petroleum ether) to give tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (8.5 g, 79% yield) as a brown solid. LCMS (MM-ES + APCI, Pos): m / z 409.1 (M+H).

[0139] Step B. tert-Butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. In a 500 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (10 g, 24 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (18 g, 49 mmol) were added, and DMF (150 mL) was added. DIEA (8.5 mL, 49 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. Water (100 mL) was added to the reaction, and the mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by trituration in ethyl acetate (25 mL) to give tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (9.3 g, 87% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 541.3 (M+H).

[0140] Step C. tert-Butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (1.6 g, 3.0 mmol) and LiBr (0.39 g, 4.4 mmol) were added, followed by NMP (20 mL). Tris(acetonitrile)pentamethylcyclopentadienylruthenium(II) trifluoromethanesulfonate (0.10 g, 0.19 mmol) was added, the vial was purged with nitrogen, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with water (100 mL) and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (30-60% ethyl acetate / petroleum ether) to give a brown solid. The solid was purified by trituration with MTBE (30 mL) to give tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.32 g, 63% yield). LCMS (MM-ES+APCI, Pos): m / z 473.2 (M+H).

[0141] [ka] tert-Butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate [ka] Step A: tert-Butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.75 g, 1.3 mmol), followed by toluene (10 mL). Xantphos (74 mg, 0.13 mmol), Pd(OAc) (33 mg, 0.13 mmol), KPO (0.54 g, 2.5 mmol), and ethyl 3-sulfanylpropanoate (0.26 g, 1.9 mmol) were added to the mixture at 25 °C. The vial was flushed with nitrogen and stirred at 80 °C under a nitrogen atmosphere for 16 hours. Water (25 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (40-50% ethyl acetate / petroleum ether) to give tert-butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (1.3 g, 93% yield) as a yellow gum. LCMS (MM-ES + APCI, Pos): m / z 525.4 (M + H).

[0142] Step B. tert-Butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.20 g, 0.36 mmol), followed by DMF (4 mL). The solution was cooled to 0 °C and treated dropwise with t-BuOK (1 M, 0.47 mL, 0.47 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under reduced pressure to give tert-butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.18 g, crude product), which was used in the next step without further purification.

[0143] [ka] tert-Butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate [ka] Step A. tert-Butyl N-[(3R)-1-(5-bromo-2-pyridyl)pyrrolidin-3-yl]carbamate. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (0.35 g, 1.9 mmol) in DMSO (7 mL). DIEA (1.3 mL, 7.6 mmol) and 5-bromo-2-fluoropyridine (0.41 g, 2.3 mmol) were added to the mixture. The vial was purged with nitrogen and heated to 90° C. for 1 hour. Water (50 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (25–35% ethyl acetate / petroleum ether) to give tert-butyl N-[(3R)-1-(5-bromo-2-pyridyl)pyrrolidin-3-yl]carbamate (1.6 g, 81% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 344.0 (M+H).

[0144] Step B. tert-Butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl N-[(3R)-1-(5-bromo-2-pyridyl)pyrrolidin-3-yl]carbamate (1.0 g, 2.9 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.1 g, 4.3 mmol) were added, followed by dioxane (15 mL). KOAc (0.57 g, 5.8 mmol) and Pd(dppf)Cl (0.22 g, 0.29 mmol) were added to the mixture, which was then stirred at 90 °C under a nitrogen atmosphere for 1 hour. The suspension was filtered, and the filter cake was washed with ethyl acetate (30 mL). The crude product was purified by silica gel column chromatography (20-25% ethyl acetate / petroleum ether) to give tert-butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate (0.70 g, 56% yield) as a brown oil. LCMS (MM-ES+APCI, Pos): m / z 308.4 (M+H).

[0145] [ka] tert-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate [ka] Step A. tert-Butyl N-methyl-N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate. To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate (1.0 g, 2.4 mmol), followed by THF (12 mL). The flask was cooled to 0 °C and evacuated and filled with nitrogen three times. NaH (60%, 0.19 g, 4.8 mmol) was added portionwise to the mixture at 0 °C, followed by CHCl (0.29 mL, 4.8 mmol) in THF (2 mL) at 0 °C, and the reaction was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous ammonium chloride (10 mL), transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give tert-butyl N-methyl-N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate (0.45 g, 37% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 406.1 (M+H).

[0146] Step B. tert-Butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Prepared according to Step A of Intermediate 2, using tert-butyl N-methyl-N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methyl-carbamate (0.30 g, 82% yield) as a yellow oil.

[0147] Step C. [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]pyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Prepared according to Step B of Intermediate 2, using tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]pyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.35 g, 84% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 569.0 (M+H).

[0148] Step D. tert-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Prepared according to Step C of Intermediate 2, using [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]pyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate (0.13 g, 41% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z499.2(M+H).

[0149] Intermediate 6 [ka] tert-Butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ka] Step A. tert-Butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate. A solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (5.0 g, 27 mmol) and DMAP (0.33 mg, 2.7 mmol) in DCM (67 mL) at 0 °C was Triethylamine (7.4 mL, 53 mmol) was added, followed by tosyl chloride (6.1 g, 32 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with DCM (50 mL), and the organics were washed with HO (100 mL), brine (100 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0–50% ethyl acetate / hexanes) to give tert-butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate (4.3 g, 47% yield). LCMS (MM-ES + APCI, Pos): m / z 242.1 (M-Boc + H).

[0150] Step B. tert-Butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2 mmol) in DMF (2.6 mL) was added tert-butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate (2.6 g, 7.7 mmol) and CsCO (3.4 g, 10 mmol). The solution was stirred at 80 °C for 2 h. The mixture was diluted with EtOAc (100 mL). The organic phase was washed with HO (100 mL), and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.9 g, quantitative yield), which was used in the next step without further purification. LCMS (MM-ES+APCI, Pos): m / z 364.3 (M+H).

[0151] Step C. tert-Butyl (S)-3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.8 g, 5.0 mmol) in 4:1 dioxane-water (17 mL) was added 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (0.80 g, 3.4 mmol) and K2CO3 (0.93 g, 6.7 mmol). The reaction was purged with argon for 5 minutes. Palladium tetrakis (0.19 g, 0.17 mmol) was added and the reaction was stirred at 80 °C for 7 hours. The reaction mixture was diluted with EtOAc (30 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was washed with brine (2x, 50 mL), concentrated in vacuo, and purified by silica gel chromatography (0-100% EtOAc / hexanes) to give tert-butyl (S)-3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.39 g, 30% yield). LCMS (MM-ES+APCI, Pos): m / z 339.20 (M-tBu+H).

[0152] Step D. tert-Butyl (S)-3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. Prepared according to Step B of Intermediate 2, using tert-butyl (S)-3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (S)-3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (67 mg, 95% yield). LCMS (MM-ES+APCI, Pos): m / z 471.1 (M-tBu+H).

[0153] Step E. tert-Butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. Prepared according to Step C of Intermediate 2, using tert-butyl (S)-3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to provide tert-butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (17 mg, 30% yield). LCMS (MM-ES+APCI, Pos): m / z401.1(M-tBu+H).

[0154] [ka] 4-Methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile [ka] Step A. tert-Butyl (3S)-3-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar was added methylsulfanyl sodium (85 mg, 1.2 mmol), followed by toluene (4 mL). tert-Butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.40 g, 0.81 mmol), Pd(OAc) (19 mg, 0.084 mmol), Xantphos (47 mg, 0.081 mmol), and CsCO (0.79 g, 2.4 mmol) were added to the mixture at 25 °C, and the reaction was stirred at 100 °C under a nitrogen atmosphere for 16 h. Water (4 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer 3 mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to give tert-butyl (3S)-3-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.28 g, 68% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 439.1 (M+H).

[0155] Step B. 4-Methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 50 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (60 mg, 0.12 mmol) was added, followed by DCM (1 mL). HCl / dioxane (4 M, 1 mL) was added to the mixture, and the reaction was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (19%-49% no acetonitrile / 0.04% no aqueous ammonia hydroxide + 10 mM no H4HCO3). After lyophilization, 4-methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (19.0 mg, 39% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z339.0(M+H).

[0156] [ka] tert-Butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate [ka] Step A. tert-Butyl (3R)-3-[[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate. Prepared according to Step A of Intermediate 2, using tert-butyl (3R)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.5 g, 76% yield) as a pale yellow solid. LCMS (MM-ES+APCI, Pos): m / z 423.2 (M+H).

[0157] Step B. tert-Butyl (3R)-3-[[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate. Prepared according to Step B of Intermediate 2, using tert-butyl (3R)-3-[[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.7 g, 93% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 555.0 (M+H).

[0158] Step C. tert-Butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate. Prepared according to Step C of Intermediate 2, using tert-butyl (3R)-3-[[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (0.76 g, 75% yield) as a grey solid. LCMS (MM-ES+APCI, Pos): m / z486.9(M+H).

[0159] [ka] tert-Butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate [ka] Step A. tert-Butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate. To a round-bottom flask equipped with a magnetic stirrer and a reflux condenser, 4-iodo-5-methyl-1H-pyrazole (10 g, 48 mmol), tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (20 g, 72 mmol), and cesium carbonate (31 g, 96 mmol) were added, followed by N,N-dimethylformamide (300 mL). The mixture was stirred at 90° C. for 4.5 hours. Water (600 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (800 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-60% EtOAc / petroleum ether) to afford tert-butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate (4.4 g, 23% yield) as a white solid.

[0160] Step B. tert-Butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 250 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate (4.4 g, 11.3 mmol), followed by THF (120 mL). Isopropylmagnesium chloride (2 M, 23 mL, 45 mmol) was added to the mixture and stirred at 25° C. for 1 hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.9 g, 56 mmol) was added to the mixture and stirred at 25° C. for 3 hours. Water (300 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (400 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-10% EtOAc / petroleum ether) to give tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (1.9 g, 40% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 392.4 (M+H).

[0161] Step C. tert-Butyl 4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Prepared according to Step A of Intermediate 2, using tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (10 g, 80% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 367.0 (M-tBu+H).

[0162] Step D. tert-Butyl 4-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Prepared according to Step B of Intermediate 2, using tert-butyl 4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (11 g, 85% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 577.1 (M+H).

[0163] Step E. tert-Butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Prepared according to Step C of Intermediate 2, using tert-butyl 4-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (11 g, 82% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 430.8 (M+H).

[0164] [ka] tert-Butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate [ka] Step A. tert-Butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate. To a 50 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (3.0 g, 16.0 mmol) and triethylamine (4.5 mL, 32 mmol) were added, followed by DCM (10 mL). The solution was cooled to 0 °C, and a solution of methanesulfonic anhydride (3.4 g, 19 mmol) in DCM (10 mL) was added dropwise. Water (20 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with DCM (20 mL × 5). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate (3.5 g, 82% yield) as a yellow oil.

[0165] Step B. tert-Butyl (3R)-3-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate. To a 100 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser, tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate (2.4 g, 9.1 mmol) and CsCO (6.0 g, 18 mmol) were added, followed by DMF (30 mL). 5-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 9.1 mmol) was added to the mixture at 25 °C. The mixture was heated to 90 °C and stirred for 2 hours. Saturated ammonium chloride (20 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (28-30% ethyl acetate / petroleum ether) to give tert-butyl (3R)-3-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate (0.48 g, 12% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 378.2 (M+H).

[0166] Step C. tert-Butyl (3R)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Prepared according to Step A of Intermediate 2, using tert-butyl (3R)-3-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (0.42 g, 92% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 352.9 (M+H).

[0167] Step D. tert-Butyl (3R)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Prepared according to the steps of Intermediate 2, using tert-butyl (3R)-3-[4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (0.42 g, 74% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 484.9 (M+H).

[0168] Step E. tert-Butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Prepared according to Step C of Intermediate 2, using tert-butyl (3R)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (0.44 g, 95% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z416.7(M+H).

[0169] [ka] tert-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate [ka] Step A. 4-(tert-Butoxycarbonylamino)cyclohexyl]methanesulfonate. Prepared according to Step A of Intermediate 10, using trans-tert-butyl N-(4-hydroxycyclohexyl)carbamate instead of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate to give 4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate (13 g, 9% yield) as a yellow solid.

[0170] Step B. tert-Butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]carbamate. Prepared according to Step A of Intermediate 9, using trans-[4-(t-butoxycarbonylamino)cyclohexyl]methanesulfonate instead of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate to give tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]carbamate (4.2 g, 31% yield) as a colorless oil.

[0171] Step C. tert-Butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]-N-methylcarbamate. To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]carbamate (1.2 g, 3.0 mmol), followed by THF (20 mL). The solution was cooled to 0 °C and treated with NaH (60%, 0.24 g, 5.9 mmol). After stirring at 0 °C for 1 h, CHCl (0.55 mL, 8.9 mmol) was added, and the reaction was warmed to 25 °C and stirred for 12 h. Water (30 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0–70% EtOAc / petroleum ether) to afford tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]-N-methylcarbamate (1.2 g, 97% yield) as a yellow solid.

[0172] Step D. tert-Butyl N-methyl-N-[4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate. Prepared according to Step A of Intermediate 9, using cis-tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]-N-methylcarbamate instead of tert-butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate to give tert-butyl N-methyl-N-[4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate (1.1 g, 85% yield) as a white solid.

[0173] Step E. tert-Butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Prepared according to Step A of Intermediate 2, using cis-tert-butyl N-methyl-N-[4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methyl-carbamate (0.60 g, 53% yield) as a brown solid.

[0174] Step F [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]-5-methylpyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Prepared according to Step B of Intermediate 2, using cis-tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]-5-methylpyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.60 g, 81% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z583.4(M+H).

[0175] Step G. tert-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Prepared according to Step C of Intermediate 2, using cis-[6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]-5-methylpyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate (0.34 g, 68% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z515.0(M+H).

[0176] [ka] 6-Bromo-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile [ka] Step A. 6-Bromo-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar, 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (0.50 g, 1.6 mmol) was added, followed by DMF (4 mL). Methanesulfonate{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.016 mmol), K2CO3 (0.44 g, 3.2 mmol), and 2-sulfanylbenzonitrile (0.17 g, 1.3 mmol) were added to the mixture at 25 °C. The flask was purged with nitrogen and stirred at 100 °C for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) to give 6-bromo-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.85 g, 72% yield) as a pale yellow solid. LCMS (MM-ES+APCI, Pos): m / z 355.0 (M+H).

[0177] [ka] 6-Bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile [ka] Step A. 6-Bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 40 mL vial equipped with a magnetic stir bar, 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (2.5 g, 8.3 mmol), Xantphos-Pd-G3 (0.47 g, 0.49 mmol), and K2CO3 (2.5 g, 18 mmol) were added, followed by DMF (20 mL). 3-Fluoropyridine-2-thiol (1.2 g, 9.3 mmol) was added to the mixture at 25 °C. The vial was purged with nitrogen for 2 minutes. The mixture was heated to 90 °C and stirred for 1 hour. Water (50 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and slurried in MeOH (20 mL) at 25 °C for 0.5 hours. After filtration and drying under vacuum, 6-bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (2.2 g, 71% yield) was obtained as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 349.3 (M+H).

[0178] V. How to use FGFR wild-type and mutant enzyme assays Activity against FGFR wild-type and mutant enzymes was measured in a biochemical assay using purified intracellular domains of each isoform using CisBio (now PerkinElmer) HTRF KinEASE-TK assay technology (catalog no. 62TK0PEC). Briefly, test compounds were tested in 11-point 1:3 serial dilutions, with typical final concentrations ranging from 10,000 nM to 0.17 nM. Test compounds were dissolved in DMSO and added to the assay plate using acoustic transduction. The enzyme was preincubated with the test compound for 30 minutes, and the assay was initiated by the addition of ATP and TK peptide substrate. After 60 minutes at room temperature, the reaction was quenched with detection reagent and incubated for an additional 60 minutes at room temperature. The plate was read using a multimode reader, and the emission ratio at 665 nm to 615 nm was determined. This ratio was converted to a percent of control (POC): [1 - (high control - sample signal) / (high control - low control)]*100. Wells without compound were used to determine high control values, and wells without enzyme were used to determine low control values. A four-parameter logistic model was used to fit POC values, and the value at which the fitted curve equaled 50 POC was reported as IC using the Signals VitroVivo software package (PerkinElmer). Final assay conditions were 50 mM HEPES (pH 7.5), 10 mM MgCl, 1 mM EDTA, 0.01% Bri®-35, 2 mM MnCl, 1 mM DTT, and 0.5 uM TK peptide. The enzyme source, catalog number, final enzyme concentration, and final ATP concentration can be found in the table below. [Table 1] [Table 2]

[0179] Detection of phosphorylated FGFR1 (pFGFR1) and FGFR2 (pFGFR2). Phosphorylated FGFR1 (pFGFR1) Cellular Assay: KG-1 cells were grown in IMDM supplemented with 20% fetal bovine serum. KG-1 cells were cultured at 10 × 10 5 Cells were plated in 384-well plates at 25 μL / well. Cells were treated with compounds using 3-fold serial dilutions with final concentrations ranging from 10 μM to 0.5 nM. Compounds were incubated on cells for 1 hour at 37°C, 5% CO2.

[0180] After 1 hour of incubation with compounds, cell lysates were prepared and phospho-FGFR1 was measured using the HTRF Phospho-FGFR1 (TYR653 / 654) Detection Kit (CisBio, Catalog No. 64FGFR1Y6PEG). Next, 8 μL of cell lysis buffer (4×) supplemented with 1× Phospho and Total Protein Blocking Reagent (CisBio, Catalog No. 64FGFR1Y6PEG, CisBio, Catalog No. 64KB1AAC) was added to the wells. The cells were incubated with the lysis buffer for 40 minutes under shaking at 4°C. The plate was centrifuged at 1500 rpm for 3 minutes, and then 16 μL of cell lysate was transferred from the cell culture plate to a small volume detection plate, and 4 μL of premixed antibody solution (CisBio, Catalog No. 64FGFR1Y6PEG) was added. The plate was centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 120 minutes, then at 4°C overnight. Plates were read on an EnVision multimode plate reader via HTRF dual wavelength detection. DMSO-treated samples were used to determine percent of control (POC), and control compounds were used to determine 0 POC. A four-parameter logistic curve as a function of compound concentration was fitted to the POC values, yielding the IC. 50 The value is the point where the curve intersects 50 POC.

[0181] Phosphorylated FGFR2-WT (pFGFR2-WT) cell assay: KATOIII cells were grown in the appropriate growth medium IMDM supplemented with 20% fetal bovine serum. 1 × 10 cells were cultured at 1 × 10 5Cells were seeded in 384-well plates at 25 μL per well. Cells were treated with compounds using 3-fold serial dilutions with final concentrations ranging from 10 μM to 0.5 nM. Compounds were incubated on cells for 1 hour at 37°C, 5% CO2.

[0182] After 1 hour of incubation with compounds, cell lysates were prepared and phospho-FGFR2 was measured using an HTRF phospho-FGFR2 (TYR653 / 654) detection kit (CisBio, catalog no. 64FGFR2Y6PEG). Next, 8 μL of cell lysis buffer (4×) supplemented with 1× phospho- and total protein blocking reagent (CisBio, catalog no. 64FGFR2Y6PEG, CisBio, catalog no. 64KB1AAC) was added to the wells. The cells were incubated with the lysis buffer for 40 minutes under shaking at 4°C. The plate was centrifuged at 1500 rpm for 3 minutes, and then 16 μL of cell lysate was transferred from the cell culture plate to a small volume detection plate, and 4 μL of premixed antibody solution (CisBio, catalog no. 64FGFR2Y6PEG) was added. The plate was centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 120 minutes, then at 4°C overnight. Plates were read on an EnVision multimode plate reader via HTRF dual wavelength detection. DMSO-treated samples were used to determine percent of control (POC), and the highest concentration of control compound was used to determine 0 POC. A four-parameter logistic curve as a function of compound concentration was fitted to the POC values ​​to determine the IC. 50 value was determined.

[0183] Phosphorylated FGFR2 mutant (pFGFR2 mutant) cell assay: HEK-293 cells were engineered to express the FGFR2-V564F / I / L or FGFR2-N549K mutations using constructs obtained from GenScript. Cells were grown in the appropriate growth medium, DMEM, supplemented with 10% fetal bovine serum and 150 μg / mL hygromycin. Cells were plated at 7 × 10 in 96-well poly-D-lysine-coated flat-bottom plates. 5Cells were plated at 1000 kJ / well and allowed to attach overnight at 37°C, 5% CO2. Cells were treated with compounds using 3-fold serial dilutions ranging from 1 μM to 0.05 nM in final concentrations. Compounds were incubated on the cells for 1 hour at 37°C, 5% CO2. Cells were stimulated with 100 ng / mL aFGF / bFGF (Gibco, Catalog No. 13241-013, Gibco Catalog No. 13256-029) for 10 minutes at 37°C, 5% CO2. The medium was removed, and cells were lysed with lysis buffer containing phosphatase and protease inhibitors (Sigma, Catalog No. P8340-5ML, Sigma, Catalog No. P5726-5ML). Phosphorylated FGFR2 was measured by ELISA (R&D Systems, Catalog No. DYC684). Optical density was measured for each well using a BioTek Cytation 5 at 450 nm wavelength. DMSO-treated samples were used to determine percent of control (POC), and control compounds were used to determine 0 POC. A four-parameter logistic curve as a function of compound concentration was fitted to the POC values ​​to obtain the IC. 50 The value is the point where the curve intersects 50 POC. [Example]

[0184] VI. Working Examples The following examples are illustrative in nature and not limiting in any way. Intermediate 1 tert-Butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate [ka] Step A. tert-Butyl 3-methylsulfonyloxypiperidine-1-carboxylate. To a 40 mL vial flask equipped with a magnetic stir bar, tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (0.50 g, 2.5 mmol) was added, followed by DCM (12 mL). Triethylamine (0.69 mL, 5.0 mmol) was added to the mixture. The solution was cooled to 0 °C, and methanesulfonic anhydride (0.86 g, 5.0 mmol) was added. The mixture was warmed to 25 °C and stirred for 1 h. Water (10 mL) was added to the reaction, the mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (0.90 g, 99% yield) as a yellow solid, which was used in the next step without further purification.

[0185] Step Bt-Butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial flask equipped with a magnetic stirrer and reflux condenser, tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (0.65 g, 2.3 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.45 g, 2.3 mmol) were added, followed by DMF (12 mL) and CsCO (1.5 g, 4.7 mmol). The mixture was heated to 90 °C and stirred for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate 50 / 1 to 30 / 1) to give the desired product, tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.80 g, 76% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 378.1 (M+H).

[0186] Intermediate 2 t-Butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate [ka] Step At-Butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 250 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser were added 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (6.0 g, 25.2 mmol) and tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (12 g, 30 mmol), followed by dioxane (60 mL) and HO (12 mL). Pd(dba) (0.46 mg, 2.5 mmol), XPhos (0.60 g, 1.3 mmol), and KCO (7.0 g, 50 mmol) were added. The flask was evacuated and backfilled with nitrogen three times, and the reaction was stirred under a nitrogen atmosphere at 90 °C for 1 h. Water (100 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid. The solid was purified by silica gel column chromatography (30–100% ethyl acetate / petroleum ether) to give tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (8.5 g, 79% yield) as a brown solid. LCMS (MM-ES + APCI, Pos): m / z 409.1 (M+H).

[0187] Step Bt-Butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. In a 500 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (10 g, 24 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (18 g, 49 mmol) were added, and DMF (150 mL) was added. DIEA (8.5 mL, 49 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. Water (100 mL) was added to the reaction, and the mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by trituration in ethyl acetate (25 mL) to give tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (9.3 g, 87% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 541.3 (M+H).

[0188] Step Ct-Butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (1.6 g, 3.0 mmol) and LiBr (0.39 g, 4.4 mmol) were added, followed by NMP (20 mL). Tris(acetonitrile)pentamethylcyclopentadienylruthenium(II) trifluoromethanesulfonate (0.10 g, 0.19 mmol) was added, the vial was purged with nitrogen, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with water (100 mL) and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (30-60% ethyl acetate / petroleum ether) to give a brown solid. The solid was purified by trituration with MTBE (30 mL) to give tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.32 g, 63% yield). LCMS (MM-ES+APCI, Pos): m / z 473.2 (M+H).

[0189] Intermediate 3 tert-Butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.75 g, 1.3 mmol), followed by toluene (10 mL). Xantphos (74 mg, 0.13 mmol), Pd(OAc) (33 mg, 0.13 mmol), KPO (0.54 g, 2.5 mmol), and ethyl 3-sulfanylpropanoate (0.26 g, 1.9 mmol) were added to the mixture at 25 °C. The vial was flushed with nitrogen and stirred at 80 °C under a nitrogen atmosphere for 16 hours. Water (25 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (40-50% ethyl acetate / petroleum ether) to give tert-butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (1.3 g, 93% yield) as a yellow gum. LCMS (MM-ES + APCI, Pos): m / z 525.4 (M + H).

[0190] Step B. tert-Butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.20 g, 0.36 mmol), followed by DMF (4 mL). The solution was cooled to 0 °C and treated dropwise with t-BuOK (1 M, 0.47 mL, 0.47 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under reduced pressure to give tert-butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.18 g, crude product), which was used in the next step without further purification.

[0191] Intermediate 4 tert-Butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate [ka] Step At-Butyl N-[(3R)-1-(5-bromo-2-pyridyl)pyrrolidin-3-yl]carbamate. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (0.35 g, 1.9 mmol) in DMSO (7 mL). DIEA (1.3 mL, 7.6 mmol) and 5-bromo-2-fluoropyridine (0.41 g, 2.3 mmol) were added to the mixture. The vial was purged with nitrogen and heated to 90° C. for 1 hour. Water (50 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (25–35% ethyl acetate / petroleum ether) to give tert-butyl N-[(3R)-1-(5-bromo-2-pyridyl)pyrrolidin-3-yl]carbamate (1.6 g, 81% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 344.0 (M+H).

[0192] Step Bt-Butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl N-[(3R)-1-(5-bromo-2-pyridyl)pyrrolidin-3-yl]carbamate (1.0 g, 2.9 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.1 g, 4.3 mmol) were added, followed by dioxane (15 mL). KOAc (0.57 g, 5.8 mmol) and Pd(dppf)Cl (0.22 g, 0.29 mmol) were added to the mixture, which was then stirred at 90 °C under a nitrogen atmosphere for 1 hour. The suspension was filtered, and the filter cake was washed with ethyl acetate (30 mL). The crude product was purified by silica gel column chromatography (20-25% ethyl acetate / petroleum ether) to give tert-butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate (0.70 g, 56% yield) as a brown oil. LCMS (MM-ES+APCI, Pos): m / z 308.4 (M+H).

[0193] Intermediate 5 t-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate [ka] Step At-Butyl N-methyl-N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate. To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate (1.0 g, 2.4 mmol), followed by THF (12 mL). The flask was cooled to 0 °C and evacuated and filled with nitrogen three times. NaH (60%, 0.19 g, 4.8 mmol) was added portionwise to the mixture at 0 °C, followed by CHCl (0.29 mL, 4.8 mmol) in THF (2 mL) at 0 °C, and the reaction was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous ammonium chloride (10 mL), transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give tert-butyl N-methyl-N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate (0.45 g, 37% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 406.1 (M+H).

[0194] Step Bt-Butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Synthesized according to Step A of Intermediate 2, using tert-butyl N-methyl-N-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methyl-carbamate (0.30 g, 82% yield) as a yellow oil.

[0195] Step C. [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]pyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Synthesized according to Step B of Intermediate 2, using tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]pyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.35 g, 84% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 569.0 (M+H).

[0196] Step D t-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Synthesized according to Step C of Intermediate 2, using [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]pyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate (0.13 g, 41% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z499.2(M+H).

[0197] Intermediate 6 t-Butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ka] Step At-Butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate. To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (5.0 g, 27 mmol) and DMAP (0.33 mg, 2.7 mmol) in DCM (67 mL) at 0 °C was added triethylamine (7.4 mL, 53 mmol), followed by tosyl chloride (6.1 g, 32 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with DCM (50 mL), and the organics were washed with HO (100 mL), brine (100 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0–50% ethyl acetate / hexanes) to give tert-butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate (4.3 g, 47% yield). LCMS (MM-ES + APCI, Pos): m / z 242.1 (M-Boc + H).

[0198] Step Bt-Butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2 mmol) in DMF (2.6 mL) was added tert-butyl (R)-3-(tosyloxy)pyrrolidine-1-carboxylate (2.6 g, 7.7 mmol) and CsCO (3.4 g, 10 mmol). The solution was stirred at 80 °C for 2 h. The mixture was diluted with EtOAc (100 mL). The organic phase was washed with HO (100 mL), and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.9 g, quantitative yield), which was used in the next step without further purification. LCMS (MM-ES+APCI, Pos): m / z 364.3 (M+H).

[0199] Step Ct-Butyl (S)-3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.8 g, 5.0 mmol) in dioxane-water (4:1, 17 mL) was added 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (0.80 g, 3.4 mmol) and K2CO3 (0.93 g, 6.7 mmol). The reaction was purged with argon for 5 minutes. Palladium tetrakis (0.19 g, 0.17 mmol) was added and the reaction was stirred at 80 °C for 7 hours. The reaction mixture was diluted with EtOAc (30 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was washed with brine (2x, 50 mL), concentrated in vacuo, and purified by silica gel chromatography (0-100% EtOAc / hexanes) to give tert-butyl (S)-3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.39 g, 30% yield). LCMS (MM-ES+APCI, Pos): m / z 339.20 (M-tBu+H).

[0200] Step D t-Butyl (S)-3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. Synthesized according to Step B of Intermediate 2, using tert-butyl (S)-3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (S)-3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (67 mg, 95% yield). LCMS (MM-ES+APCI, Pos): m / z 471.1 (M-tBu+H).

[0201] Step Et-butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. Synthesized according to Step C of Intermediate 2, using tert-butyl (S)-3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (17 mg, 30% yield). LCMS (MM-ES+APCI, Pos): m / z401.1(M-tBu+H).

[0202] Intermediate 7 4-Methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile [ka] Step At-Butyl (3S)-3-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar was added methylsulfanyl sodium (85 mg, 1.2 mmol), followed by toluene (4 mL). t-Butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.40 g, 0.81 mmol), Pd(OAc) (19 mg, 0.084 mmol), Xantphos (47 mg, 0.081 mmol), and CsCO (0.79 g, 2.4 mmol) were added to the mixture at 25 °C, and the reaction was stirred at 100 °C under a nitrogen atmosphere for 16 h. Water (4 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to give tert-butyl (3S)-3-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.28 g, 68% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 439.1 (M+H).

[0203] Step B. 4-Methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 50 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (60 mg, 0.12 mmol) was added, followed by DCM (1 mL). HCl / dioxane (4 M, 1 mL) was added to the mixture, and the reaction was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (19%-49% no acetonitrile / 0.04% no aqueous ammonia hydroxide + 10 mM no H4HCO3). After lyophilization, 4-methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (19.0 mg, 39% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z339.0(M+H).

[0204] Intermediate 8 t-Butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate [ka] Step At -Butyl (3R)-3-[[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate. Synthesized according to Step A of Intermediate 2, using tert-butyl (3R)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.5 g, 76% yield) as a pale yellow solid. LCMS (MM-ES+APCI, Pos): m / z 423.2 (M+H).

[0205] Step Bt-Butyl (3R)-3-[[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate. Synthesized according to Step B of Intermediate 2, using tert-butyl (3R)-3-[[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.7 g, 93% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 555.0 (M+H).

[0206] Step Ct-Butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate. Synthesized according to Step C of Intermediate 2, using tert-butyl (3R)-3-[[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (0.76 g, 75% yield) as a gray solid. LCMS (MM-ES+APCI, Pos): m / z486.9(M+H).

[0207] Intermediate 9 t-Butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate [ka] Step At-Butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate. To a round-bottom flask equipped with a magnetic stirrer and a reflux condenser, 4-iodo-5-methyl-1H-pyrazole (10 g, 48 mmol), tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (20 g, 72 mmol), and cesium carbonate (31 g, 96 mmol) were added, followed by N,N-dimethylformamide (300 mL). The mixture was stirred at 90° C. for 4.5 hours. Water (600 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (800 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-60% EtOAc / petroleum ether) to afford tert-butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate (4.4 g, 23% yield) as a white solid.

[0208] Step Bt-Butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 250 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate (4.4 g, 11.3 mmol), followed by THF (120 mL). Isopropylmagnesium chloride (2 M, 23 mL, 45 mmol) was added to the mixture and stirred at 25° C. for 1 hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.9 g, 56 mmol) was added to the mixture and stirred at 25° C. for 3 hours. Water (300 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (400 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-10% EtOAc / petroleum ether) to give tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (1.9 g, 40% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 392.4 (M+H).

[0209] Step Ct-Butyl 4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Intermediate 2, using tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to afford tert-butyl 4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (10 g, 80% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 367.0 (M-tBu+H).

[0210] Step D t-Butyl 4-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step B of Intermediate 2, except that tert-butyl 4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (11 g, 85% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 577.1 (M+H).

[0211] Step Et-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Intermediate 2, except that tert-butyl 4-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (11 g, 82% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 430.8 (M+H).

[0212] Intermediate 10 t-Butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate [ka] Step At-Butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate. To a 50 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (3.0 g, 16.0 mmol) and triethylamine (4.5 mL, 32 mmol) were added, followed by DCM (10 mL). The solution was cooled to 0 °C, and a solution of methanesulfonic anhydride (3.4 g, 19 mmol) in DCM (10 mL) was added dropwise. Water (20 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with DCM (20 mL × 5). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate (3.5 g, 82% yield) as a yellow oil.

[0213] Step Bt-Butyl (3R)-3-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate. To a 100 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser, tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate (2.4 g, 9.1 mmol) and CsCO (6.0 g, 18 mmol) were added, followed by DMF (30 mL). 5-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 9.1 mmol) was added to the mixture at 25 °C. The mixture was heated to 90 °C and stirred for 2 hours. Saturated ammonium chloride (20 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (28-30% ethyl acetate / petroleum ether) to give tert-butyl (3R)-3-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate (0.48 g, 12% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 378.2 (M+H).

[0214] Step Ct-Butyl (3R)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Synthesized according to Step A of Intermediate 2, using tert-butyl (3R)-3-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (0.42 g, 92% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 352.9 (M+H).

[0215] Step D t-Butyl (3R)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Synthesized according to the steps of Intermediate 2, using tert-butyl (3R)-3-[4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate, to give tert-butyl (3R)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (0.42 g, 74% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 484.9 (M+H).

[0216] Step Et-butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Synthesized according to Step C of Intermediate 2, using tert-butyl (3R)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (0.44 g, 95% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z416.7(M+H).

[0217] Intermediate 11 t-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate [ka] Step A. 4-(t-Butoxycarbonylamino)cyclohexyl]methanesulfonate. Synthesized according to Step A of Intermediate 10, using trans-tert-butyl N-(4-hydroxycyclohexyl)carbamate instead of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate to give 4-(tert-butoxycarbonylamino)cyclohexyl]methanesulfonate (13 g, 9% yield) as a yellow solid.

[0218] Step Bt-Butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]carbamate. Synthesized according to Step A of Intermediate 9, using trans-[4-(t-butoxycarbonylamino)cyclohexyl]methanesulfonate instead of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate to give tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]carbamate (4.2 g, 31% yield) as a colorless oil.

[0219] Step Ct-Butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]-N-methylcarbamate. To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]carbamate (1.2 g, 3.0 mmol), followed by THF (20 mL). The solution was cooled to 0 °C and treated with NaH (60%, 0.24 g, 5.9 mmol). After stirring at 0 °C for 1 h, CHCl (0.55 mL, 8.9 mmol) was added, and the reaction was warmed to 25 °C and stirred for 12 h. Water (30 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0–70% EtOAc / petroleum ether) to afford tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]-N-methylcarbamate (1.2 g, 97% yield) as a yellow solid.

[0220] Step D t-Butyl N-methyl-N-[4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate. Synthesized according to Step A of Intermediate 9, using cis-tert-butyl N-[4-(4-iodo-5-methylpyrazol-1-yl)cyclohexyl]-N-methylcarbamate instead of tert-butyl 4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate to give tert-butyl N-methyl-N-[4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate (1.1 g, 85% yield) as a white solid.

[0221] Step Et-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Synthesized according to Step A of Intermediate 2, using cis-tert-butyl N-methyl-N-[4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexyl]carbamate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methyl-carbamate (0.60 g, 53% yield) as a brown solid.

[0222] Step F. [6-[1-[4-[t-Butoxycarbonyl(methyl)amino]cyclohexyl]-5-methylpyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Synthesized according to Step B of Intermediate 2, using cis-tert-butyl N-[4-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give [6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]-5-methylpyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.60 g, 81% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z583.4(M+H).

[0223] Step G: t-Butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Synthesized according to Step C of Intermediate 2, using cis-[6-[1-[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]-5-methylpyrazol-4-yl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate (0.34 g, 68% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z515.0(M+H).

[0224] Intermediate 12 6-Bromo-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile [ka] Step A. 6-Bromo-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar, 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (0.50 g, 1.6 mmol) was added, followed by DMF (4 mL). Methanesulfonate{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.016 mmol), K2CO3 (0.44 g, 3.2 mmol), and 2-sulfanylbenzonitrile (0.17 g, 1.3 mmol) were added to the mixture at 25 °C. The flask was purged with nitrogen and stirred at 100 °C for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) to give 6-bromo-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.85 g, 72% yield) as a pale yellow solid. LCMS (MM-ES+APCI, Pos): m / z 355.0 (M+H).

[0225] Intermediate 13 6-Bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile [ka] Step A. 6-Bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 40 mL vial equipped with a magnetic stir bar, 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (2.5 g, 8.3 mmol), Xantphos-Pd-G3 (0.47 g, 0.49 mmol), and K2CO3 (2.5 g, 18 mmol) were added, followed by DMF (20 mL). 3-Fluoropyridine-2-thiol (1.2 g, 9.3 mmol) was added to the mixture at 25 °C. The vial was purged with nitrogen for 2 minutes. The mixture was heated to 90 °C and stirred for 1 hour. Water (50 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and slurried in MeOH (20 mL) at 25 °C for 0.5 hours. After filtration and drying under vacuum, 6-bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (2.2 g, 71% yield) was obtained as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 349.3 (M+H).

[0226] Example 1 [ka] 6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (1) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.30 g, 0.63 mmol), pyridine-2-thiol (0.11 g, 0.95 mmol), and DMF (5 mL) were added. CsCO (0.41 g, 1.3 mmol) was added to the mixture, which was then stirred at 120 °C for 1 hour. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (50-75% EtOAc / petroleum ether) to give tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.17 g, 52% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 502.1 (M+H).

[0227] Step B. 6-[1-[(3S)-3-Piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 50 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.12 g, 0.23 mmol), followed by DCM (2 mL). HCl / dioxane (4 M, 2 mL) was added to the mixture at 25 °C and stirred for 0.5 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (16%-46% acetonitrile / 0.05% aqueous ammonium hydroxide + 10 mM NH4HCO3). After lyophilization, 6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (47 mg, 49% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 402.2 (M+H).

[0228] Example 2 [ka] 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (2) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Example 1, using 3-fluoropyridine-2-thiol instead of pyridine-2, to give tert-butyl (3S)-3-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.12 g, 41% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 520.2 (M+H).

[0229] Step B. 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was carried out according to Step B of Example 1, except that tert-butyl (3S)-3-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (24 mg, 48% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z420.3(M+H).

[0230] Example 3 [ka] 4-[(2-Fluoro-3-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (3) [ka] Step A. Ethyl 3-[(2-fluoro-3-pyridyl)sulfanyl]propanoate. To a 40 mL vial equipped with a magnetic stir bar was added 3-bromo-2-fluoropyridine (1.0 g, 5.7 mmol), ethyl 3-sulfanylpropanoate (0.76 g, 5.7 mmol), Pd(dba) (0.16 g, 0.17 mmol), Xantphos (99 mg, 0.17 mmol), and KPO (1.5 g, 6.8 mmol), followed by dioxane (10 mL). The vial was purged with nitrogen for 2 minutes and stirred at 100 °C under a nitrogen atmosphere for 3 hours. Water (40 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-40% EtOAc / petroleum ether) to give ethyl 3-[(2-fluoro-3-pyridyl)sulfanyl]propanoate (1.0 g, 79% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 230.2 (M+H).

[0231] Step B. 2-Fluoropyridine-3-thiol. To a 40 mL vial equipped with a magnetic stir bar was added ethyl 3-[(2-fluoro-3-pyridyl)sulfanyl]propanoate (0.20 g, 0.87 mmol), followed by DMF (10 mL). The solution was cooled to 0 °C, and t-BuOK (1 M, 1.1 mL) was added dropwise. The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under reduced pressure to give crude 2-fluoropyridine-3-thiol (0.10 g, crude) as a yellow oil, which was used in the next step without further purification.

[0232] Step Ct-Butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.20 g, 0.42 mmol), 2-fluoropyridine-3-thiol (0.10 g, 0.77 mmol), and CsCO (0.32 mg, 0.98 mmol) were added, followed by DMF (10 mL) at 25 °C. The mixture was stirred at 110 °C for 2 hours. Water (30 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-60% EtOAc / petroleum ether) to give tert-butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.30 g, crude product) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 420.4 (M-Boc+H).

[0233] Step D. 4-[(2-Fluoro-3-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 40 mL vial equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.20 g, 0.38 mmol), followed by dichloromethane (5 mL). Hydrochloride in dioxane (4 M, 5 mL) was added to the mixture, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (30%-60% acetonitrile / 0.04% aqueous ammonium hydroxide + 10 mM NH4HCO3). After lyophilization, 4-[(2-fluoro-3-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (2.9 mg, 2% yield) was obtained as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 420.2 (M+H).

[0234] Example 4 [ka] 6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (4) [ka] Step A. Ethyl 3-(3-pyridylsulfanyl)propanoate. Synthesized according to Step A of Example 3, using 3-bromopyridine instead of 3-bromo-2-fluoropyridine, to give ethyl 3-(3-pyridylsulfanyl)propanoate (1.56 g, crude) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 212.6 (M+H).

[0235] Step B. Pyridine-3-thiol. Synthesized according to Step B of Example 3, using ethyl 3-(3-pyridylsulfanyl)propanoate instead of ethyl 3-[(2-fluoro-3-pyridyl)sulfanyl]propanoate to afford pyridine-3-thiol (0.10 g, crude) as a yellow oil.

[0236] Step Ct-Butyl (3S)-3-[4-[3-cyano-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using pyridine-3-thiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.31 g, 94% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 502.3 (M+H).

[0237] Step D. 6-[1-[(3S)-3-Piperidyl]pyrazol-4-yl]-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step D of Example 3, using tert-butyl (3S)-3-[4-[3-cyano-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to obtain 6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (42 mg, 27% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 402.2 (M+H).

[0238] Example 5 [ka] 4-[(3-fluoro-6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (5) [ka] Step A. 3-Fluoro-6-methylpyridine-2-thiol. To a 250 mL three-necked round-bottom flask equipped with a magnetic stir bar, 2-bromo-3-fluoro-6-methylpyridine (2.0 g, 10 mmol) was added, followed by toluene (25 mL). The solution was cooled to -78 °C and purged with nitrogen three times. n-BuLi (2.5 M, 6.3 mL, 15.8 mmol) was added dropwise, and the mixture was stirred at -78 °C for 1 hour. Sulfur (0.64 g, 20 mmol) was added to the mixture, and the mixture was stirred at -78 °C for 0.5 hours and at 25 °C for 1 hour. Water (25 mL) was added to the reaction, and the pH of the mixture was adjusted to 5 using hydrochloric acid (1 M). The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (50–100% EtOAc / petroleum ether) to give 3-fluoro-6-methylpyridine-2-thiol (1.0 g, 58% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 144.3 (M+H).

[0239] Step Bt-Butyl (3S)-3-[4-[3-cyano-4-[(3-fluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to step C of example 3, except that 3-fluoro-6-methylpyridine-2-thiol was used instead of 2-fluoropyridine-3-thiol, to obtain tert-butyl (3S)-3-[4-[3-cyano-4-[(3-fluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.14 g, 79% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 534.5 (M+H).

[0240] Step C. 4-[(3-Fluoro-6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was carried out according to Step D of Example 3, using tert-butyl (3S)-3-[4-[3-cyano-4-[(3-fluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-fluoro-6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (10 mg, 10% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z434.4(M+H).

[0241] Example 6 [ka] 4-[(5-fluoro-6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (6) [ka] Step A. 5-Fluoro-6-methylpyridine-2-thiol. Synthesized according to Step A of Example 5, using 6-bromo-3-fluoro-2-methylpyridine instead of 2-bromo-3-fluoro-6-methylpyridine, to give 5-fluoro-6-methylpyridine-2-thiol (0.29 g, 77% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 144.1 (M+H).

[0242] Step Bt-Butyl (3S)-3-[4-[3-cyano-4-[(5-fluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to step C of example 3, using 5-fluoro-6-methylpyridine-2-thiol instead of 2-fluoropyridine-3-thiol, to obtain tert-butyl (3S)-3-[4-[3-cyano-4-[(5-fluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.17 g, 97% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 534.2 (M+H).

[0243] Step C. 4-[(5-Fluoro-6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was carried out according to Step D of Example 3, except that tert-butyl (3S)-3-[4-[3-cyano-4-[(5-fluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(5-fluoro-6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (60 mg, 44% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z434.0(M+H).

[0244] Example 7 [ka] 4-(1H-indazol-7-ylsulfanyl)-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (7) [ka] Step A. 2-[(7-bromoindazol-1-yl)methoxy]ethyltrimethylsilane. To a solution of 7-bromo-1H-indazole (3.0 g, 15 mmol) in DMF (30 mL) was added SEM-Cl (3.8 g, 23 mmol) and K2CO3 (4.2 g, 31 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (10-20% EA / petroleum ether / ethyl acetate) followed by reverse-phase column chromatography (58-88% acetonitrile / 10 μm NH4HCO3) to give 2-[(7-bromoindazol-1-yl)methoxy]ethyltrimethylsilane (3.9 g, 78% yield) as a colorless oil. LCMS (MM-ES+APCI, Pos): m / z 328.8 (M+H).

[0245] Step B. Ethyl 3-[1-(2-trimethylsilylethoxymethyl)indazol-7-yl]sulfanylpropanoate. Synthesized according to Step A of Example 3, using 2-[(7-bromoindazol-1-yl)methoxy]ethyltrimethylsilane instead of 3-bromo-2-fluoropyridine, to give ethyl 3-[1-(2-trimethylsilylethoxymethyl)indazol-7-yl]sulfanylpropanoate (0.35 g, 67% yield) as a pale yellow oil. LCMS (MM-ES+APCI, Pos): m / z 381.8 (M+H).

[0246] Step C. 1-(2-Trimethylsilylethoxymethyl)indazole-7-thiol. Synthesized according to Step B of Example 3, using ethyl 3-[1-(2-trimethylsilylethoxymethyl)indazol-7-yl]sulfanylpropanoate instead of ethyl 3-[(2-fluoro-3-pyridyl)sulfanyl]propanoate to afford 1-(2-trimethylsilylethoxymethyl)indazole-7-thiol (0.18 g, 73% yield) as a pale yellow oil. LCMS (MM-ES+APCI, Pos): m / z 281.0 (M+H).

[0247] Step D t-Butyl (3S)-3-[4-[3-cyano-4-[1-(2-trimethylsilylethoxymethyl)indazol-7-yl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 1-(2-trimethylsilylethoxymethyl)indazole-7-thiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-[1-(2-trimethylsilylethoxymethyl)indazol-7-yl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.13 g, 36% yield). LCMS (MM-ES+APCI, Pos): m / z 671.5 (M+H).

[0248] Step E. 4-(1H-Indazol-7-ylsulfanyl)-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step D of Example 3, using tert-butyl (3S)-3-[4-[3-cyano-4-[1-(2-trimethylsilylethoxymethyl)indazol-7-yl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-[(2-fluoro-3-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-(1H-indazol-7-ylsulfanyl)-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (24 mg, 29% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z440.9(M+H).

[0249] Example 8 [ka] 6-[1-[(3R)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8) [ka] Step At -Butyl (3R)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Example 1, except that tert-butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to obtain tert-butyl (3R)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (51 mg, 85% yield) as a pale yellow solid. LCMS (MM-ES+APCI, Pos): m / z 502.4 (M+H).

[0250] Step B. 6-[1-[(3R)-3-Piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of Example 1, using (3R)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to obtain 6-[1-[(3R)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (45 mg, 42% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 402.2 (M+H).

[0251] Example 9 [ka] 6-[5-methyl-1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (9) [ka] Step A. 6-[5-Methyl-1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (50 mg, 0.089 mmol) and pyridine-3-thiol (13 mg, 0.11 mmol) were added, followed by DMF (2 mL). CsCO (58 mg, 0.18 mmol), CuI (5.1 mg, 0.027 mmol), and 1,10-phenanthroline (4.8 mg, 0.027 mmol) were added to the mixture at 25 °C. The mixture was stirred at 120 °C for 48 h. The suspension was filtered, and the filter cake was washed with MeOH (5 mL). The concentrate was purified by preparative HPLC (25%-55% acetonitrile / 0.04% aqueous ammonium hydroxide + 10 mM NH4HCO3). After lyophilization, 6-[5-methyl-1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(3-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (11 mg, 30% yield) was obtained as an off-white solid. LCMS (MM-ES + APCI, Pos): m / z 416.1 (M+H).

[0252] Example 10 [ka] 4-[(1R)-1-(3,5-dichloro-4-pyridyl)ethyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (10) [ka] Step A. [(1S)-1-(3,5-Dichloro-4-pyridyl)ethyl]methanesulfonate. To a 40 mL vial equipped with a magnetic stir bar, (1S)-1-(3,5-dichloro-4-pyridyl)ethanol (1.0 g, 5.2 mmol) and triethylamine (1.0 mL, 7.8 mmol) were added, followed by DCM (9 mL). The solution was cooled to 0 °C. Methylsulfonylmethanesulfonate (2.3 g, 13 mmol) in DCM (3 mL) was added dropwise. The mixture was warmed to 25 °C and stirred for 15 minutes. DMAP (63 mg, 0.52 mmol) in DCM (0.5 mL) was added dropwise. The mixture was stirred at 25 °C for 1 hour. Water (30 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl]methanesulfonate (1.3 g, 92% yield), which was used in the next step without further purification.

[0253] Step Bt-Butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.15 g, 0.35 mmol) and [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl]methanesulfonate (0.12 g, 0.42 mmol) were added, followed by DMF (3 mL). CsCO (0.17 mg, 0.53 mmol) was added to the mixture at 25 °C and stirred at 90 °C for 1 h. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (50-60% EtOAc / petroleum ether) to afford tert-butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-(3,5-dichloro-4-pyridyl)ethyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.18 g, 84% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 598.2 (M+H).

[0254] Step C. 4-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-(3,5-dichloro-4-pyridyl)ethyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(1R)-1-(3,5-dichloro-4-pyridyl)ethyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (70 mg, 53% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z499.9(M+H).

[0255] Example 11 [ka] 4-(2-Fluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (11) [ka] Step At -Butyl (3R)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 2-fluorothiophenol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.18 g, 99% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 519.2 (M+H).

[0256] Step B. 6-[1-[(3R)-3-Piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 20 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.17 g, 0.31 mmol), followed by DCM (2 mL). TFA (0.40 mL, 5.4 mmol) was added to the mixture, which was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (31%-61% acetonitrile / 0.05% aqueous ammonium hydroxide + 10 mM NH4HCO3). After lyophilization, 4-(2-fluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.10 g, 72% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 419.1 (M+H).

[0257] Example 12 [ka] 4-[(3-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (12) [ka] Step At -Butyl (3S)-3-[4-[4-[(3-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 3-chloropyridine-2-thiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[4-[(3-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.17 g, crude) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 558.4 (M+Na + ).

[0258] Step B. 4-[(3-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 11, using tert-butyl (3S)-3-[4-[4-[(3-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (41 mg, 34% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z436.0(M+H).

[0259] Example 13 [ka] 4-[(3-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (13) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-[(3-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 3-methylpyridine-2-thiol instead of 2-fluoropyridine-3-thiol to give tert-butyl (3S)-3-[4-[3-cyano-4-[(3-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.26 g, crude) as a yellow solid.

[0260] Step B. 4-[(3-Methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 11, using tert-butyl (3S)-3-[4-[3-cyano-4-[(3-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 27% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z416.2(M+H).

[0261] Example 14 [ka] 4-[(6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (14) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-[(3-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 6-methylpyridine-2-thiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-[(6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.15 g, 74% yield). LCMS (MM-ES+APCI, Pos): m / z 516.5 (M+H).

[0262] Step B. 4-[(6-Methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 11, using tert-butyl (3S)-3-[4-[3-cyano-4-[(6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(6-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (48 mg, 35%) as a white solid. LCMS (MM-ES+APCI, Pos): m / z416.2(M+H).

[0263] Example 15 [ka] 4-(2,3-Difluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (15) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-(2,3-difluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 2,3-difluorobenzenethiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-(2,3-difluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.16 g, 74% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 537.3 (M+H).

[0264] Step B. 4-(2,3-Difluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of Example 1, using tert-butyl (3S)-3-[4-[3-cyano-4-(2,3-difluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to obtain 4-(2,3-difluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (16 mg, 17% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 437.1 (M+H).

[0265] Example 16 [ka] 4-(2,6-Difluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (16) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-(2,3-difluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 2,6-difluorobenzenethiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-(2,6-difluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.22 g, 54% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 537.3 (M+H).

[0266] Step B. 4-(2,6-Difluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of Example 11, using tert-butyl (3S)-3-[4-[3-cyano-4-(2,6-difluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to obtain 4-(2,6-difluorophenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (80 mg, 54% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 437.1 (M+H).

[0267] Example 17 [ka] 4-(2-Methoxyphenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (17) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-(2-methoxyphenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 2-methoxybenzenethiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-(2-methoxyphenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.14 g, 63% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 531.3 (M+H).

[0268] Step B. 4-(2-Methoxyphenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of Example 1, except that tert-butyl (3S)-3-[4-[3-cyano-4-(2-methoxyphenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-(2-methoxyphenyl)sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (55 mg, 64% yield) as a pink solid. LCMS (MM-ES+APCI, Pos): m / z 431.1 (M+H).

[0269] Example 18 [ka] 4-[(6-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (18) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-[(6-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to step C of example 3, using 6-fluoropyridine-2-thiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[3-cyano-4-[(6-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.14 g, 67% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 464.3 (M-tBu+H).

[0270] Step B. 4-[(6-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was carried out according to Step B of Example 1, except that tert-butyl (3S)-3-[4-[3-cyano-4-[(6-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(6-fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (37 mg, 44% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z420.3(M+H).

[0271] Example 19 [ka] 4-[(6-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (19) [ka] Step At -Butyl (3S)-3-[4-[4-[(6-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using 6-chloropyridine-2-thiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[4-[(6-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.15 g, 59% yield) as a pale yellow oil. LCMS (MM-ES+APCI, Pos): m / z 536.3 (M+H).

[0272] Step B. 4-[(6-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3S)-3-[4-[4-[(6-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(6-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (56 mg, 55% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z436.1(M+H).

[0273] Example 20 [ka] 4-[(1R)-1-(2,6-dichlorophenyl)ethyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (20) [ka] Step A. [(1S)-1-(2,6-dichlorophenyl)ethyl]methanesulfonate. To an 8 mL vial equipped with a magnetic stir bar were added (1S)-1-(2,6-dichlorophenyl)ethanol (90 mg, 0.47 mmol) and DMAP (6.0 mg, 0.045 mmol), followed by DCM (2 mL). Triethylamine (0.20 mL, 1.4 mmol) and methylsulfonylmethanesulfonate (0.16 g, 0.94 mmol) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 1 h. Water (5 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give [(1S)-1-(2,6-dichlorophenyl)ethyl]methanesulfonate (0.12 g, 95% yield) as a yellow oil, which was used in the next step without further purification.

[0274] Step Bt-Butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-(2,6-dichlorophenyl)ethyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Example 10, using [(1S)-1-(2,6-dichlorophenyl)ethyl]methanesulfonate instead of [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl]methanesulfonate, to afford tert-butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-(2,6-dichlorophenyl)ethyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.13 g, 83% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 597.5 (M+H).

[0275] Step C. 4-[(1R)-1-(2,6-dichlorophenyl)ethyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-(2,6-dichlorophenyl)ethyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(1R)-1-(2,6-dichlorophenyl)ethyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (54 mg, 55% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z497.1(M+H).

[0276] Example 21 [ka] 4-[(6-amino-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (21) [ka] Step At-Butyl N-(6-sulfanyl-2-pyridyl)carbamate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl N-(6-bromo-2-pyridyl)carbamate (0.90 g, 3.3 mmol) was added, followed by toluene (10 mL). Triisopropyl(sulfanyl)silane (0.92 mL, 4.3 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and Cs2CO3 (1.4 g, 4.3 mmol) were added to the mixture at 25 °C. The vial was purged with nitrogen for 3 minutes and stirred at 100 °C under a nitrogen atmosphere for 15 hours. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (40-50% ethyl acetate / petroleum ether) to give tert-butyl N-(6-sulfanyl-2-pyridyl)carbamate (0.68 g, 80% yield) as an orange solid. LCMS (MM-ES+APCI, Pos): m / z 171.0 (M+H).

[0277] Step Bt-Butyl (3S)-3-[4-[4-[[6-(tert-butoxycarbonylamino)-2-pyridyl]sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using tert-butyl N-(6-sulfanyl-2-pyridyl)carbamate instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-[4-[[6-(tert-butoxycarbonylamino)-2-pyridyl]sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.26 g, 64% yield) as an orange solid. LCMS (MM-ES+APCI, Pos): m / z 517.8 (M+H).

[0278] Step C. 4-[(6-Amino-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3S)-3-[4-[4-[[6-(tert-butoxycarbonylamino)-2-pyridyl]sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(6-amino-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (58 mg, 43% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z417.1(M+H).

[0279] Example 22 [ka] 6-(6-piperazin-1-yl-3-pyridyl)-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (22) [ka] Step At -Butyl 4-[5-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]piperazine-1-carboxylate. Synthesized according to Step A of Intermediate 2, using tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[5-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]piperazine-1-carboxylate (0.24 g, 36% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z 364.9 (M+H).

[0280] Step Bt-Butyl 4-[5-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate. Synthesized according to Step B of Intermediate 2, using tert-butyl 4-[5-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]piperazine-1-carboxylate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[5-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate (0.59 g, 80% yield) as a gray solid. LCMS (MM-ES+APCI, Pos): m / z 553.1 (M+H).

[0281] Step Ct-Butyl 4-[5-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]piperazine-1-carboxylate. Synthesized according to Step C of Intermediate 2, using tert-butyl 4-[5-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[5-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]piperazine-1-carboxylate (0.41 g, 88% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z 485.0 (M+H).

[0282] Step D t-Butyl 4-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate. Synthesized according to Step A of Example 1, except that tert-butyl 4-[5-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]piperazine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate (0.22 g, 53% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 514.3 (M+H).

[0283] Step E. 6-(6-Piperazin-1-yl-3-pyridyl)-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Example 1, Step B, using tert-butyl 4-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 6-(6-piperazin-1-yl-3-pyridyl)-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 33% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 414.3 (M+H).

[0284] Example 23 [ka] 6-(6-morpholino-3-pyridyl)-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (23) [ka] Step A. 4-Hydroxy-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step A of Intermediate 2, using 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]morpholine instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give 4-hydroxy-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.33 g, 58% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z 322.1 (M+H).

[0285] Step B. [3-Cyano-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Synthesized according to Step B of Intermediate 2, using 4-hydroxy-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate, to give [3-cyano-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.3 g, 93% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 454.0 (M+H).

[0286] Step C. 4-Bromo-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step C of Intermediate 2, using [3-cyano-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate, to give 4-bromo-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.21 g, 69% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z 384.2 (M+H).

[0287] Step D t-Butyl 4-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]piperazine-1-carboxylate. Synthesized according to Step A of Example 1, using tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of 4-bromo-6-(6-morpholino-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile to give 6-(6-morpholino-3-pyridyl)-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (52 mg, 35% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 414.9 (M+H).

[0288] Example 24 [ka] 6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (24) [ka] Step A. 2-[(5-bromo-2-pyridyl)oxy]-N,N-dimethylethanamine. To a 40 mL vial flask were added 5-bromo-2-fluoropyridine (1.0 g, 5.7 mmol) and 2-(dimethylamino)ethanol (0.51 g, 5.7 mmol), followed by DMF (15 mL). Cs2CO3 (3.7 g, 11 mmol) was added to the mixture. The flask was purged with nitrogen three times and stirred under a nitrogen atmosphere at 60 °C for 16 h. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (0–10% dichloromethane / methanol) to give 2-[(5-bromo-2-pyridyl)oxy]-N,N-dimethylethanamine (2.5 g, 90% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z246.9(M+H).

[0289] Step B N,N-Dimethyl-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethanamine. To a 50 mL round-bottom flask were added 2-[(5-bromo-2-pyridyl)oxy]-N,N-dimethylethanamine (0.50 g, 2.0 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.78 g, 3.1 mmol), followed by dioxane (15 mL). KOAc (0.60 g, 6.1 mmol) and Pd(dppf)Cl2 (0.15 g, 0.20 mmol) were added to the mixture. The flask was purged with nitrogen three times. The mixture was stirred at 90 °C under a nitrogen atmosphere for 1 hour. The suspension was filtered through a Celite pad, and the Celite was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to give the crude product N,N-dimethyl-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethanamine (1.2 g) as a dark brown gum, which was used in the next step without further purification.

[0290] Step C. 6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step A of Intermediate 2, using N,N-dimethyl-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethanamine instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give 6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (0.80 g, 87% yield) as a brown gum. LCMS (MM-ES+APCI, Pos): m / z 324.2 (M+H).

[0291] Step D. [3-Cyano-6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Synthesized according to Step B of Intermediate 2, using 6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to afford [3-cyano-6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.40 g, crude) as a brown gum, which was used in the next step without further purification.

[0292] Step E. 4-Bromo-6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step C of Intermediate 2, using [3-cyano-6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-bromo-6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.10 g, 24% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 386.1 (M+H).

[0293] Step F. 6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step A of Example 1, using 4-bromo-6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give 6-[6-[2-(dimethylamino)ethoxy]-3-pyridyl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (21 mg, 24% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 417.3 (M+H).

[0294] Example 25 [ka] 6-[6-[(3R)-3-aminopyrrolidin-1-yl]-3-pyridyl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (25) [ka] Step At -Butyl N-[(3R)-1-[5-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate. Synthesized according to Step A of Intermediate 2, using tert-butyl N-[(3R)-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate instead of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[(3R)-1-[5-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate (0.30 g, 46% yield) as a pale solid. LCMS (MM-ES+APCI, Pos): m / z 421.2 (M+H).

[0295] Step B. [6-[6-[(3R)-3-(t-butoxycarbonylamino)pyrrolidin-1-yl]-3-pyridyl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Synthesized according to Step B of Intermediate 2, using tert-butyl N-[(3R)-1-[5-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give [6-[6-[(3R)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-pyridyl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (0.32 g, 88% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 553.3 (M+H).

[0296] Step Ct-Butyl N-[(3R)-1-[5-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate. Synthesized according to Step C of Intermediate 2, using [6-[6-[(3R)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-pyridyl]-3-cyanopyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[(3R)-1-[5-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate (0.20 g, 74% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z485.1(M+H).

[0297] Step D t-Butyl N-[(3R)-1-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]pyrrolidin-3-yl]carbamate. Synthesized according to Step A of Example 1, using tert-butyl N-[(3R)-1-[5-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[(3R)-1-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]pyrrolidin-3-yl]carbamate (0.18 g, crude) as a brown solid.

[0298] Step E. 6-[6-[(3R)-3-aminopyrrolidin-1-yl]-3-pyridyl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl N-[(3R)-1-[5-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]-2-pyridyl]pyrrolidin-3-yl]carbamate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 6-[6-[(3R)-3-aminopyrrolidin-1-yl]-3-pyridyl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (46 mg, 36% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z414.2(M+H).

[0299] Example 26 [ka] 4-[(5-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (26) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-[(5-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.18 g, 0.38 mmol) was added, followed by DMF (4 mL). 5-Methylpyridine-2-thiol (74 mg, 0.57 mmol), CsCO (0.25 g, 0.76 mmol), 1,10-phenanthroline (7.0 mg, 0.040 mmol), and copper iodide (7.0 mg, 0.034 mmol) were added to the mixture at 25 °C. The flask was purged with nitrogen for 2 minutes and stirred at 100 °C under a nitrogen atmosphere for 2 hours. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (50-60% EtOAc / petroleum ether) to give tert-butyl (3S)-3-[4-[3-cyano-4-[(5-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (60 mg, 30% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 516.3 (M+H).

[0300] Step B. 4-[(5-Methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, tert-butyl (3S)-3-[4-[3-cyano-4-[(5-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate using tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(5-methyl-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (26 mg, 65% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z416.0(M+H).

[0301] Example 27 [ka] 4-[(5-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (27) [ka] Step A. (S)-4-((5-fluoropyridin-2-yl)thio)-6-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step A of Example 25, using 5-fluoropyridine-2-thiol instead of 5-methylpyridine-2-thiol, to give (S)-4-((5-fluoropyridin-2-yl)thio)-6-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.13 g, 72% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 463.9 (M-tBu+H).

[0302] Step B. 4-[(5-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was performed according to Step B of Example 1, using tert-butyl (3S)-3-[4-[3-cyano-4-[(5-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(5-fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (32 mg, 34% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z420.0(M-tBu+H).

[0303] Example 28 [ka] 4-[(5-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (28) [ka] Step At -Butyl (3S)-3-[4-[4-[(5-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Example 25, using 5-chloropyridine-2-thiol instead of 5-methylpyridine-2-thiol, to give tert-butyl (3S)-3-[4-[4-[(5-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (99 mg, 46% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 536.1 (M+H).

[0304] Step B. 4-[(5-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using (3S)-3-[4-[4-[(5-chloro-2-pyridyl)sulfanyl]-3-cyanopyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 4-[(5-chloro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (34 mg, 54% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z436.2(M+H).

[0305] Example 29 [ka] 4-Phenylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (29) [ka] Step At -Butyl (3S)-3-[4-(3-cyano-4-phenylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step C of Example 3, using benzenethiol instead of 2-fluoropyridine-3-thiol, to give tert-butyl (3S)-3-[4-(3-cyano-4-phenylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.20 g, crude product) as a dark brown oil. LCMS (MM-ES+APCI, Pos): m / z 501.0 (M+H).

[0306] Step B. 4-Phenylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of example 11, using tert-butyl (3S)-3-[4-(3-cyano-4-phenylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of 2-fluoropyridine-3-thiol to give 4-phenylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 23% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 401.2 (M+H).

[0307] Example 30 [ka] 6-[1-[(3S)-1-(2-hydroxyacetyl)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (30) [ka] Step A. 6-[1-[(3S)-1-[2-[t-butyl(dimethyl)silyl]oxyacetyl]-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar, 2-[tert-butyl(dimethyl)silyl]oxyacetic acid (72 mg, 0.38 mmol) was added, followed by DMF (1 mL). HATU (0.14 g, 0.37 mmol), DIEA (0.13 mL, 0.75 mmol), and 6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.11 g, 0.25 mmol) were stirred at 25 °C for 1 h. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel chromatography (50–100% EtOAc / petroleum ether) to afford 6-[1-[(3S)-1-[2-[tert-butyl(dimethyl)silyl]oxyacetyl]-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl), pyrazolo[1,5-a]pyridine-3-carbonitrile (0.14 mg, 91% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 574.2 (M+H).

[0308] Step B. 6-[1-[(3S)-1-(2-hydroxyacetyl)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using 6-[1-[(3S)-1-[2-[tert-butyl(dimethyl)silyl]oxyacetyl]-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 6-[1-[(3S)-1-(2-hydroxyacetyl)-3-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (32 mg, 30% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z460.1(M+H).

[0309] Example 31 [ka] 4-[(4-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (31) [ka] Step At -Butyl (3S)-3-[4-[4-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to step A of example 25, using 4-fluoropyridine-2-thiol instead of 5-methylpyridine-2-thiol, to obtain tert-butyl (3S)-3-[4-[3-cyano-4-[(4-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (25 mg, 12% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 520.2 (M+H).

[0310] Step B. 4-[(4-Fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was carried out according to Step B of Example 1, except that tert-butyl (3S)-3-[4-[3-cyano-4-[(4-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(4-fluoro-2-pyridyl)sulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (5 mg, 37% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z420.0(M+H).

[0311] Example 32 [ka] 6-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]-4-methylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (32) [ka] Step A. 4-Hydroxy-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 40 mL flask equipped with a magnetic stir bar were added 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.0 g, 4.2 mmol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.4 g, 5.0 mmol), followed by dioxane (20 mL) and HO (4 mL). KCO (1.2 g, 8.4 mmol), Pd(dba) (80 mg, 0.087 mmol), and XPhos (0.10 g, 0.21 mmol) were added to the mixture at 25 °C. The flask was purged with nitrogen, heated to 90 °C, and stirred for 16 h. Water (40 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by slurry (50% petroleum ether / ethyl acetate) (20 mL). After filtration and drying under vacuum, 4-hydroxy-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.3 g, 88% yield) was obtained as a brown solid. LCMS (MM-ES + APCI, Pos): m / z 226.0 (M-THP + H).

[0312] Step B. [3-Cyano-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate. Synthesized according to Step B of Intermediate 2, using 4-hydroxy-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give [3-cyano-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (1.8 g, 68% yield) as a gray solid. LCMS (MM-ES+APCI, Pos): m / z 464.1 (M+Na+H).

[0313] Step C. 4-Bromo-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Intermediate 2, using [3-cyano-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-bromo-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (680 mg, 43% yield) as a green solid. LCMS (MM-ES+APCI, Pos): m / z 290.0 (M-THP+H).

[0314] Step D. 4-Bromo-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 50 mL flask equipped with a magnetic stir bar was added 4-bromo-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.68 g, 1.7 mmol), followed by DCM (5 mL). HCl / dioxane (4 M, 5 mL) was added to the mixture at 25 °C and stirred for 1 h. The mixture was concentrated under reduced pressure to give 4-bromo-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.55 g, 98% yield, HCl salt) as a white solid, which was used in the next step without further purification.

[0315] Step Et-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, 4-bromo-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.55 g, 1.7 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (1.0 g, 3.8 mmol) were added, followed by DMF (8 mL). CsCO (1.7 g, 5.1 mmol) was added to the mixture at 25 °C. The mixture was stirred at 100 °C for 48 h. Water (8 mL) was added to the reaction mixture and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (30–50% petroleum ether / ethyl acetate) to give tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.41 g, 46% yield) as a white solid. LCMS (MM-ES + APCI, Pos): m / z 416.8 (M-tBu + H).

[0316] Step F. tert-Butyl 4-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate. To an 8 mL vial equipped with a magnetic stir bar, tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.20 g, 0.38 mmol) and sodium thiomethoxide (41 mg, 0.58 mmol) were added, followed by toluene (3 mL). Pd(OAc) (9.0 mg, 0.040 mmol), Xantphos (25 mg, 0.043 mmol), and CsCO (0.38 g, 1.17 mmol) were added to the mixture at 25 °C. The vial was purged with nitrogen and stirred at 100 °C for 16 h. Water (2 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (30-50% EtOAc / petroleum ether) to afford tert-butyl 4-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.14 g, 65% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 383.0 (M-tBu+H).

[0317] Step G. 4-Methylsulfanyl-6-[1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl 4-[4-(3-cyano-4-methylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 4-methylsulfanyl-6-[1-(4-piperidyl)pyrazol-4-ylazolo[1,5-a]pyridine-3-carbonitrile (88 mg, 99% yield, HCl salt) as a white solid, which was used in the next step without further purification.

[0318] Step H. 6-[1-(1-Isopropyl-4-piperidyl)pyrazol-4-yl]-4-methylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL flask equipped with a magnetic stir bar, 4-methylsulfanyl-6-[1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (68 mg, 0.18 mmol) and 2-iodopropane (48 mg, 0.28 mmol) were added, followed by MeCN (1.5 mL). K2CO3 (78 mg, 0.56 mmol) was added to the mixture and stirred at 70 °C for 4 h. Water (5 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative HPLC (29%-59% acetonitrile / 0.04% aqueous ammonium hydroxide + 10 mM NH4HCO3). After lyophilization, 6-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]-4-methylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (69 mg, 77% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 381.1 (M+H).

[0319] Example 33 [ka] 6-[1-[(3S)-1-(2-hydroxyethyl)-3-piperidyl]pyrazol-4-yl]-4-methylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (33) [ka] Step A. 4-Methylsulfanyl-6-[1-[(3S)-1-(2-tetrahydropyran-2-yloxyethyl)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial, 2-(2-bromoethoxy)tetrahydropyran (89 mg, 0.42 mmol) and 4-methylsulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.12 g, 0.28 mmol) were added, followed by DMF (1.5 mL). CsCO (0.19 g, 0.59 mmol) was added to the mixture at 25 °C. The mixture was stirred at 90 °C for 34 h. Water (2 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (2 mL × 3). The combined organic phase was washed with brine (6 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 4-methylsulfanyl-6-[1-[(3S)-1-(2-tetrahydropyran-2-yloxyethyl)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.14 g, 84% yield) as a brown oil, which was used in the next step without further purification.

[0320] Step B. 6-[1-[(3S)-1-(2-hydroxyethyl)-3-piperidyl]pyrazol-4-yl]-4-methylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using 4-methylsulfanyl-6-[1-[(3S)-1-(2-tetrahydropyran-2-yloxyethyl)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 6-[1-[(3S)-1-(2-hydroxyethyl)-3-piperidyl]pyrazol-4-yl]-4-methylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (15 mg, 14% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 382.2 (M+H).

[0321] Example 34 [ka] 6-[1-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]methyl]pyrazol-4-yl]-4-isopropylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (34) [ka] Step At -Butyl (3R)-3-[[4-(3-cyano-4-isopropylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate. Synthesized according to Step F of Example 32, except that tert-butyl (3R)-3-[[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate was used instead of tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate and propane-2-thiol was used instead of methylsulfanyl sodium to give tert-butyl (3R)-3-[[4-(3-cyano-4-isopropylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (0.26 g, 80% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z481.2(M+H).

[0322] Step B. 4-Isopropylsulfanyl-6-[1-[[(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3R)-3-[[4-(3-cyano-4-isopropylsulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 4-isopropylsulfanyl-6-[1-[[(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.18 g, crude, HCl salt) as a yellow solid, which was not further purified.

[0323] Step C. 6-[1-[[(3R)-1-[2-[t-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]methyl]pyrazol-4-yl]-4-isopropylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar, 4-isopropylsulfanyl-6-[1-[[(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.18 g, 0.43 mmol) and 2-bromoethoxy-tert-butyl-dimethylsilane (0.12 mg, 0.52 mmol) were added, followed by DMF (3 mL). KCO (0.12 g, 0.87 mmol) and NaI (13 mg, 0.087 mmol) were added to the mixture at 25 °C. The mixture was stirred at 80 °C for 21 h. Water (5 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 6-[1-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]methyl]pyrazol-4-yl]-4-isopropylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.23 g, crude) as a brown oil, which was used without further purification.

[0324] Step D. 6-[1-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]methyl]pyrazol-4-yl]-4-isopropylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using 6-[1-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]methyl]pyrazol-4-yl]-4-isopropylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 6-[1-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]methyl]pyrazol-4-yl]-4-isopropylsulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (19 mg, 12% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z425.2(M+H).

[0325] Example 35 [ka] 6-[1-[(3S)-1-(2-hydroxyethyl)-3-piperidyl]pyrazol-4-yl]-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (35) [ka] Step A. [(1S)-1-Methylpropyl]methanesulfonate. To a 40 mL round-bottom flask equipped with a magnetic stir bar was added (2S)-butan-2-ol (0.40 g, 5.4 mmol), followed by DCM (8 mL). Triethylamine (2.3 mL, 16 mmol) and methylsulfonyl chloride (1.9 g, 11 mmol) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 1 hour. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give [(1S)-1-methylpropyl]methanesulfonate (0.80 g, 97% yield) as a yellow liquid, which was used in the next step without further purification.

[0326] Step Bt-Butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl (3S)-3-[4-(3-cyano-4-sulfanylpyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate (0.35 g, 0.82 mmol), followed by DMF (5 mL). [(1S)-1-Methylpropyl]methanesulfonate (0.19 g, 1.2 mmol) and CsCO (0.40 mg, 1.2 mmol) were added to the mixture at 25 °C. The mixture was stirred at 90 °C for 1 hour. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (25–50% EtOAc / petroleum ether) to give tert-butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.30 g, 71% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 481.0 (M+H).

[0327] Step C. 4-[(1R)-1-Methylpropyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3S)-3-[4-[3-cyano-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 4-[(1R)-1-methylpropyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.22 g, 96% yield) as a yellow solid, which was used in the next step without further purification. LCMS (MM-ES+APCI, Pos): m / z381.3(M+H).

[0328] Step D. 4-(((R)-sec-butyl)thio)-6-(1-((3S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step C of Example 35, using 4-[(1R)-1-methylpropyl]sulfanyl-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile instead of 4-isopropylsulfanyl-6-[1-[[(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile to give 4-(((R)-sec-butyl)thio)-6-(1-((3S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.10 g, 34% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z539.5(M+H).

[0329] Step E. 6-[1-[(3S)-1-(2-hydroxyethyl)-3-piperidyl]pyrazol-4-yl]-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using 6-[1-[(3S)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]pyrazol-4-yl]-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 6-[1-[(3S)-1-(2-hydroxyethyl)-3-piperidyl]pyrazol-4-yl]-4-[(1R)-1-methylpropyl]sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (43 mg, 68% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z425.3(M+H).

[0330] Example 36 [ka] 6-[1-[1-(2-hydroxyacetyl)-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (36) [ka] Step At -Butyl 4-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Example 1, using tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.96 g, 59% yield) as a pale yellow solid.

[0331] Step B. 6-[1-(4-piperidyl)pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl 4-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to provide 6-[1-(4-piperidyl)pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.80 g, crude, HCl salt) as a pale yellow solid, which was used without further purification.

[0332] Step C. 6-[1-[1-[2-[t-Butyl(dimethyl)silyl]oxyacetyl]-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 40 mL vial equipped with a magnetic stir bar, 2-[tert-butyl(dimethyl)silyl]oxyacetic acid (98 mg, 0.51 mmol), HOBt (98 mg, 0.72 mmol), and EDCI (0.14 g, 0.70 mmol) were added, followed by DCM (5 mL). DIEA (0.30 mL, 1.7 mmol) was added to the mixture at 25 °C. The mixture was stirred at 25 °C for 30 minutes. 6-[1-(4-piperidyl)pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.15 g, 0.34 mmol) was added, and the mixture was stirred at 25 °C for 20.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (50-55% EtOAc / petroleum ether) to give 6-[1-[1-[2-[tert-butyl(dimethyl)silyl]oxyacetyl]-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (60 mg, 0.097 mmol, 28% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z 574.3 (M+H).

[0333] Step D. 6-[1-[1-(2-hydroxyacetyl)-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using 6-[1-[1-2-[tert-butyl(dimethyl)silyl]oxyacetyl]-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 6-[1-[1-(2-hydroxyacetyl)-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (21 mg, 64% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z460.0(M+H).

[0334] Example 37 [ka] 6-[1-[1-[(2R)-1-methylpyrrolidine-2-carbonyl]-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (37) [ka] Step A. 6-[1-[1-[(2R)-1-Methylpyrrolidine-2-carbonyl]-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar, (2R)-1-methylpyrrolidine-2-carboxylic acid (60 mg, 0.46 mmol) and HATU (0.22 g, 0.57 mmol) were added, followed by DMF (3 mL). DIEA (0.19 mL, 1.1 mmol) was added to the mixture at 25° C. and stirred for 30 minutes. 6-[1-(4-piperidyl)pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.12 g, 0.27 mmol) was added to the mixture and stirred at 25° C. for 2 hours. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative HPLC (19%-49% acetonitrile / water (10 mM HHCO). After lyophilization, 6-[1-[1-[(2R)-1-methylpyrrolidine-2-carbonyl]-4-piperidyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (73 mg, 54% yield) was obtained as a yellow solid. LCMS (MM-ES + APCI, Pos): m / z 513.3 (M + H).

[0335] Example 38 [ka] 6-[1-[4-(methylamino)cyclohexyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (38) [ka] Step At -Butyl N-[4-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Synthesized according to Step A of Example 1, except that tert-butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]cyclohexyl]-N-methylcarbamate was used instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]cyclohexyl]-N-methylcarbamate (80 mg, 63% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 530.2 (M+H).

[0336] Step B. 6-[1-[4-(methylamino)cyclohexyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of Example 1, except that tert-butyl N-[4-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]cyclohexyl]-N-methylcarbamate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 6-[1-[4-(methylamino)cyclohexyl]pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (37 mg, 67% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 430.4 (M+H).

[0337] Example 39 [ka] 6-[1-[(3S)-1-acetyl-3-piperidyl]pyrazol-4-yl]-4-[2-(dimethylamino)ethylsulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (39) [ka] Step At -Butyl (3S)-3-[4-[3-cyano-4-[2-(dimethylamino)ethylsulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Example 10, using 2-bromo-N,N-dimethyl-ethanamine instead of [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl]methanesulfonate, to give tert-butyl (3S)-3-[4-[3-cyano-4-[2-(dimethylamino)ethylsulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (0.17 g, 96% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 496.5 (M+H).

[0338] Step B. 4-[2-(Dimethylamino)ethylsulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl (3S)-3-[4-[3-cyano-4-[2-(dimethylamino)ethylsulfanyl]pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[2-(dimethylamino)ethylsulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.12 g, 99% yield) as a yellow solid.

[0339] Step C. 6-[1-[(3S)-1-Acetyl-3-piperidyl]pyrazol-4-yl]-4-[2-(dimethylamino)ethylsulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar was added 4-[2-(dimethylamino)ethylsulfanyl]-6-[1-[(3S)-3-piperidyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.10 g, 0.23 mmol), followed by DCM (2 mL). The solution was cooled to 0 °C, and triethylamine (70 mg, 0.69 mmol) and acetyl chloride (22 mg, 0.28 mmol) were added dropwise at 0 °C. The mixture was warmed to 25 °C and stirred for 0.5 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (19%-49% acetonitrile / 0.05% aqueous ammonium hydroxide). After lyophilization, 6-[1-[(3S)-1-acetyl-3-piperidyl]pyrazol-4-yl]-4-[2-(dimethylamino)ethylsulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (46 mg, 45% yield) was obtained as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 438.2 (M+H).

[0340] Example 40 [ka] 6-(1-((S)-1-(methyl-L-prolyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-4-(pyridin-2-ylthio)pyrazolo[1,5-a]pyridine-3-carbonitrile (40) [ka] Step At-Butyl (S)-3-(4-(3-cyano-4-(pyridin-2-ylthio)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate. Synthesized according to Step A of Experiment 1, using tert-butyl (S)-3-(4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (S)-3-(4-(3-cyano-4-(pyridin-2-ylthio)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (9 mg, 53% yield). LCMS (MM-ES+APCI, Pos): m / z 488.3 (M+H).

[0341] Step B. (S)-4-(pyridin-2-ylthio)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step B of Example 1, except that tert-butyl (S)-3-(4-(3-cyano-4-(pyridin-2-ylthio)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to obtain (S)-4-(pyridin-2-ylthio)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (84 mg, quantitative yield). LCMS (MM-ES+APCI, Pos): m / z 388.2 (M+H).

[0342] Step C. 6-(1-((S)-1-(methyl-L-prolyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-4-(pyridin-2-ylthio)pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step A of Example 37, except that (S)-4-(pyridin-2-ylthio)-6-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile was used instead of 6-[1-(4-piperidyl)pyrazol-4-yl]-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridine-3-carbonitrile, and (2S)-1-methylpyrrolidine-2-carboxylic acid was used instead of (2R)-1-methylpyrrolidine-2-carboxylic acid to give 6-(1-((S)-1-(methyl-L-prolyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-4-(pyridin-2-ylthio)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 65% yield). LCMS (MM-ES+APCI, Pos): m / z499.3(M+H).

[0343] Example 41 [ka] 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (41) [ka] Step At -Butyl 4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Experiment 1, using tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (2.8 g, 99% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 534.2 (M+H).

[0344] Step B. 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was performed according to Step B of Example 1, using tert-butyl 4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (35 mg, 46% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z434.1(M+H).

[0345] Example 42 [ka] 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (42) [ka] Step At -Butyl (3R)-3-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate. Synthesized according to Step A of Experiment 1, using tert-butyl (3R)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (88 mg, 66% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z520.1(M+H).

[0346] Step B. 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesis was carried out according to step B of Example 1, except that tert-butyl (3R)-3-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (34 mg, 49% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z420.0(M+H).

[0347] Example 43 [ka] 4-(2-Cyanophenyl)sulfanyl-6-[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (43) [ka] Step At -Butyl 4-[4-[3-cyano-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Experiment 1, except that tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate and 2-sulfanylbenzonitrile was used instead of pyridine-2-thiol to give tert-butyl 4-[4-[3-cyano-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (166 mg, 74% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z540.3(M+H).

[0348] Step B. 4-(2-Cyanophenyl)sulfanyl-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl 4-[4-[3-cyano-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-(2-cyanophenyl)sulfanyl-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (24 mg, 48% yield) as a white solid.

[0349] Step C. 4-(2-Cyanophenyl)sulfanyl-6-[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 40 mL vial equipped with a magnetic stir bar was added 4-(2-cyanophenyl)sulfanyl-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (70 mg, 0.15 mmol, HCl salt), followed by DCE (10 mL). Acetic acid (0.05 mL, 0.88 mmol) and formaldehyde (0.021 mL, 0.29 mmol) were added to the mixture, and the reaction was stirred at 30 °C for 0.5 h. NaBH(OAc) (94 mg, 0.44 mmol) was added under nitrogen. The reaction was stirred at 30 °C for 1 h, concentrated under reduced pressure, and purified by preparative HPLC (25%-55% acetonitrile / 0.04% aqueous ammonium hydroxide + 10 mM NH4HCO3) to give 4-(2-cyanophenyl)sulfanyl-6-[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (28 mg, 42% yield) as a white solid. LCMS (MM-ES + APCI, Pos): m / z 454.3 (M+H).

[0350] Example 44 [ka] 4-[(1-methyl-6-oxo-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (44) [ka] Step A. 1-Methyl-6-sulfanyl-pyridin-2-one. To a 10 mL round-bottom flask equipped with a magnetic stir bar was added 6-bromo-1-methylpyridin-2-one (0.15 g, 0.79 mmol), followed by DMF (2 mL) and HO (1 mL). Sodium hydrosulfide (90 mg, 1.6 mmol) was added to the mixture, which was stirred at 60 °C for 1 hour under a nitrogen atmosphere. Water (6 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (2 mL × 3). The combined organic layers were concentrated under reduced pressure to give 1-methyl-6-sulfanyl-pyridin-2-one (0.28 g, crude product) as a yellow gum.

[0351] Step Bt-Butyl 4-[4-[3-cyano-4-[(1-methyl-6-oxo-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. To a 10 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (0.16 g, 0.33 mmol) and 1-methyl-6-sulfanyl-pyridin-2-one (0.28 g, 2.0 mmol) were added, followed by DMSO (2 mL). DIEA (0.13 mL, 0.76 mmol) was added to the mixture. The flask was purged with nitrogen three times and stirred at 110 °C under a nitrogen atmosphere for 16 hours. Water (6 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (2 mL × 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative TLC (1:1 petroleum ether / ethyl acetate) to give tert-butyl 4-[4-[3-cyano-4-[(1-methyl-6-oxo-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (80 mg, 45% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 546.4 (M+H).

[0352] Step C. 4-[(1-methyl-6-oxo-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, except that tert-butyl 4-[4-[3-cyano-4-[(1-methyl-6-oxo-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(1-methyl-6-oxo-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 24% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z446.0(M+H).

[0353] Example 45 [ka] 6-[5-Methyl-1-(4-piperidyl)pyrazol-4-yl]-4-[(2-oxo-1H-pyridin-4-yl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (45) [ka] Step A. 4-Bromo-1-(2-trimethylsilylethoxymethyl)pyridin-2-one. Synthesized according to Step A of Example 7, using 4-bromo-1H-pyridin-2-one instead of 7-bromo-1H-indazole, to give 4-bromo-1-(2-trimethylsilylethoxymethyl)pyridin-2-one (0.32 g, 44% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 303.9 (M+H).

[0354] Step B. 4-Sulfanyl-1-(2-trimethylsilylethoxymethyl)pyridin-2-one. Synthesized according to Step A of Example 45, using 4-bromo-1-(2-trimethylsilylethoxymethyl)pyridin-2-one instead of 6-bromo-1-methylpyridin-2-one, to give 4-sulfanyl-1-(2-trimethylsilylethoxymethyl)pyridin-2-one (0.13 g, crude) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 258.0 (M+H).

[0355] Step Ct-Butyl 4-[4-[3-cyano-4-[[2-oxo-1-(2-trimethylsilylethoxymethyl)-4-pyridyl]sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step B of Example 45, using 4-sulfanyl-1-(2-trimethylsilylethoxymethyl)pyridin-2-one instead of 1-methyl-6-sulfanylpyridin-2-one, to give tert-butyl 4-[4-[3-cyano-4-[[2-oxo-1-(2-trimethylsilylethoxymethyl)-4-pyridyl]sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (74 mg, 77% yield) as a colorless gum. LCMS (MM-ES+APCI, Pos): m / z 662.4 (M+H).

[0356] Step D. 6-[5-Methyl-1-(4-piperidyl)pyrazol-4-yl]-4-[(2-oxo-1H-pyridin-4-yl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 11, using tert-butyl 4-[4-[3-cyano-4-[[2-oxo-1-(2-trimethylsilylethoxymethyl)-4-pyridyl]sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-fluorophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]-4-[(2-oxo-1H-pyridin-4-yl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 48% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z423.3(M+H).

[0357] Example 46 [ka] 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[4-(methylamino)cyclohexyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (46) [ka] Step At -Butyl N-[4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate. Synthesized according to Step A of Experiment 1, using tert-butyl N-[4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl N-[4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate (90 mg, 82% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z562.2(M+H).

[0358] Step B. 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[4-(methylamino)cyclohexyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl N-[4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]cyclohexyl]-N-methylcarbamate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[4-(methylamino)cyclohexyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (12 mg, 49% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z462.4(M+H).

[0359] Example 47 [ka] 4-(2-cyano-3-methylphenyl)sulfanyl-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (47) [ka] Step A. 2-Methyl-6-sulfanylbenzonitrile. To a 40 mL vial equipped with a magnetic stir bar, 2-fluoro-6-methylbenzonitrile (0.30 g, 2.2 mmol) was added, followed by DMF (5 mL) at 25 °C. Sodium sulfide (0.12 mL, 2.4 mmol) was added, and the mixture was stirred under a nitrogen atmosphere at 25 °C for 19 h. The reaction mixture was quenched with 1 M NaOH (10 mL). The mixture was washed with DCM (10 mL × 3). The pH of the aqueous layer was adjusted to 1-2 with 12 M HCl and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (20-30% EtOAc / petroleum ether) to give 2-methyl-6-sulfanylbenzonitrile (0.17 g, 51% yield) as a white solid.

[0360] Step Bt-Butyl 4-[4-[3-cyano-4-(2-cyano-3-methylphenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. To a 40 mL vial equipped with a magnetic stir bar, tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (0.20 g, 0.41 mmol) and 2-methyl-6-sulfanylbenzonitrile (73 mg, 0.49 mmol) were added, followed by DMF (4 mL) at 25 °C. K2CO3 (0.17 g, 1.2 mmol) was added, and the reaction was purged with nitrogen for 2 minutes and stirred at 110 °C for 18 hours. Water (15 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (10–50% EtOAc / petroleum ether) to give tert-butyl 4-[4-[3-cyano-4-(2-cyano-3-methylphenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (0.23 g, 99% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 554.4 (M+H).

[0361] Step C. 4-(2-Cyano-3-methylphenyl)sulfanyl-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl 4-[4-[3-cyano-4-(2-cyano-3-methylphenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-(2-cyano-3-methylphenyl)sulfanyl-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (98 mg, 58% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z454.3(M+H).

[0362] Example 48 [ka] 6-[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (48) [ka] Step A. 7-Bromo-1H-pyrazolo[3,4-c]pyridine. To a solution of 2-bromo-4-methylpyridin-3-amine (5.8 g, 31 mmol) in AcOH (50 mL) was added KOAc (4.0 g, 40 mmol) and NaNO (4.5 g, 65 mmol) in water (14 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. Aqueous NaHCO was added to the mixture until the pH of the solution reached 8, and the aqueous layer was extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (0–30% EtOAc / petroleum ether) to give 7-bromo-1H-pyrazolo[3,4-c]pyridine (6.4 g, 98% yield) as a white solid. LCMS (MM-ES + APCI, Pos): m / z 198.0 (M+H).

[0363] Step B. 7-Bromo-1-methylpyrazolo[3,4-c]pyridine. To a stirred solution of 7-bromo-1H-pyrazolo[3,4-c]pyridine (6.4 g, 30 mmol) in DMF (65 mL) was added NaH (60%, 2.4 g, 61 mmol). The reaction mixture was stirred at 25 °C for 1 h. MeI (2.8 mL, 45.5 mmol) was added to the mixture, and the reaction was stirred at 25 °C for 11 h. Water (200 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (0–30% EtOAc / petroleum ether) to give 7-bromo-1-methylpyrazolo[3,4-c]pyridine (1.5 g, 23% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z212.1(M+H).

[0364] Step C. 1-Methylpyrazolo[3,4-c]pyridine-7-thiol. To a solution of 7-bromo-1-methylpyrazolo[3,4-c]pyridine (0.70 g, 3.3 mmol) in EtOH (5 mL) and HO (1 mL) was added thiourea (0.37 g, 4.9 mmol). The mixture was stirred at 100 °C for 4 h. The reaction was filtered. The filtrate was concentrated under reduced pressure and purified by recrystallization from EtOAc (15 mL) to give 1-methylpyrazolo[3,4-c]pyridine-7-thiol (0.44 g, 81% yield) as a yellow solid. LCMS (MM-ES + APCI, Pos): m / z 165.9 (M + H).

[0365] Step D t-Butyl 4-[4-[3-cyano-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. Synthesized according to Step A of Experiment 1, except that tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)pyrazol-1-yl]piperidine-1-carboxylate to give tert-butyl 4-[4-[3-cyano-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (80 mg, 35% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 570.3 (M+H).

[0366] Step E. 6-[5-Methyl-1-(4-piperidyl)pyrazol-4-yl]-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, using tert-butyl 4-[4-[3-cyano-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (80 mg, crude, HCl salt) as a white solid.

[0367] Step F. 6-[5-Methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar was added 6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (70 mg, 0.14 mmol), followed by DCE (2 mL). Formaldehyde (37% in water, 0.21 mL, 2.8 mmol) and acetic acid (0.23 g, 0.83 mmol) were added to the mixture at 25 °C and stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (88 mg, 0.41 mmol) was added, and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (23%-53% acetonitrile / water (10 mM NH4HCO3)). After lyophilization, 6-[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-(1-methylpyrazolo[3,4-c]pyridin-7-yl)sulfanylpyrazolo[1,5-a]pyridine-3-carbonitrile (45 mg, 67% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 484.2 (M+H).

[0368] Example 49 [ka] 4-[(3,5-Difluoro-6-methyl-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (49) [ka] Step A. Ethyl 3-[(6-bromo-3,5-difluoro-2-pyridyl)sulfanyl]propanoate. To an 8 mL vial equipped with a magnetic stir bar, 2,6-dibromo-3,5-difluoropyridine (0.30 g, 1.1 mmol) and ethyl 3-sulfanylpropanoate (0.16 g, 1.2 mmol) were added, followed by dioxane (3 mL). Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.21 mmol), and K3PO4 (0.45 g, 2.1 mmol) were added. The vial was purged with nitrogen, and the mixture was stirred at 90 °C for 1 h. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (0-5% EtOAc / petroleum ether) to give ethyl 3-[(6-bromo-3,5-difluoro-2-pyridyl)sulfanyl]propanoate (0.26 g, 71% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 325.7 (M+H).

[0369] Step B. Ethyl 3-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]propanoate. Ethyl 3-[(6-bromo-3,5-difluoro-2-pyridyl)sulfanyl]propanoate (0.24 g, 0.72 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.0 mL, 3.6 mmol, 50% purity) were added to a 40 mL vial equipped with a magnetic stir bar, followed by dioxane (5 mL). Pd(dppf)Cl2·CHCl2 (60 mg, 0.074 mmol) and CsCO3 (0.48 g, 1.5 mmol) were added to the mixture at 25 °C. The vial was purged with nitrogen, and the mixture was stirred at 90 °C for 1 h. Water (15 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (0-5% EtOAc / petroleum ether) to give ethyl 3-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]propanoate (0.15 g, 80% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 262.0 (M+H).

[0370] Step C. 3,5-Difluoro-6-methylpyridine-2-thiol. Synthesized according to Step B of Intermediate 3, using ethyl 3-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]propanoate instead of tert-butyl (3S)-3-[4-[3-cyano-4-(3-ethoxy-3-oxopropyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to afford 3,5-difluoro-6-methylpyridine-2-thiol (60 mg, 97% yield) as a white solid.

[0371] Step D t-Butyl 4-[4-[3-cyano-4-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate. To an 8 mL vial equipped with a magnetic stir bar, tert-butyl 4-[4-(4-bromo-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate (0.12 g, 0.24 mmol) and 3,5-difluoro-6-methylpyridine-2-thiol (60 mg, 0.37 mmol) were added, followed by DMSO (2 mL). DIEA (0.086 mL, 0.49 mmol) was added, and the mixture was stirred at 110 °C for 16 hours. Water (5 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The aqueous mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (30–50% EtOAc / petroleum ether) to afford tert-butyl 4-[4-[3-cyano-4-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate (0.13 g, 27% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 566.3 (M+H).

[0372] Step E. 4-[(3,5-Difluoro-6-methyl-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to Step B of Example 1, except that tert-butyl 4-[4-[3-cyano-4-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]piperidine-1-carboxylate was used instead of tert-butyl (3S)-3-[4-[3-cyano-4-(2-pyridylsulfanyl)pyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate to give 4-[(3,5-difluoro-6-methyl-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (18 mg, 55% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z466.1(M+H).

[0373] Example 50 [ka] 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(1-methylsulfonyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (153) [ka] Step A. 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(1-methylsulfonyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To an 8 mL vial equipped with a magnetic stir bar was added 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.11 mmol), followed by DCM (4 mL). The solution was cooled to 0 °C, and methylsulfonylmethanesulfonate (40 mg, 0.23 mmol) and TEA (0.07 mL, 0.49 mmol) were added. The mixture was warmed to 25 °C and stirred for 1 h. The mixture was concentrated and purified by preparative HPLC (30%-60% acetonitrile / 0.04% aqueous ammonium hydroxide + 10 mM NH4HCO3). After lyophilization, 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(1-methylsulfonyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (36.0 mg, 61% yield) was obtained as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 512.1 (M+H).

[0374] Example 51 [ka] 6-[1-[(3S,4S)-3-Fluoro-4-piperidyl]-5-methylpyrazol-4-yl]-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (154) [ka] Step A. tert-Butyl (3S,4R)-3-fluoro-4-methylsulfonyloxypiperidine-1-carboxylate. To a solution of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.28 mmol) in DCM (8 mL) was added TEA (0.6 mL, 4.57 mmol) at 25° C. Next, a solution of methylsulfonylmethanesulfonate (800 mg, 4.59 mmol) in DCM (8 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Water (10 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3S,4R)-3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate (50 mg, 96% yield) as a yellow solid.

[0375] Step B. tert-Butyl (3S,4S)-3-fluoro-4-(4-iodopyrazol-1-yl)piperidine-1-carboxylate. To a solution of tert-butyl (3S,4R)-3-fluoro-4-methylsulfonyloxypiperidine-1-carboxylate (650 mg, 2.19 mmol) and 4-iodo-1H-pyrazole (430 mg, 2.22 mmol) in DMF (10 mL) was added CsCO (1.42 g, 4.37 mmol) and stirred at 25-90 °C for 15 h. Water was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO, 10-15% petroleum ether in ethyl acetate) to afford tert-butyl (3S,4S)-3-fluoro-4-(4-iodopyrazol-1-yl)piperidine-1-carboxylate (450 mg, 48% yield) as a colorless oil. LCMS (MM-ES+APCI, Pos): m / z 340.0 (M+H).

[0376] Step C. tert-Butyl (3S,4S)-3-fluoro-4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate. To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl (3S,4S)-3-fluoro-4-(4-iodopyrazol-1-yl)piperidine-1-carboxylate (200 mg, 0.46 mmol), followed by THF (4 mL). The solution was cooled to -65 °C. LDA (2 M, 0.5 mL) was added dropwise. The mixture was stirred at -65 °C for 1 hour. MeI (0.05 mL, 0.91 mmol) was added portionwise, and the reaction was stirred for 2 hours. NH4Cl (5 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (30-60% ethyl acetate in petroleum ether) to give tert-butyl (3S,4S)-3-fluoro-4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate (198 mg, 98% yield) as a colorless oil. LCMS (MM-ES+APCI, Pos): m / z 353.9 (M+H).

[0377] Step D. tert-Butyl (3S,4S)-3-fluoro-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate. To a 100 mL round-bottom flask equipped with a magnetic stir bar, tert-butyl (3S,4S)-3-fluoro-4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate (156.45 mg, 0.36 mmol) was added, followed by THF (10 mL). i-PrMgCl (2 M, 0.36 mL) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (231 mg, 1.46 mmol) was added to the mixture at 25 °C, and the mixture was stirred for 1 hour. NH4Cl (5 mL) was added to the reaction, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (30–60% ethyl acetate in petroleum ether) to afford tert-butyl (3S,4S)-3-fluoro-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (140 mg, 76% yield) as a colorless oil.

[0378] Step E. tert-Butyl (3S,4S)-4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]-3-fluoropiperidine-1-carboxylate. To an 8 mL vial equipped with a magnetic stir bar was added tert-butyl (3S,4S)-3-fluoro-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (140 mg, 0.34 mmol), KCO (101 mg, 0.73 mmol), Pd(dba) (26 mg, 0.028 mmol), and XPhos (28 mg, 0.058.74 mmol), followed by 1,4-dioxane (5 mL) and HO (1 mL). 6-Bromo-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (120 mg, 0.28 mmol) was added to 25 mL of HCl. ℃ The mixture was added at 90 ℃ The mixture was heated to RT and stirred for 1 h. Water (10 mL) was added to the reaction mixture, and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (50–75% ethyl acetate in petroleum ether) to afford tert-butyl (3S,4S)-4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]-3-fluoropiperidine-1-carboxylate (126 mg, 70% yield) as a brown oil. LCMS (MM-ES + APCI, Pos): m / z 552.1 (M+H).

[0379] Step F. 6-[1-[(3S,4S)-3-Fluoro-4-piperidyl]-5-methylpyrazol-4-yl]-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile. To a 50 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl (3S,4S)-4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]-3-fluoropiperidine-1-carboxylate (115 mg, 0.18 mmol), followed by DCM (4 mL). Next, HCl / dioxane (4 M, 4 mL) was added to the mixture at 25 °C and stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give the crude product as a pale yellow solid, which was purified by preparative HPLC (25%-55% acetonitrile / 0.04% aqueous ammonia hydroxide + 10 mM NH4HCO3). After lyophilization, 6-[1-[(3S,4S)-3-fluoro-4-piperidyl]-5-methylpyrazol-4-yl]-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (43.4 mg, 51% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 453.1 (M+H).

[0380] Example 52 [ka] 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[(1S)-1-(4-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (161) [ka] Step A. tert-Butyl 4-[(1R)-1-methylsulfonyloxyethyl]piperidine-1-carboxylate. Synthesized according to Step A of Example 50, using 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile instead of tert-butyl 4-[(1R)-1-hydroxyethyl]piperidine-1-carboxylate to give tert-butyl 4-[(1R)-1-methylsulfonyloxyethyl]piperidine-1-carboxylate (1.43 g, crude) as a yellow oil.

[0381] Step B. tert-Butyl 4-[(1S)-1-(4-iodopyrazol-1-yl)ethyl]piperidine-1-carboxylate. Synthesized according to step B of example 51, using tert-butyl (3S,4R)-3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate instead of tert-butyl 4-[(1R)-1-methylsulfonyloxyethyl]piperidine-1-carboxylate, to obtain tert-butyl 4-[(1S)-1-(4-iodopyrazol-1-yl)ethyl]piperidine-1-carboxylate (1 g, 70% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 350.1 (M-tBu+H).

[0382] Step C. tert-Butyl 4-[(1S)-1-(4-iodo-5-methylpyrazol-1-yl)ethyl]piperidine-1-carboxylate. Synthesized according to step C of example 51, using tert-butyl (3S,4S)-3-fluoro-4-(4-iodopyrazol-1-yl)piperidine-1-carboxylate instead of tert-butyl 4-[(1S)-1-(4-iodopyrazol-1-yl)ethyl]piperidine-1-carboxylate, obtain tert-butyl 4-[(1S)-1-(4-iodo-5-methylpyrazol-1-yl)ethyl]piperidine-1-carboxylate (830 mg, yield 99%) as colorless oil. LCMS (MM-ES+APCI, Pos): m / z 420.2 (M+H).

[0383] Step D. tert-Butyl 4-[(1S)-1-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate. Synthesized according to Step D of Example 51, using tert-butyl (3S,4S)-3-fluoro-4-(4-iodo-5-methylpyrazol-1-yl)piperidine-1-carboxylate instead of tert-butyl 4-[(1S)-1-(4-iodo-5-methylpyrazol-1-yl)ethyl]piperidine-1-carboxylate to give tert-butyl 4-[(1S)-1-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate (800 mg, 79% yield) as a colorless oil.

[0384] Step E. tert-Butyl 4-[(1S)-1-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]ethyl]piperidine-1-carboxylate. Synthesized according to Step E of Example 51, using tert-butyl (3S,4S)-3-fluoro-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl 4-[(1S)-1-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate to obtain tert-butyl 4-[(1S)-1-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]ethyl]piperidine-1-carboxylate (180 mg, 33% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z562.2(M+H).

[0385] Step F. 4-[(3-Fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[(1S)-1-(4-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step F of Example 51, tert-butyl (3S,4S)-4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]-3-fluoropiperidine-1-carboxylate to afford tert-butyl 4-[(1S)-1-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl ]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]ethyl]piperidine-1-carboxylate to give 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-[(1S)-1-(4-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (27.6 mg, 44% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 462.3 (M+H).

[0386] Example 53 [ka] 4-(2-Cyanophenyl)sulfanyl-6-[5-methyl-1-[[(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (170) [ka] Step A. tert-Butyl (3R)-3-[[4-[3-cyano-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]methyl]piperidine-1-carboxylate. Synthesized according to Step E of Example 51, using tert-butyl (3S,4S)-3-fluoro-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate instead of tert-butyl (3R)-3-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate to give tert-butyl (3R)-3-[[4-[3-cyano-4-(2-cyanophenyl)sulfanylpyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]methyl]piperidine-1-carboxylate (150 mg, 58% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z554.4(M+H).

[0387] Step B. 4-(2-Cyanophenyl)sulfanyl-6-[5-methyl-1-[[(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. Synthesized according to step F of Example 51, tert-butyl (3S,4S)-4-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]-3-fluoropiperidine-1-carboxylate to afford tert-butyl 4-[(1S)-1-[4-[3-cyano-4-[(3-fluoro-2-pyridyl)sulfanyl]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]-3-fluoropiperidine-1-carboxylate [(3R)-3-piperidyl]methyl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (14.8 mg, 14% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 454.1 (M+H).

[0388] Example 54 [ka] 4-(2-cyanophenyl)sulfanyl-6-[1-(4-hydroxy-4-methylcyclohexyl)-5-methylpyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (260) [ka] Step A. 1,4-Dioxaspiro[4.5]decan-8-yl methanesulfonate. Synthesized according to Step A of Example 50, using 4-[(3-fluoro-2-pyridyl)sulfanyl]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile instead of 1,4-dioxaspiro[4.5]decan-8-ol to afford 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (22 g, 98%) as a yellow solid.

[0389] Step B. 1-(1,4-Dioxaspiro[4.5]decan-8-yl)-4-iodopyrazole. Synthesized according to Step B of Example 51, using tert-butyl (3S...

Claims

1. A compound having the structure of formula (I): 【Chemical 463】 (In the formula, R １ is -CN, -Cl, -Br, -CF ２ H, or -CF ３ and R ２ But C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, aryl, heteroaryl, fused bicyclic, C ３ -C ８ Cycloalkyl, C ３ -C ８ heterocycloalkyl, or —NR ３ R ４ and R ３ and R ４ are each independently H or C １ -C ４ is alkyl, R ５ -H, -OH, -CN, -F, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Heteroalkyl, 5-6 membered heteroaryl, C ３ -C ８ Heterocycloalkyl, —C(═O)R ６ , —OC(═O)R ６ , -CH ２ C(=O)OR ６ , -NR ７ R ８ , -NR ７ C(=O)R ６ , -NR ７ C(=O)OR ６ , -CH ２ C(=O)NR ７ N ８ , -NR ７ R ８ CH ２ C(=O)NR ７ N ８ , -CH ２ NR ７ C(=O)R ６ , sulfonylmethane, oxo, phosphate, or a combination thereof; R ５ The above C １ -C ６ Alkyl or C １ -C ６ Heteroalkyl is 【Chemical 464】 or optionally substituted with —OH, R ６ But hydrogen, C １ -C ４ Alkyl, C １ -C ５ heteroalkyl, or C ４ -C ６ is heterocycloalkyl, Said C ４ -C ６ Heterocycloalkyl is 【Chemical 465】 or halo-substituted, R ７ and R ８ are independently H, C １ -C ６ Alkyl, C １ -C ６ Alkyl alcohol, sulfonylmethane, C ３ -C ６ cycloalkyl, or 5- to 6-membered heteroaryl, １ -C ６ Alkyl or C ３ -C ６ Cycloalkyl is fluoro, C ３ -C ６ optionally substituted with cycloalkyl, or 5- to 6-membered heteroaryl; X is -(CH ２ ) n-, -(CH ２ )nO-,-(CHCH ３ )n-,-(CHCH ３ )n-(CH ２ )m-,-(CHCH ３ )n-(CH ２ ) mO—, or a direct bond; Y is -CH ２ --, --CHCH ３ -, -C(CH ３ ) ２ -, -(CH ２ )pC(=O)-,-NCH ３ - or a direct bond, n is an integer from 1 to 4, m is an integer from 1 to 4, p is an integer from 0 to 4; A is aryl, 5-6 membered heteroaryl, halo, or a fused heterocycle; B is C ３ -C ８ Cycloalkyl, C ３ -C ８ heterocycloalkyl, fused bicyclic, bridged bicyclic, spirocyclic, or absent) or a stereoisomer of said compound, a salt or tautomer of said compound.

2. R １ The compound of claim 1 , wherein: 【Chemical 466】

3. R １ The compound according to any one of claims 1 to 2, wherein is -CN.

4. The compound has the structure of formula (IA): 【Chemistry 467】 4. The compound of claim 3, or a stereoisomer, salt or tautomer of said compound, wherein:

5. The compound according to any one of claims 1 to 4, wherein n is an integer of 1 or 2.

6. The compound according to any one of claims 1 to 5, wherein m is an integer of 1 or 2.

7. The compound of any one of claims 1 to 6, wherein X is a direct bond.

8. The compound has the structure of formula (IB): 【Chemical 468】 Alternatively, the compound of claim 7 is a stereoisomer of said compound, a salt of said compound, or a tautomer of said compound.

9. The compound of any one of claims 1 to 8, wherein the aryl of A is phenyl.

10. The compound of any one of claims 1 to 9, wherein the 5- to 6-membered heteroaryl of A is a 5-membered heteroaryl.

11. The compound of any one of claims 1 to 10, wherein the 5-membered heteroaryl is pyrazole or triazole.

12. The compound of any one of claims 1 to 10, wherein the 5- to 6-membered heteroaryl of A is a 6-membered heteroaryl.

13. The compound of any one of claims 1 to 12, wherein the 6-membered heteroaryl is pyridine.

14. The 5- to 6-membered heteroaryl of A may further be C １ -C ４ Alkyl, C １ -C ４ The compound of any one of claims 1 to 13, which is substituted with heteroalkyl or halo.

15. The compound of any one of claims 1 to 14, wherein the 5- to 6-membered heteroaryl is 5-methylpyrazole.

16. The compound of any one of claims 1 to 15, wherein A is -F, -Cl, or -Br.

17. 17. The compound of any one of claims 1 to 16, wherein the fused heterocycle of A is indole, isoindole, benzimidazole, purine, indazole, benzoxazole, benzisoxazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phthalazine, 5H-pyrrolo[2,3-b]pyrazine, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

18. The compound of any one of claims 1 to 17, wherein the fused heterocycle of A is 5H-pyrrolo[2,3-b]pyrazine or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

19. The aryl, 5- to 6-membered heteroaryl, or fused heterocycle of A is —CH ３ , -F, -Cl, -CN, -NH ２ , -CH ２ OCH ３ 19. The compound of any one of claims 1 to 18, which is mono- or di-substituted with:

20. The compound of any one of claims 1 to 19, wherein A has one of the following structures: 【Chemistry 469】 (wherein * indicates the position of the bond to Y).

21. The compound of any one of claims 1 to 20, wherein A has one of the following structures: 【Chemical 470】 (wherein * indicates the position of the bond to Y).

22. 22. The compound of claim 21, wherein A has one of the following structures: 【Chemistry 471】 (wherein * indicates the position of the bond to Y).

23. The compound has the structure of the following formulas (IC) to (IG): 【Chemistry 472-1】 【Chemistry 472-2】 23. The compound of claim 22, or a stereoisomer, salt or tautomer of said compound, wherein:

24. Y is -CH ２ The compound according to any one of claims 1 to 23, wherein

25. Y is -CHCH ３ The compound according to any one of claims 1 to 24, wherein

26. Y is C(CH ３ ) ２ The compound according to any one of claims 1 to 25, wherein

27. Y is -(CH ２ ) ｐ The compound of any one of claims 1 to 26, wherein C(=O)- and p is an integer from 0 to 2.

28. Y is -NCH ３ The compound according to any one of claims 1 to 27, wherein

29. The compound of any one of claims 1 to 28, wherein Y is a direct bond.

30. The compound has the structure of the following formulas (IH) to (IL): 【Chemistry 473-1】 【Chemistry 473-2】 30. The compound of claim 29, or a stereoisomer, salt or tautomer of said compound, wherein:

31. R ２ wherein the aryl, heteroaryl, or fused bicyclic ring is further selected from the group consisting of fluoro, chloro, cyano, methyl, amine, —OCH ３ , -CF ２ H, -CF ３ , C １ -C ３ Alkyl alcohol, C １ -C ３ The compound of any one of claims 1 to 30, substituted with alkoxyl, or a combination thereof.

32. R ２ The compound of any one of claims 1 to 31, wherein the fused bicyclic ring of has one of the following structures: 【Chemistry 474】

33. R ２ The compound of any one of claims 1 to 32, wherein the fused bicyclic ring system has one of the following structures: 【Chemistry 475】

34. R ２ The compound of any one of claims 1 to 33, wherein said aryl has one of the following structures: 【Chemistry 476-1】 【Chemistry 476-2】

35. R ２ The compound of any one of claims 1 to 34, wherein said heteroaryl has one of the following structures: 【Chemistry 477-1】 【Chemistry 477-2】

36. R ２ The above C ３ -C ８ Cycloalkyl or C ３ -C ８ The compound of any one of claims 1 to 35, wherein the heterocycloalkyl has one of the following structures: 【Chemistry 478】

37. R ２ The compound of any one of claims 1 to 36, wherein has one of the following structures: 【Chemistry 479-1】 【Chemistry 479-2】 【Chemistry 479-3】

38. R ３ and R ４ are each independently H or C １ The compound of any one of claims 1 to 37, which is alkyl.

39. B's C ３ -C ８ Cycloalkyl, C ３ -C ８ 39. The compound of any one of claims 1 to 38, wherein the heterocycloalkyl, fused bicyclic, bridged bicyclic, or spirocyclic is further substituted with fluoro, -OH, or methyl.

40. B's C ３ -C ８ The compound of any one of claims 1 to 39, wherein the heterocycloalkyl is a sulfoximine or sulfone.

41. B's C ３ -C ８ The compound of any one of claims 1 to 40, wherein heterocycloalkyl is: 【Chemical 480】

42. B is C ６ -C ７ Cycloalkyl, C ４ -C ６ The compound of any one of claims 1 to 41, which is heterocycloalkyl, fused bicyclic, bridged bicyclic, or spirocyclic.

43. B is C ６ Cycloalkyl, C ４ -C ５ The compound of any one of claims 1 to 42, which is heterocycloalkyl, fused bicyclic, bridged bicyclic, or spirocyclic.

44. 44. The compound of any one of claims 1 to 43, wherein the fused bicyclic ring of B is octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3.2.0]heptane, or 3-azabicyclo[3.1.0]hexane.

45. 45. The compound of any one of claims 1 to 44, wherein the bridged bicyclic ring of B is 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, or 2-azabicyclo[2.2.1]heptane.

46. 46. ​​The compound of any one of claims 1 to 45, wherein the spiro ring of B is 1-azaspiro[4.5]decane, 2-azaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 1-azaspiro[3.3]heptane, or spiro[3.3]heptane.

47. The compound of any one of claims 1 to 46, wherein B has one of the following structures: 【Chemistry 481】 (where * indicates the position of the bond to R5).

48. B is one or more R ５ 48. The compound of any one of claims 1 to 47, substituted with:

49. The compound of any one of claims 1 to 48, wherein B is absent.

50. R ５ -H, -OH, -CN, -F, C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ４ Heteroalkyl, 6-membered heteroaryl, C ４ -C ６ Heterocycloalkyl, —OC(═O)R ６ , -CH ２ C(=O)OR ６ , -NR ７ R ８ , -NR ７ C(=O)R ６ , -NR ７ C(=O)OR ６ , -CH ２ C(=O)NR ７ N ８ , -NR ７ R ８ CH ２ C(=O)NR ７ N ８ , -CH ２ NR ７ C(=O)R ６ 50. The compound of any one of claims 1 to 49, which is a sulfonylmethane, oxo, phosphate, or a combination thereof.

51. R ５ The above C １ -C ６ Heteroalkyl is C １ -C ６ 51. The compound of any one of claims 1 to 50, which is deuteranolic.

52. R ６ The above C ４ -C ６ The compound of any one of claims 1 to 51, wherein heterocycloalkyl is pyrrolidine or 1-methylpyrrolidine.

53. R ６ But C １ -C ３ Alkyl, C １ -C ４ heteroalkyl, or C ４ -C ５ The compound of any one of claims 1 to 52, which is a heterocycloalkyl.

54. R ６ The above C １ -C ４ Heteroalkyl is C １ -C ４ 54. The compound of any one of claims 1 to 53, which is fluoroalkyl.

55. R ６ The above C ４ -C ６ Heterocycloalkyl is 【Chemistry 482】 or fluoro. 【Request Item 56】 【Chemistry 483】 R substituted with ６ The above C ４ -C ６ The compound of any one of claims 1 to 55, wherein heterocycloalkyl is: 【Chemical 484】

57. Fluoro-substituted R ６ The above C ４ -C ６ The compound of any one of claims 1 to 56, wherein heterocycloalkyl is: 【Chemistry 485】

58. R ５ The compound of any one of claims 1 to 57, wherein said 5- to 6-membered heteroaryl is: 【Chemical 486】

59. R ５ The above C ３ -C ８ The compound of any one of claims 1 to 58, wherein heterocycloalkyl is: 【Chemistry 487】

60. R ５ The above C ３ -C ８ The compound of any one of claims 1 to 59, wherein cycloalkyl is: 【Chemical 488】

61. R ５ The compound of any one of claims 1 to 60, wherein said oxo is: 【Chemistry 489】

62. R ５ 62. The compound of any one of claims 1 to 61, wherein the phosphate of 【Chemistry 490】

63. R ７ and R ８ are independently H, C １ -C ３ Alkyl, C １ -C ３ Alkyl alcohol, sulfonylmethane, C ３ -C ４ cycloalkyl, or 6-membered heteroaryl, C １ -C ３ Alkyl or C ３ -C ４ Cycloalkyl is fluoro or C ３ -C ４ 63. The compound of any one of claims 1 to 62, optionally substituted with cycloalkyl.

64. R ５ The compound of any one of claims 1 to 63, wherein has one of the following structures: 【Chemistry 491-1】 【Chemistry 491-2】

65. 10. The compound of claim 1, wherein the compound has one of the following structures: 【Chemistry 492-1】 【Chemistry 492-2】 【Chemistry 492-3】 【Chemistry 492-4】 【Chemistry 492-5】 【Chemistry 492-6】 【Chemistry 492-7】 【Chemistry 492-8】 【Chemistry 492-9】 【Chemistry 492-10】 【Chemistry 492-11】 【Chemistry 492-12】 【Chemistry 492-13】 【Chemistry 492-14】 【Chemistry 492-15】 【Chemistry 492-16】 【Chemistry 492-17】 【Chemistry 492-18】 【Chemistry 492-19】 【Chemistry 492-20】 【Chemistry 492-21】 【Chemistry 492-22】 【Chemistry 492-23】 【Chemistry 492-24】 【Chemistry 492-25】 【Chemistry 492-26】 【Chemistry 492-27】 【Chemistry 492-28】 【Chemistry 492-29】 【Chemistry 492-30】 【Chemistry 492-31】 【Chemistry 492-32】 【Chemistry 492-33】 【Chemistry 492-34】 【Chemistry 492-35】 【Chemistry 492-36】 【Chemistry 492-37】 【Chemistry 492-38】 【Chemistry 492-39】 【Chemistry 492-40】 【Chemistry 492-41】 【Chemistry 492-42】 [Chemistry 492-43] [Chemistry 492-44] [Chemistry 492-45] [Chemistry 492-46] 【Chemistry 492-47】 [Chemistry 492-48] 【Chemistry 492-49】 【Chemistry 492-50】 【Chemistry 492-51】 【Chemistry 492-52】 [Chemistry 492-53] [Chemistry 492-54] 【Chemistry 492-55】 [Chemistry 492-56] 【Chemistry 492-57】 [Chemistry 492-58] 【Chemistry 492-59】 【Chemistry 492-60】 【Chemistry 492-61】 【Chemistry 492-62】 [Chemistry 492-63] [Chemistry 492-64] 【Chemistry 492-65】 【Chemistry 492-66】 【Chemistry 492-67】 【Chemistry 492-68】

66. A pharmaceutical composition comprising a compound of claim 1 and a therapeutic agent.

67. A compound according to any one of claims 1 to 65 or a pharmaceutical composition according to claim 66 for use in the treatment of a disease associated with a mutation in fibroblast growth factor receptor 2 (FGFR2) or fibroblast growth factor receptor 3 (FGFR3).

68. 67. A method for treating a disease associated with a mutation in FGFR2 or FGFR3, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 65 or a pharmaceutical composition according to claim 66.

69. 69. The method of claim 68, wherein the subject is an animal.

70. 70. The method of any one of claims 68 to 69, wherein the subject is a human.

71. The method according to any one of claims 68 to 70, wherein the disease associated with a mutation in FGFR2 is cancer or craniosynostosis syndrome.

72. 72. The method of any one of claims 68 to 71, wherein the cancer is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, ovarian cancer, endometrial cancer, non-small cell lung cancer, urothelial carcinoma, colorectal cancer, colon cancer, metastatic cholangiocarcinoma, cholangiocarcinoma, osteosarcoma, gastroesophageal junction adenocarcinoma, biliary tract cancer, anaplastic thyroid carcinoma, ganglioglioma, intraductal tubulopapillary neoplasm of the pancreas, gallbladder cancer, renal cell carcinoma, mucinous lipocarcinoma, triple-negative breast cancer, or rectal cancer.

73. 72. The method of any one of claims 68 to 71, wherein the craniosynostosis syndrome is craniosynostosis, kyphotic dysplasia, Crouzon syndrome, Apert syndrome, Pfeiffer syndrome, Antley-Bixler, Bear-Stevenson syndrome, Jackson-Weiss syndrome, or Sæthle-Hjötzen-like syndrome.

74. The method of any one of claims 68 to 70, wherein the disease associated with a mutation in FGFR3 is systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal skeletal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN syndrome), Muenke syndrome, FGFR3-related cancer, hypochondroplasia, FGFR3-related craniosynostosis, LADD syndrome, or Alzheimer's disease.

Images