Compounds that inhibit POLO-like kinase 4

Abstract

Disclosed herein are compounds according to Formula (I). Compounds according to Formula (I) inhibit PLK4 and are useful for the treatment of cancer and other diseases. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.

Description

224990 / 23-003-PC / 554457 COMPOUNDS THAT INHIBIT POLO-LIKE KINASE 4 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application Nos.63 / 601,053, filed November 20, 2023, and 63 / 718,369, filed November 8, 2024, each of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to compounds that inhibit polo-like kinase 4 (PLK4).The disclosure also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds to treat diseases, disorders, or conditions responsive to inhibition of PLK4. BACKGROUND OF THE INVENTION

[0003] The polo-like kinase (PLK) family of serine / threonine kinases comprises at least fourknown members: PLK1, PLK2, PLK3, and PLK4. PLK4 is the most divergent PLK member of the PLK family. PLK4 is involved in the control of mitotic entry and exit, and it regulates centriole biogenesis. Depletion or inhibition of its kinase activity prevents centriole formation, while overexpression may trigger centriole overduplication which can lead to cancer. To date, small molecule PLK4 inhibitors have been lacking. Thus, a need exists for compounds that inhibit PLK4 for the treatment of cancers. SUMMARY OF THE INVENTION

[0004] In one aspect, the present disclosure provides novel compounds that are PLK4inhibitors.

[0005] The present disclosure provides a compound according to Formula (I):or a pharmaceutically acceptable salt

[0006] In some embodiments,R1is (C6-C10)aryl or 5- to 14-membered heteroaryl; L is a bond, -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa- C(=O)-CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; 1 58226332.1224990 / 23-003-PC / 554457 ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl; R1is substituted with 0, 1, 2, 3, or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0- C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0- C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0- C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, (C0-C6)alkylene-N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1- C6)alkoxy, (C1-C6)haloalkyl, -O-(C3-C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; and optionally wherein two R5, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; ring A is substituted with 0, 1, 2, 3, or 4 R4; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0- C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -CH2-N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, -O-(C3- 2 58226332.1224990 / 23-003-PC / 554457 C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R4, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; and each Rais independently H, -C(=O)OH, (C1-C8)alkyl, (C2-C6)alkenyl, (C3- C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, phenyl, or benzhydryl, wherein each cycloalkyl, heterocycloalkyl, phenyl, and benzhydryl portion of any Rais independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C3-C6)cycloalkyl, and -O-(C3-C6)cycloalkyl; and optionally wherein two Ra, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; provided that when R1is thiazolyl and ring A is 3- to 14-membered heterocyclyl, then: ring A is 6- to 14-membered oxygen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1- C6)hydroxyalkyl, or ring A is 3- to 14-membered nitrogen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C0-C6)alkylene-(C1-C6)alkoxy, and (C1- C6)hydroxyalkyl.

[0007] In some embodiments,R1is (C6-C10)aryl or 5- to 14-membered heteroaryl; L is a bond, -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa-C(=O)- CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl, wherein R1and ring A are each independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, oxo, (C0-C6)alkylene-C(=O)ORa, - SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein the 3 58226332.1224990 / 23-003-PC / 554457 cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are each further independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, -O-(C1- C6)haloalkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)hydroxyalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; and each Ra independently is H, (C1-C8)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, or phenyl, wherein the cycloalkyl, heterocycloalkyl and phenyl each independently is substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C6)cycloalkyl, and -O-(C3-C6)cycloalkyl; alternatively two substituents, together with the atom(s) to which they are attached, optionally form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl, provided that when R1is thiazolyl and ring A is 3- to 14-membered heterocyclyl, then: ring A is 6- to 14-membered oxygen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1- C6)haloalkyl, and (C1-C6)hydroxyalkyl, or ring A is 3- to 14-membered nitrogen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, cyano, -N(Ra)2, (C1-C6)alkyl, -(C1-C6)haloalkyl, (C0-C6)alkylene-(C1- C6)alkoxy, and (C1-C6)hydroxyalkyl.

[0008] Another aspect of the present disclosure provides a method of treating or preventingconditions or diseases associated with enzymatic activity of PLK4, using compounds according to Formula (I), (II), (III) and / or (IV) as described herein, or pharmaceutically acceptable salts thereof.

[0009] Another aspect of the present disclosure provides a medical use of compoundsaccording to Formula (I), (II), (III) and / or (IV) as described herein, or pharmaceutically acceptable salts thereof, for treating or preventing conditions or diseases associated with enzymatic activity of PLK4.

[0010] Another aspect of the present disclosure provides a use of compounds according toFormula (I), (II), (III) and / or (IV) as described herein, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating or preventing conditions or diseases associated with enzymatic activity of PLK4.

[0011] Another aspect provides pharmaceutical compositions comprising a compound of thedisclosure and an excipient and / or pharmaceutically acceptable carrier. Also provided is the use 4 58226332.1224990 / 23-003-PC / 554457 of such compositions for treating or preventing conditions or diseases associated with enzymatic activity of PLK4.

[0012] Another aspect provides processes for making compounds of the disclosure.

[0013] These and other aspects and embodiments are described below.DETAILED DESCRIPTION OF THE INVENTION Definitions

[0014] As used herein, the singular forms “a,” “an,” and “the” include plural references unlessthe context clearly dictates otherwise.

[0015] When a variable is defined generically, with a number of possible substituents, eachindividual radical can be defined with or without the bond. For example, if R1can be hydrogen, this can be indicated as “–H” or “H” in the definition of R1.

[0016] When chemical structures are depicted or described, unless explicitly stated otherwise,all carbon atoms are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below, there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, –CH2CH2–. It is understood by one of ordinary skill in the art that the aforementioned descriptive expressions are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.

[0017] If a group “R” isas for example in the formula:then, unless otherwise defined, areside on any atom of the ring system, including any atom of a bicyclic or tricyclic ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

[0018] The term “Cn-m” or “Cn-Cm” indicates a range which includes the endpoints, wherein nand m are integers and indicate the number of carbon atoms. Examples include C1-4, C1-C4, C1-6, C1-C6, and the like. 5 58226332.1224990 / 23-003-PC / 554457

[0019] “Alkyl” refers to a branched or straight hydrocarbon chain having from 1 to 10 carbonatoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl. The term “Cn-m alkyl” or (Cn-Cm) alkyl, refers to an alkyl group having n to m carbon atoms. In some embodiments, alkyl refers to (C1-C6)alkyl.

[0020] “Alkylene” refers to an optionally substituted bivalent saturated aliphatic radicalhaving from 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. The term “Cn-m alkylene” refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethan- 1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2- methyl-propan-1,3-diyl and the like.

[0021] “Alkenyl” refers to a straight or branched chain hydrocarbon having from 1 to 10carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms and containing at least one carbon-carbon double bond. When the indicated number of carbon atoms is 1, then the Ci alkenyl is double bonded to a carbon (i.e., methylene). In certain aspects, the chain includes 1 to 10, about 2 to 10, about 2 to 8, or about 2 to 6 carbon atoms. Examples of an alkenyl group may include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, allenyl, butadienyl, pentadienyl, 3-(l,4- pentadienyl), and hexadienyl.

[0022] “Alkoxy” refers to a moiety of the formula –OR’, wherein R’ is an (C1-C6)alkyl moietyas defined herein. The term “Cn-malkoxy” or (Cn-Cm) alkoxy refers to an alkoxy group, the alkyl group of which has n to m carbon atoms. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0023] “Aryl” refers to a monovalent six- to fourteen-membered, mono-, bi, or tri-carbocyclicring (e.g., having two or three fused rings), wherein the monocyclic ring is aromatic and at least one of the rings in the bi- or tri-cyclic ring is aromatic. The term “Cn-m aryl” or “(Cn-Cm) aryl” refers to an aryl group having from n to m ring carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have 10 carbon atoms. Unless stated otherwise, the point of attachment of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.

[0024] “Carbocyclyl” refers to a saturated, partially unsaturated, or aromatic ring having 3 to14 carbon atoms. The carbocyclyl can be a 3 to 7 membered monocycle, 6 to 12 membered 6 58226332.1224990 / 23-003-PC / 554457 bicycle or polycycle. The bicycle or polycycle can be a bridged-ring, fused-ring, or spiro-ring system.

[0025] “Cycloalkyl” refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic,spirocyclic, or polycyclic), including cyclized alkyl and alkenyl groups. The term “Cn-m cycloalkyl” or “(Cn-Cm) cycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring- forming carbon atoms (C3-14). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-14cycloalkyl group. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring- forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo group. Cycloalkyl groups also include cycloalkylidenes. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, cycloalkyl includes a single saturated carbocyclic ring of three to eight ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0026] A cycloalkyl group can be unsubstituted or optionally substituted. When optionallysubstituted, one or more hydrogen atoms of the cycloalkyl group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a substituent moiety as described. In some embodiments, a substituted cycloalkyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en- 1-yl).

[0027] “Cyano” and “nitrile” refer to a group of formula –C≡N, which also may be written as–CN or CN.

[0028] “Halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0029] “Haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms hasbeen replaced by a halogen atom. The term “Cn-m haloalkyl” or (Cn-Cm) haloalkyl refers to a Cn-malkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1} halogen atoms, which may either be the same or different. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the halogen atoms include fluoro atoms. In some embodiments, the haloalkyl group is a fluoroalkyl group. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like. 7 58226332.1224990 / 23-003-PC / 554457

[0030] “Heteroatom” refers to an atom other than carbon and hydrogen. Examples of aheteroatom include boron, phosphorus, sulfur, oxygen, and nitrogen.

[0031] “Heterocyclyl” refers to a saturated, partially unsaturated, or aromatic ring or ringsystem, which has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and which has 4-14 ring members, 4-10 ring members, 4-7 ring members, or 4-6 ring members. Heterocyclyl groups can include mono- or bicyclic or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spirocycles. In some embodiments, the heterocyclyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfonyl group or other oxidized linkage (e.g., C(O), S(O), C(S), S(O)2, N-oxide, and the like), and a nitrogen atom can be optionally quaternized. In some embodiments, the heterocyclyl group is an aromatic monocyclic or bicyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Example of heterocyclyl groups include pyridinyl, naphthyridinyl, pyridazopyrazinyl, pyridopyrazinyl, quinolinyl, quinoxalinyl, and the like.

[0032] “Heteroaryl” refers to an aromatic monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more (e.g., one, two, three, or four) ring members independently selected from nitrogen, sulfur, and oxygen, and the remaining ring atoms being carbon. Unless stated otherwise, the point of attachment may be located on any atom of any ring of the heteroaryl group, valency rules permitting. The term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, pyrazolopyridinyl, and derivatives thereof (e.g., an N-oxide or a protected derivative).

[0033] “Heterocycloalkyl” refers to a saturated or partially unsaturated monocyclic, bicyclic,spirocyclic, or tricyclic ring structure containing three to fourteen ring members, in which one, two, or three of the ring atoms is a heteroatom. In some embodiments, each heteroatom is independently oxygen, sulfur, or nitrogen. A bicyclic ring structure includes the fused, spiro, or bridged moiety. In some embodiments, the heterocycloalkyl has three heteroatoms. In some embodiments, the heterocycloalkyl has two heteroatoms. In some embodiments, the heterocycloalkyl has one heteroatom. Non-limiting exemplary heterocycloalkyl groups include thiacyclohexanyl, oxiranyl, aziridinyl, oxazinyl, oxetanyl, azetidinyl, thietanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydro-2H- pyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydropyrimidine, pyrrolidinyl, dihydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, 8 58226332.1224990 / 23-003-PC / 554457 thioxanyl, trithianyl, bicyclo[1.1.1]pentanyl, imidazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, dihydropyridinyl, thianyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, 1,3-oxazetidinyl, 2-oxa-6- azaspiro[3.3]heptanyl, and thiocanyl.

[0034] “Hydroxyl” and “hydroxy” refer to an –OH moiety.

[0035] “Hydroxyalkyl” refers to an alkyl group, as defined herein, substituted with at least onehydroxy group, e.g., 1, 2, 3, or 4, hydroxy groups. The term “Cn-mhydroxyalkyl” or (Cn-Cm) hydroxyalkyl refers to a hydroxyalkyl group, the hydroxyalkyl group of which has n to m carbon atoms. In some embodiments, the hydroxyalkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0036] “Hydroxyhaloalkyl” refers to a haloalkyl group, as defined herein, substituted with atleast one hydroxy group, e.g., 1, 2, or 3 hydroxy groups. The term “Cn-m hydroxyhaloalkyl” or (Cn-Cm) hydroxyhaloalkyl refers to a hydroxyhaloalkyl group having n to m carbon atoms. In some embodiments, the hydroxyhaloalkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0037] “Oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl groupwhen attached to carbon, a sulfoxide or sulfone group when attached to sulfur, or an N-oxide group when attached to nitrogen. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (=O) substituents.

[0038] “Subject” for the purposes of the present disclosure includes humans and any otheranimals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In some embodiments, the subject is a human or other mammal. Examples of other mammals include mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and non-human primates.

[0039] “Therapeutically effective amount” is an amount of a compound as described hereinthat, when administered to a patient, ameliorates a symptom of a disease. The amount of a compound which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.

[0040] “Cancer” refers to cellular-proliferative disease states, including carcinomas, sarcomas,leukemias, and lymphomas.

[0041] “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid additionsalts” and “pharmaceutically acceptable base addition salts.” “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness of the free bases andthat are not biologically or otherwise undesirable, formed with inorganic acids as well as organicacids. “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases and organic bases. 9 58226332.1224990 / 23-003-PC / 554457

[0042] The term “compound” as used herein is meant to include all stereoisomers, geometricisomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

[0043] Compounds as described herein can also include all isotopes of atoms occurring insynthetic intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, provided herein is a compound of the invention wherein one or more hydrogen atoms are replaced with deuterium.

[0044] “Protecting group” refers to a chemical moiety that is suitable for preventing undesiredreactions at an otherwise group in a molecule (e.g., an amino nitrogen or a hydroxy oxygen). Representative protecting groups include, but are not limited to acyl groups, such as formyl, acetyl and trifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9- fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and 1,1- di-(4'-methoxyphenyl)methyl; silyl groups such as 2-(trimethylsilyl)ethoxymethyl (SEM); and tetrahydropyranyl group (THP).

[0045] “Leaving group” refers to a molecular fragment that departs with a pair of electrons inheterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), tosyl, mesyl, and besyl. In certain embodiments, the leaving group is a halogen.

[0046] Any one of the process steps or sequences disclosed and / or claimed herein can beperformed under an inert gas atmosphere, more particularly under argon or nitrogen. In addition, the methods of the present disclosure may be carried out as semi-continuous or continuous processes.

[0047] In general, the nomenclature used in this Application is based on naming conventionsadopted by the International Union of Pure and Applied Chemistry (IUPAC). Chemical structures shown herein were prepared using CHEMDRAW®. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. 10 58226332.1224990 / 23-003-PC / 554457 Compounds of the Disclosure

[0048] One aspect of the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable R1is (C6-C10)aryl or 5- toL is a bond, -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa- C(=O)-CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl; R1is substituted with 0, 1, 2, 3, or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0- C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, (C0-C6)alkylene-N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1- C6)alkoxy, (C1-C6)haloalkyl, -O-(C3-C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R5, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; ring A is substituted with 0, 1, 2, 3, or 4 R4; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, 11 58226332.1224990 / 23-003-PC / 554457 (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0- C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -CH2-N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, -O-(C3- C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R4, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; and each Rais independently H, -C(=O)OH, (C1-C8)alkyl, (C2-C6)alkenyl, (C3- C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, phenyl, or benzhydryl, wherein each cycloalkyl, heterocycloalkyl, phenyl, and benzhydryl portion of any Rais independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C3-C6)cycloalkyl, and -O-(C3-C6)cycloalkyl; optionally wherein two Ra, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; provided that when R1is thiazolyl and ring A is 3- to 14-membered heterocyclyl, then: ring A is 6- to 14-membered oxygen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1- C6)hydroxyalkyl, or ring A is 3- to 14-membered nitrogen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, cyano, - N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C0-C6)alkylene-(C1-C6)alkoxy, and (C1- C6)hydroxyalkyl.

[0049] In some embodiments, compounds according to Formula (I):12 58226332.1224990 / 23-003-PC / 554457 and pharmaceutically acceptable salts R1is (C6-C10)aryl or 5- to 14-L is a bond, -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa-C(=O)- CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl, wherein R1and ring A are each independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), -NHCH2-(3- to 6- membered heterocycloalkyl), oxo, (C0-C6)alkylene- C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are each further independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -CH2-N(Ra)2, - C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, -O-(C3- C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; each Raindependently is H, -C(=O)OH, (C1-C8)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, phenyl, or -C(H)(phenyl)2, wherein the cycloalkyl, heterocycloalkyl and phenyl each independently is substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C6)cycloalkyl, and -O-(C3- C6)cycloalkyl; alternatively two substituents, together with the atom(s) to which they are attached, optionally form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; provided that when R1is thiazolyl and ring A is 3- to 14-membered heterocyclyl, then: 13 58226332.1224990 / 23-003-PC / 554457 ring A is 6- to 14-membered oxygen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1- C6)alkoxy, -(C1-C6)haloalkyl, and (C1-C6)hydroxyalkyl, or ring A is 3- to 14-membered nitrogen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, cyano, -N(Ra)2, (C1-C6)alkyl, -(C1-C6)haloalkyl, (C0-C6)alkylene-(C1-C6)alkoxy, and (C1-C6)hydroxyalkyl.

[0050] In some embodiments, each R3 is independently selected from the group consisting ofhydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, -N(Ra)2, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -C(=O)N(Ra)2, oxo, -C(=O)ORa, -SO2- (C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-(C3-C10)cycloalkyl, (C6-C10)aryl, (C0-C6)alkylene-(3- to 14-membered heterocycloalkyl), and 5- to 10-membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; and each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, and -O-(C1-C6)haloalkyl.

[0051] In some embodiments, R1 is phenyl substituted with 0, 1, or 2 R3; and each R3 isindependently selected from the group consisting of cyano, hydroxy, halogen, -N(Ra)2, (C1- C6)alkyl, and (C1-C6)alkoxy.

[0052] In some embodiments, R1 is 5- to 10- membered heteroaryl substituted with 0, 1, 2, 3,or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, -N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -C(=O)N(Ra)2, -C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0- C6)alkylene-(3- to 10-membered heterocycloalkyl), and 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, or 3 R5; and each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, and -O-(C1-C6)haloalkyl.

[0053] In some embodiments, R1 is14 58226332.1224990 / 23-003-PC / 554457subscript n is 0, 1, 2, 3, or 4; and each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, and -O-(C1- C6)haloalkyl.

[0054] In some embodiments, R1 is:, , , ,each R3is independently hydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, -N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -C(=O)NH2, -C(=O)NCH3, -C(=O)OH, -C(=O)OMe, -SO2-(C1-C6)alkyl, -SO2-(C3- C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 6-membered heterocycloalkyl), or 5- to 6- membered heteroaryl, wherein 15 58226332.1224990 / 23-003-PC / 554457 each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, or 3 R5; and each R5is independently selected from the group consisting of cyano, oxo, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, and -O-(C1- C6)haloalkyl.

[0055] In some embodiments, R1 is,

[0056] In some embodiments, each R3 is independently hydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, -O-(C1- C6)haloalkyl, -C(=O)NH2, -C(=O)NCH3, -SO2-CH3, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C3)alkylene-(C3-C6)cycloalkyl, or (C0-C3)alkylene-(3- to 6-membered heterocycloalkyl), wherein each cycloalkyl and heterocycloalkyl portion of any R3is independently substituted with 0, 1, or 2 R5; and each R5is independently selected from the group consisting of hydroxy, halogen, oxo, (C1-C6)alkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy.

[0057] In some embodiments, R3 is selected from the group consisting of:; each R5(C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; optionally wherein two 16 58226332.1224990 / 23-003-PC / 554457 R5, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; and each subscript k is independently 0, 1, 2, 3, or 4.

[0058] In some embodiments, ring A is (C3-C10) carbocyclyl substituted with 0, 1, 2, 3, or 4R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl.

[0059] In some embodiments, ring A is monocyclic (C3-C7)cycloalkyl substituted with 0, 1,2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, and phenyl.

[0060] In some embodiments, ring A is bicyclic (C6-C10)cycloalkyl substituted with 0, 1, or 2R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)hydroxyalkyl.

[0061] In some embodiments, ring A is phenyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -C(=O)N(Ra)2, (C3-C6)cycloalkyl, and 4- to 6- membered heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl.

[0062] In some embodiments, ring A is 3- to 14-membered heterocyclyl substituted with 0, 1,2, 3, or 4 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1- C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2- 17 58226332.1224990 / 23-003-PC / 554457 (C1-C6)alkyl, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene- (3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, 5- to 6- membered heteroaryl, and (C3- C6)cycloalkyl;

[0063] In some embodiments, ring A is 4- to 7-membered monocyclic nitrogen- or oxygen-containing heterocycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, and (C0-C6)alkylene-C(=O)ORa.

[0064] In some embodiments, ring A is 5- to 6-membered monocyclic heteroaryl substitutedwith 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, -N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C2-C6)alkenyl, -C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, -C(=O)ORa, (C3-C6)cycloalkyl, and (C6-C10)aryl, wherein each cycloalkyl and aryl portion of any R4is independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, and (C1-C6)haloalkyl.

[0065] In some embodiments, ring A is 6- to 14-membered bicyclic or tricyclic heterocyclylsubstituted with 0, 1, 2, 3, or 4 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0- C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, oxo, (C0-C6)alkylene- C(=O)ORa, -SO2-(C1-C6)alkyl, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C3-C6)cycloalkyl.

[0066] In some embodiments, ring A is 6- to 10-membered bicyclic fused-, spiro-, or bridge-heterocycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the 18 58226332.1224990 / 23-003-PC / 554457 group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -C(=O)-(C1-C6)alkyl, -N(Ra)2, -C(=O)N(Ra)2, -(C0-C3)alkylene-C(=O)ORa, (C0-C3)alkylene-(C3-C6)cycloalkyl, -O-(C6- C10)aryl, and (C0-C3)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, and heteroaryl portion of any R4is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1- C6)haloalkyl, and (C1-C6)alkoxy.

[0067] In some embodiments, ring A is selected from the group consisting ofX2 X2X21X1X3X1X3X1m ,224990 / 23-003-PC / 554457X2and X3are independently CH, CH2, NH, N, or O; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, - NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkoxy, and (C3-C6)cycloalkyl; and subscript m is independently 0, 1, 2, 3, or 4.

[0068] In some embodiments, each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portionof any R4is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1- C6)alkoxy.

[0069] In some embodiments, L is -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-. 20 58226332.1224990 / 23-003-PC / 554457

[0070] In some embodiments, L is -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, or -NRa-C(=O)-C(Ra)2-.

[0071] In some embodiments, L is -NH-, -NH-C(=O)-, -N(CH3)-C(=O)-, -NH-C(=O)-NH-, -N(CH3)-C(=O)-NH-, -NH-C(=O)-NCH3-, -NH-C(=O)-CH2-, -NH-C(=O)-CH(OCH3)-, -NH- C(=O)-O-, -NH-C(=O)-CH2-O-, -NH-C(=O)-N(cyclopropyl)-CH2-, -NH-C(=O)- N(cyclopropyl)-, -NH-C(=O)NH-CH(phenyl)-, -NH-C(=O)NH-CH(CH2CH2C(CH3)3)-, -NH- C(=O)NH-CH(tetrahydropyranyl)-, or -NH-C(=O)NH-CH2-.

[0072] In some embodiments, L is -NH- or -NH-C(=O)-.

[0073] In some embodiments, L is -NH-.

[0074] In some embodiments, L is –NH-C(=O)-.

[0075] In some embodiments, each Ra independently is H, (C1-C8)alkyl, (C3-C6)cycloalkyl,or phenyl.

[0076] In some embodiments, each Ra independently is H, -Me, cyclopropyl, or phenyl.

[0077] In some embodiments, each Ra independently is H or -Me.

[0078] In some embodiments, compounds of Formula (II):and pharmaceuticallyY1and Y2are independently C, CH, or N; each R3ais independently cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)alkoxy, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, - C(=O)N(Ra)2, -C(=O)ORa, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), (C6-C10)aryl, or 5- to 10- membered heteroaryl, or two R3atogether with the atoms to which they are attached can form 5- or 6- membered heteroaryl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkoxy, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)ORa, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 6-membered heterocycloalkyl), and 5- to 6- membered heteroaryl, 21 58226332.1224990 / 23-003-PC / 554457 wherein the cycloalkyl, heterocycloalkyl, and heteroaryl are independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, -O-(C1-C6)haloalkyl, (C0-C6)alkylene-(C1- C6)alkoxy, and (C1-C6)haloalkyl; and subscript n is 0, 1, 2, 3, or 4.C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -C(=O)N(Ra)2, (C0-C3)alkylene-(C3- C6)cycloalkyl, (C0-C3)alkylene-(3- to 8- membered heterocycloalkyl), -SO2-(3- to 6- membered heterocycloalkyl), or 5- to 6- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl of any R3is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, oxo, halogen, hydroxy, -N(Ra)2, (C1- C6)alkyl, (C1-C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; and subscript n is 0, 1, 2, 3, or 4. 22 58226332.1224990 / 23-003-PC / 554457

[0080] In some embodiments, ring A is;or each R4is independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- C6)hydroxyhaloalkyl, -C(=O)-(C1-C6)alkyl, -N(Ra)2, -C(=O)N(Ra)2, -(C0-C3)alkylene- C(=O)ORa, -(C0-C3)alkylene-C(=O)ORa, (C0-C3)alkylene-(C3-C6)cycloalkyl, -O-(C6-C10)aryl, and (C0-C3)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, and heteroaryl portion of any R4is substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; and subscript m is 0, 1, 2, or 3.

[0081] In some embodiments, L is -NH-C(=O)-.

[0082] In some embodiments, compounds of Formula (III):and pharmaceuticallyeach R3is independently cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, -SO2-(C1-C6)alkyl, - SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)ORa, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(3- to 14-membered heterocycloalkyl), or 23 58226332.1224990 / 23-003-PC / 554457 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R4ais independently cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -N(Ra)2, -SO2-(C1-C6)alkyl, -C(=O)- (C1-C6)alkyl, -C(=O)N(Ra)2, -NRa-C(=O)(C1-C6)alkyl, -(C0-C6)alkylene-C(=O)ORa, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 10- membered heterocycloalkyl), (C0- C6)alkylene-(C6-C10)aryl, -O-(C6-C10)aryl, or (C0-C6)alkylene-(5- to 10- membered heteroaryl), alternatively, two R4a, together with the piperidine ring to which they are attached, form a fused, spiro, or bridged bicyclic 8- to 12- membered heterocycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- C6)hydroxyhaloalkyl, -N(Ra)2, -SO2-(C1-C6)alkyl, -C(=O)-(C1-C6)alkyl, -C(=O)N(Ra)2, -NRa- C(=O)(C1-C6)alkyl, -(C0-C6)alkylene-C(=O)ORa, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0- C6)alkylene-(3- to 10- membered heterocycloalkyl), (C0-C6)alkylene-(C6-C10)aryl, -O-(C6- C10)aryl, and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein the cycloalkyl, aryl, and heteroaryl are further substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; subscript m is 0, 1, 2, 3, or 4; and subscript n is 0, 1, 2, or 3.C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -C(=O)-(C1- C6)alkyl, -N(Ra)2, -C(=O)N(Ra)2, -(C0-C3)alkylene-C(=O)ORa, (C0-C3)alkylene-(C3- 24 58226332.1224990 / 23-003-PC / 554457 C6)cycloalkyl, -O-(C6-C10)aryl, and (C0-C3)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, and heteroaryl of any R4ais substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1- C6)haloalkyl, and (C1-C6)alkoxy; and subscript m is 0, 1, or 2.

[0084] In some embodiments, each R4a is independently selected from the group consistingof -F, -Cl, -OH, -CH3, -CH2CH3, =CH2, -CF3, -CHF2, -CH2CF3, -CH(OH)CF3, -CH2OH, -OCH3, -NH2, -NHCH3, -CH2NH2, C(=O)CH3, -C(=O)NH2, -CH2C(=O)OCH3,some cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, -SO2- CH3, -SO2-(3- to 6- membered heterocycloalkyl), -C(=O)NH2, -C(=O)NCH3, (C0-C3)alkylene- (C3-C6)cycloalkyl, or (C0-C3)alkylene-(3- to 6-membered heterocycloalkyl), wherein each cycloalkyl and heterocycloalkyl of any R3is independently substituted with 0, 1, or 2 R5; wherein each R5is independently selected from the group consisting of halogen, oxo, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy.

[0086] In some embodiments, each R3 is independently F, Cl, -CN, -CH3, -CH(CH3)2, -CF3,,224990 / 23-003-PC / 554457

[0087] In some embodiments, each R3 is independently F, Cl, -CN, -CH3, -CH(CH3)2, -CF3,-OCH3, -OCH2CH(CH3)2, -CONH2, -CON(CH3)2, -CONHCH3, or -SO2-CH3.

[0088] In some embodiments, subscript m is 0, 1, or 2.

[0089] In some embodiments, each R3 is independently cyano, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C0-C6)alkyl-(C3-C6)cycloalkyl, or (C0-C6)alkyl-(4- to 6- membered heterocycloalkyl), wherein each cycloalkyl and heterocycloalkyl portion of any R3is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of oxo, cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, -O-(C1- C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; ,L is -NH-C(=O)-; subscript m is 0, 1, or 2; and subscript n is 0, 1, or 2.

[0090] In some embodiments, ring A is selected from the group consisting of,X2 is CH, CH2, NH, N, or O; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- 26 58226332.1224990 / 23-003-PC / 554457 C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, - NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, oxo, -SO2-(C1-C6)alkyl, (C0-C6)alkylene-(C3- C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkoxy, and (C3-C6)cycloalkyl; and subscript m is 0, 1, 2, 3, or 4.

[0091] In some embodiments, at least one R3 is selected from the group consisting of:,(C1-C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy, -O-(C1-C3)alkylene- (C1-C3)alkoxy, or two R5, together with the atom(s) to which they are attached, form a 3- to 8- membered heterocycloalkyl or (C3-C6)cycloalkyl; and each subscript k is independently 0, 1, 2, 3, or 4.

[0092] In some embodiments, L is -NH-C(=O)-.

[0093] In some embodiments, compounds of Formula (IV):and pharmaceuticallyeach R3bis independently cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, -SO2-(C1-C6)alkyl, - SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), -NHCH2-(3- to 6- membered heterocycloalkyl), -C(=O)ORa, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(3- to 14- 27 58226332.1224990 / 23-003-PC / 554457 membered heterocycloalkyl), or 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3bis independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -CH2-N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, -O-(C1-C6)haloalkyl, (C0- C6)alkylene-(C1-C6)alkoxy, -O-(C1-C6)alkylene-(C1-C6)alkoxy, -O-(C3-C6)cycloalkyl, and -O- (C1-C3)alkylene-(C1-C3)alkoxy; each R4bis independently cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -N(Ra)2, -SO2-(C1-C6)alkyl, - C(=O)-(C1-C6)alkyl, -C(=O)N(Ra)2, -NRa-C(=O)(C1-C6)alkyl, -(C0-C6)alkylene-C(=O)ORa, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 10- membered heterocycloalkyl), (C0- C6)alkylene-(C6-C10)aryl, -O-(C6-C10)aryl, or (C0-C6)alkylene-(5- to 10- membered heteroaryl), alternatively, two R4b, together with the piperidine ring to which they are attached, form a fused, spiro, or bridged tricyclic 10- to 12- membered heterocycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1- C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -N(Ra)2, -SO2-(C1-C6)alkyl, -C(=O)-(C1-C6)alkyl, - C(=O)N(Ra)2, -NRa-C(=O)(C1-C6)alkyl, -(C0-C6)alkylene-C(=O)ORa, (C0-C6)alkylene-(C3- C6)cycloalkyl, (C0-C6)alkylene-(3- to 10- membered heterocycloalkyl), (C0-C6)alkylene-(C6- C10)aryl, -O-(C6-C10)aryl, and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein the cycloalkyl, aryl, and heteroaryl are further substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1- C6)haloalkyl, and (C1-C6)alkoxy; subscript m is 0, 1, 2, 3, or 4; and subscript n is 0, 1, 2, or 3.

[0093] In some embodiments, each R4b is independently cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyhaloalkyl, - N(Ra)2, -SO2-(C1-C6)alkyl, -C(=O)-(C1-C6)alkyl, or -C(=O)N(Ra)2.

[0094] Another aspect of the present disclosure provides compounds selected from any of theCompounds in Table 1, or a pharmaceutically acceptable salt thereof. 28 58226332.1No. Structure No. Structure29 58226332.1224990 / 23-003-PC / 554457 No. Structure No. Structure30 58226332.1224990 / 23-003-PC / 554457 No. Structure No. Structure31 58226332.1224990 / 23-003-PC / 554457 No. Structure No. Structure224990 / 23-003-PC / 554457 No. Structure No. Structure224990 / 23-003-PC / 554457 No. Structure No. Structure

[0095] In some embodiments, one or more Compounds in Table 2 and pharmaceuticallyacceptable salts thereof are provided.

[0096] In some embodiments, one or more Compounds in Table 3 and pharmaceuticallyacceptable salts thereof are provided.

[0097] In some embodiments, one or more Compounds in Table 4 and pharmaceuticallyacceptable salts thereof are provided.

[0098] In some embodiments, one or more Compounds in Table 5 and pharmaceuticallyacceptable salts thereof are provided.

[0099] In some embodiments, one or more Compounds in Table 6 and pharmaceuticallyacceptable salts thereof are provided. 34 58226332.1224990 / 23-003-PC / 554457

[0100] In some embodiments, one or more Compounds in Table 7 and pharmaceuticallyacceptable salts thereof are provided.

[0101] In some embodiments, one or more Compounds in Table 8 and pharmaceuticallyacceptable salts thereof are provided.

[0102] In some embodiments, one or more Compounds in Table 9 and pharmaceuticallyacceptable salts thereof are provided. 35 58226332.17,),),)H,541 d,(H,s11s(H,,s71s,s( ,s6(45( 2.( 5.2( 8.0 3.5 / CP-300-32 / 099422lerutcurtS 1.23 36. 2 o9 28N5061657,)H,,)7 H)554455 / CP-300-32 / 099422R M N 1Hz / +) +) +) m H H H S + + + M- M(M(M(C 77 46 9 L 4 4 73 erutcurtS 1.23 36. 2 o2 28N6364657,s,),),)HH H 654455 / CP-300-32 / 099422R M N 1HN,)6,)N1 5N1 93 11.3 114.84.11486,1HH H H H. .1d(z / +) +) +) m H H H S + + + M- M(M 0(M 0(C 8 2 4 L 4 4 34 erutcurtS 1.23 36. 2 o5 6 7 28N6 6 657,)H,54455 / CP-300-32 / 099422R M N 1H z / m H H H S + + + M- M(M(M(C 19 2 4 L 4 94 24 erutcurtS 1.23 36. 2 o1 2 28N7 73757,)3,6)H54455 / CP-300-32 / 099422R M N 1H z / S M- CL 94 64 94 erutcurtS 1.23 36. 2 o4 5 6 28N7 7 7577,54455 / CP-300-32 / 099422R M N 1H z / S M-C 8 2 9 L 74 24 84 O N H H N N r H S e N utcuN rtS N N C3 C H 3 H 1.23 36. 2 o7 8 28N7 79757,),s,)H(H54455 / CP-300-32 / 099422R M N 1H z / m+ S M + + M-(M(M(C3.5 2 L 59 15 6 3 4 erutcurtS 1.23 36. 2 o0 1 28N8 82857,)8,),)H0HsH54455 / CP-300-32 / 099422R M N 1Hz / +) +) ) + m H H H S + + + M- M(M(M(C 05 30 8 L 4 5 54 erutcurtS 1.23 36. 2 o3 28N8485857,) ,,)H H54455 / CP-300-32 / 099422R M N 1Hz / +) +) +) m H H H S + + + M- M(M M 2( (C L 9 2 4 9 2 4 94 erutcurtS 1.23 36. 2 o6 28N8788857,),),)H H H54455 / CP-300-32 / 099422R M N 1H z / S M-C 8 4 5 L 74 64 54 erutcurtS 1.23 36. 2 o9 0 28N8 91957,),) ,,)H HmH,)54455 / CP-300-32 / 099422R M N 1H z / SM M M-( (M 8(C.88.5 L 7 8 4 7 3 4 4 erutcurtS 1.23 36. 2 o2 3 28N9 94957,)H5)0)4455 / CP-300-32 / 099422R M N 1H z / m+ + S +2.6H M- M(M 5+ 3(9 3 C 6 2M(L 4 5 erutcurtS 1.23 36. 2 o5 6 28N9 97957,)5 4 H,8 35).)4455 / CP-300-32 / 099422R M N 1H z / SM- M(M(M(C 97 0 0 L 4 14 14 erutcurtS 1.23 36. 2 o8 9028N9 9015, ,7m m,s5)4455 / CP-300-32 / 099422R M N 1H z / S M- C LerutcurtS 1.23 36. 2 o 1 2 3 428N0101010157 86 6 28 8 ,)54455 / CP-300-32 / 099422R M N 1H z / S M- C LerutcurtS 1.23 36. 2 o 5 6 7 828N0101010157,) ,Hs ,)54455 / CP-300-32 / 099422R M N 1H z / S M- C LerutcurtS 1.23 36. 2 o 9 0 1 228N0111111153 2,7d54455 / CP-300-32 / 099422R M N 1HD5,4 ,z9.mD 61( ,z .,tH7,)6 H6, (2) )7 MH.001 2H H - 1M15.1 4,s4,0 (3.d 0,4d,)( 4(3( (H R1.2,)8.R2 51,M8N ,)H10,M.)7d ,)( 3651HH,1d(HN61HH 26.1 z / +) +) m H H S + + M- M(M 1(C 7 L 25 74 erutcurtS 1.23 36. 2 o 3 428N111157 ,s54455 / CP-300-32 / 099422R M N 1H z / m H H H S + + + M- M(M M 7( (C L 1 7 5 7 5 4 04 erutcurtS 1.23 36. 2 o 72N18 981111157,),),). H H Hl5a4455 / CP-300-32 / 099422R M N 1H / +) ) z +) + m H H H + + S + M- M M ((M(C 58.8.L 0 70 5 4 5 05 erutcurtS 1.23 36. 2 o 0 1 228N21212157,) ,Hd(,)H 954455 / CP-300-32 / 099422R M N 1H z / mS + + + M- M(M(M(C 80 67 8 L 5 5 74 erutcurtS 1.23 36. 2 o 32N24 5812121573,2) ,Hq5(4455 / CP-300-32 / 099422R M N 1H z / + + + m H H H S + + + M- M(M(M(C 4 8 9 L 45 15 44 erutcurtS 1.23 36. 2 o 0 1 228N3131315,),),H H) )RMNHz / + + +mH H H S + + +M- M(M C 9(M 7(9 L 44 15 45erutcurtS 1.23 36.2o3 4 62N31381315,m 4,m,RMNHz / mS + + +M- M(M(M(C 5 3 7 L 35 65 95erutcurtS 1.23 36.2o7 8 928N3131315754455 / CP-300-32 / 099422R M N 1Hz / +) +) m H H S + + M- M(M 4(C 0 2 L 5 15 3 F C O N O H H N N H N eru N t curtS N N C N 3 H C3 H N2 H1.23 36. 2 o 1 4 628N414141571,9),)H 1 H54455 / CP-300-32 / 099422R M N 1H z / m+5+5+ S M 5H 5H M-(5+ 5+ C 26M(M(L 5 3 3 3 F F F C C C O O O N O N O N O H H H H H NNH NNN N erH H H N N N utcuN N N rtS N N N N H N N N O C N N 3 C C C C 3 C 3 3 H 3 H 3 C3 H H H H H 1.23 36. 2 o 7 82N4981414157,)H5)4.)4455 / CP-300-32 / 099422R M N 1Hz / +) ) m ) + H + H S +1+ M- M(8H 5+ M C 3(6M(5 L 5 75 erutcurtS 1.23 36. 2 o 0 1 328N51515157.) ,,),s(H(54455 / CP-300-32 / 099422R M N 1H / ) +) z + +) m H H H + + S + M- M(M M(C 8(77.L 15 7 3 5 06 erutcurtS 1.23 36. 2 o 4 5 628N5151515,)5,) ,7H5Hm54455 / CP-300-32 / 099422R M N 1H+) +) z / +) m H + H H + + S M M-(M M(C8.(7 32.L 7 2 9 5 6 15 erutcurtS 1.23 36. 2 o 7 8 928N51515157,)H 1,),Hs,(),)H H 154455 / CP-300-32 / 099422R M N 1H z / S M- C LO N H N N H erN utN curtS N N C3 C H 3 H 1.23 36. 2 o 0 1 22N616381616157,)H54455 / CP-300-32 / 099422.0,1),)H R,)H 12M H,s,sN1 ( (,8 1s9 H( 2.4.7518.,),)21 HH δ11,),t6( d(d- 2 74O.S51.,2M),)DH , 1 H z,1,Hs(2m(M 1.0 082.04,)2–)( H H R10 ,3.1Ms(N02 ,s,)( 8961H2.8H 17.0 z / +) m H S + M- M(C 0 L 64 erutcurtS 1.23 36. 2 o 428N615224990 / 23-003-PC / 554457 Pharmaceutical Composition and Medical Treatment or Uses

[0103] Another aspect provides a pharmaceutical composition comprising any of thecompounds disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0104] Compounds of the present disclosure inhibit PLK4 and are thus useful in the treatmentor prevention of a variety of diseases and conditions. In particular, compounds of the present disclosure are useful in methods of treating or preventing a disease or condition wherein inhibition of PLK4 provides a benefit. It has further been discovered that certain 1-substituted pyrazolo[4,3-c]pyridines exhibit particularly advantageous selectivity for inhibition of PLK4 over other kinases such as AurA and AurB, which regulate proper centrosome maturation and segregation of chromosomes in mitosis. One aspect provides methods for treating cancer comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0105] A related aspect provides for the use of any of the compounds disclosed herein, or apharmaceutically acceptable salt thereof, or use of a pharmaceutical composition comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof in methods for treating cancer, or in the manufacture of medicaments for treating cancer.

[0106] Administration of the compounds provided herein, or their pharmaceuticallyacceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, oral, nasal, parenteral (intravenous, intramuscular, or subcutaneous), topical, transdermal, intravaginal, intravesical, intracisternal, or rectal, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, optionally in unit dosage forms suitable for simple administration of precise dosages.

[0107] The compositions will typically include a conventional pharmaceutical carrier orexcipient and a compound of Formula I as the / an active agent, and, in addition, carriers, adjuvants, and the like. Excipients may include, for example, preserving, wetting, suspending, 69 58226332.1224990 / 23-003-PC / 554457 sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents. If desired, a pharmaceutical composition may also contain substances such as wetting or emulsifying agents, pH buffering agents, isotonic agents, and antioxidants.

[0108] Compositions suitable for parenteral injection may comprise physiologicallyacceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders,and granules.

[0110] Liquid dosage forms for oral administration include pharmaceutically acceptableemulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, or otherwise combining, a compound(s) of the present disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in an aqueous or non-aqueous carrier to thereby form a solution or suspension. Suspensions, in addition to the active compounds, may contain suspending agents.

[0111] Compositions for rectal administration include, for example, suppositories that can beprepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.

[0112] Dosage forms for topical administration include ointments, powders, sprays, andinhalants. The active component is typically admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for use in topical administration.

[0113] Generally, depending on the intended mode of administration, the pharmaceuticallyacceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In some embodiments, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients. Methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see 70 58226332.1224990 / 23-003-PC / 554457 Remington The Science and Practice of Pharmacy, 23rd Ed., (Academic Press 2020). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state as described herein.

[0114] The compounds described herein, or their pharmaceutically acceptable salts, aregenerally administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode, and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered, for example, to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. Examples Abbreviations

[0115] The following abbreviations and terms have the indicated meanings throughout:Abbreviation Meaning Boc Tert-butoxycarbonyl-71 58226332.1224990 / 23-003-PC / 554457 Abbreviation Meaning eq or equiv EquivalentdeGeneral Synthetic Methods

[0116] Compounds of this invention can be made by the synthetic procedures describedbelow. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made. The 72 58226332.1224990 / 23-003-PC / 554457 starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0117] The compounds disclosed and claimed herein have asymmetric carbon atoms orquaternized nitrogen atoms in their structure and may be prepared through the syntheses described herein as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates, and geometric isomers, and mixtures thereof are intended to be within the scope of this invention.

[0118] Various methods can be used for the preparation and / or separation and isolation ofsingle stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers, or separation and isolation of single tautomers from mixtures of tautomers. For example, supercritical fluid chromatography (SFC) and / or HPLC can be used for separation of chiral molecules. Further, optically active and isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) and atropisomers (M- and P-isomers) may be resolved, for example, by: formation of diastereomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereomeric derivatives which may be separated, for example, by crystallization; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.

[0119] The compounds disclosed and claimed herein can be prepared according to GeneralSynthetic Scheme 1 shown below. 73 58226332.1224990 / 23-003-PC / 554457 General Synthetic Scheme 1 AL1P P P Hto a group not to and the like. “P” represents H or a protecting group such as tetrahydropyranyl (THP), tert- butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), 2-(trimethylsilyl)ethoxymethyl (SEM), and the like. L1 is H, -COOH, or a leaving group.

[0121] One aspect of the present disclosure provides a process for making a compound ofFormula (I), or a pharmaceutically acceptablecomprises combining a compound of Formula S-4 and a compound of Formula S-5 to form a compound of Formula (I) wherein:P is H or a protecting group; L1is H, -COOH, or a leaving group; and R1, L and ring A are as defined herein.

[0122] In some embodiments, the process further comprises:74 58226332.1224990 / 23-003-PC / 554457 (a) coupling a compound of Formula S-1 with a compound of Formula S-2 to form a compound of Formula S-3: ; and (b) reducing the compound of Formula S-3 to form a compound of Formula S-4: ; wherein: Lv is a leaving group; and P is H or a protecting group.

[0123] In some embodiments of the processes, L is –NH-, or –NH-C(=O)-.

[0124] In some embodiments, Lv is a halogen group. In some embodiments, Lv is –Br or -Cl.

[0125] Step 1 can be carried out in the presence of a suitable base, catalyst, and solvent. Thebase may be an inorganic base or an organic base. Non-limiting examples of the inorganic base may include bicarbonates, carbonates, phosphates, and acetates. The organic base may include amines, e.g., tertiary amines. The catalyst is any catalyst suitable for cross coupling, and includes but is not limited to nickel, copper, palladium, and platinum catalysts. Non-limiting examples are CuI(Xantphos), NiCl2(dppf), PdCl2(PPh3)4, Pd(OAc)2, XPhos, and PdCl2(dppf)- CH2Cl2adduct. The suitable solvent includes but is not limited to protic and aprotic solvents such as water, methanol, ethanol, DMF, DME, DCM, THF, DMSO, ether, ketone, 1,4-dioxane, and the like. The suitable solvent may also be a combination of two or three solvents. The reaction can be carried out in a temperature ranging from room temperature (about 20 °C) to about 200 °C. In some embodiments, the reaction temperature is about 80 °C to about 150 °C. In some embodiments, the reaction temperature is about 100 °C to about 120 °C.

[0126] In step 2 of the process, the compound of formula S-3 can be converted to thecompound of formula S-5 by reduction, such as hydrogenation reaction with a catalyst including 75 58226332.1224990 / 23-003-PC / 554457 but not limited to platinum, palladium, rhodium and ruthenium catalysts. The reduction can also be carried out with a metal such as Fe, Zn, Sn in the presence of an acid such as HCl.

[0127] In step 3 of the process, when L1 is H, the compound of formula S-4 and thecompound of formula S-5 can react with DSC or CDI in the presence of a base and a suitable solvent. The base may be an inorganic base or an organic base. Non-limiting examples of the inorganic base may include hydride, hydroxides, bicarbonates, carbonates, phosphates, and acetates. The organic base may include but is not limited to amines, e.g., tertiary amines such as DIPEA, TEA, and pyridine. The suitable solvent includes but is not limited to DMF, DCM, THF, DMSO, ether, ketone, 1,4-dioxane, and the like. The suitable solvent may also be a combination of two or three solvents.

[0128] In step 3, when L1 is -COOH, the coupling between the compound of formula S-4 andthe compound of formula S-5 can be carried out in the presence of a suitable base, a coupling reagent, and a solvent. The suitable base may be an inorganic base or an organic base. Non- limiting examples of the inorganic base may include bicarbonates, carbonates, phosphates, and acetates. The organic base may include but is not limited to amines, e.g., tertiary amines. The coupling reagent can be a suitable peptide coupling agent including, without limitation, dicyclohexylcarbodiimide (DCC) or l-(3-dirnethylarninopropyl)-3-ethylcarbodiirnide (EDC), benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and O-(lH- benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU). The suitable solvent includes but is not limited to DMF, THF, DMSO, acetonitrile, ethers, 1,4-dioxane, and the like.

[0129] In step 3, when L1 is a leaving group such as halogen, the compound of formula S-4and the compound of formula S-5 can be carried out in the presence of an acid such as TsOH and a solvent such as n-BuOH. The reaction temperature can be about 80 °C to about 150 °C. In some embodiments, the reaction temperature is about 100 °C to about 150 °C. In some embodiments, the reaction temperature is about 120 °C.

[0130] In each step of the process, protection or deprotection of the ring nitrogen may beinvolved. For example, the pyrazole ring amino group can be protected with THP, SEM, or other protecting group, and deprotected with an acid including an organic acid or an inorganic acid.

[0131] The following examples are provided for the purpose of further illustration and are notintended to limit the scope of the claimed invention. 76 58226332.1224990 / 23-003-PC / 554457 Synthetic Examples Scheme 14- yl)-8-(trifluoromethyl)-5-azaspiro[3.5]nonane-5-carboxamide (Compound 1).

[0132] Step 1: tert-Butyl 8-(trifluoromethyl)-8-((trimethylsilyl)oxy)-5-azaspiro[3.5]nonane-5-carboxylate.

[0133] tert-Butyl 8-oxo-5-azaspiro[3.5]nonane-5-carboxylate (0.737 g, 3.08 mmol, 1 equiv.)and cesium fluoride (650 mg, 4.28 mmol, 1.4 equiv.) were added to a 40 mL vial containing 77 58226332.1224990 / 23-003-PC / 554457 THF (10 mL) under an atmosphere of nitrogen gas. Trimethyl(trifluoromethyl)silane (3 equiv.) was added slowly over 10 min to avoid an exotherm and the mixture was stirred at rt for a further 1 hr. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and the solvent removed. The residue was dissolved in subjected to FCC (Hexanes:EtOAc, 100:0 to 80:20) to obtain the title compound (973 mg, 83%) as a clear brown oil of sufficient purity for the next step.

[0134] Step 2: 8-(Trifluoromethyl)-5-azaspiro[3.5]nonan-8-ol 2,2,2-trifluoroacetate.

[0135] tert-Butyl 8-nonane-5-carboxylate (1-1, 500 mg, 1.31 mmol, 1 equiv.) was dissolved in a mixture of DCM (2 mL), TFA (2 mL), and water (0.2 mL) in a loosely capped vial and incubated at rt for 30 min. The mixture was then sealed and heated to 55 °C 1 hr. The solvent was removed, water and a small amount of MeOH were added, and the mixture was lyophilized to yield the title compound (475 mg, 112% crude) as a sticky tan solid of sufficient purity for the next step.

[0136] Step 3: 6-Chloro-1-isobutyl-1H-pyrazolo[4,3-c]pyridine.

[0137] 6-Chloro-1H-was dissolved in N-methylpyrrolidone (NMP) (30 mL). Potassium carbonate (1.4 equiv.) and 1-bromo-2-methyl- propane (1.1 equiv.) were added and the mixture was stirred at 100 °C for 4 hr. The mixture was cooled, poured into water (75 mL), and extracted with EtOAc (150 mL). The organic layer was washed with brine (75 mL), dried over MgSO4, filtered, and the solvent removed. The residue was subjected to FCC (Hexanes:EtOAc, 100:0 to 0:100) to obtain the title compound (5.2 g, 63%) as a yellow oil.

[0138] Step 4: 6-(1-Benzyl-4-nitro-1H-pyrazol-3-yl)-1-isobutyl-1H-pyrazolo[4,3-c]pyridine. 78 58226332.1224990 / 23-003-PC / 554457

[0139] 6- , 1-benzyl-4-nitro-pyrazole (1.4 equiv.), dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2- yl]phosphane (XPhos, 0.6 equiv.), copper iodide (0.3 equiv.), and cesium pivalate (3 equiv.) were added to a microwave vial. 1,4-Dioxane (15 mL) was added, and the mixture was sparged with nitrogen gas. Palladium diacetate (0.3 equiv.) was added, and the mixture was heated to 120 °C overnight. The reaction mixture was filtered through Celite®, rinsed with EtOAc, and the solvent removed. The residue was adsorbed onto Celite®and subjected to FCC (Hexanes:EtOAc, 100:0 to 0:100) to obtain the title compound (27%) as a brown glassy solid.

[0140] Step 5: 3-(1-Isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine.

[0141] 6-(1-(1-4, 0.278mmol, 1 equiv.) was dissolved in ethanol (10 mL) and sparged with nitrogen gas. Pd(OH)2 on carbon 20pc (250 mg, 100 mass%) was added, the mixture was sparged with hydrogen gas and stirred at 60 °C for 3 hours. The mixture was sparged with nitrogen gas, filtered through Celite®, rinsed with DCM / EtOH (4:1) and the solvent removed. The residue was subjected to FCC (DCM:MeOH, 100:0 to 90:10) to obtain the title compound (26 mg, 36%) as a white solid.

[0142] Step 6: 8-Hydroxy-N-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-8-(trifluoromethyl)-5-azaspiro[3.5]nonane-5-carboxamide.224990 / 23-003-PC / 554457

[0143] 3-(1-Isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine (1-5, 0.18 mmol, 1equiv.) was dissolved in DMF (1 mL) and DIPEA (8 equiv.). bis(2,5-dioxopyrrolidin-1-yl) carbonate (DSC, 1.2 equiv.) was added, the mixture was sonicated until dissolution, then incubated at rt for 15 min. 2,2,2-trifluoroacetic acid 8-(trifluoromethyl)-5-azaspiro[3.5]nonan- 8-ol (1-2, 1.7 equiv.) was added and the mixture was incubated for 30 min. Formic acid (8 equiv.) was added, the solution diluted with DMF, filtered, and subjected to HPLC (0.1% formic acid (FA), Water:MeCN, 90:10 to 0:100) to obtain the title compound (63 mg, 71%).1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.28 (s, 1H), 9.17 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 6.08 (s, 1H), 4.30 (d, 2H), 3.77 (d, 1H), 3.22 (t, 1H), 2.85 – 2.73 (m, 1H), 2.72 – 2.54 (m, 1H), 2.34 – 2.06 (m, 3H), 2.00 (q, 1H), 1.88 (d, 1H), 1.83 – 1.44 (m, 4H), 0.86 (d, 6H). LC-MS m / z 492 (M+H+). Scheme 2pyrazol-4- yl)-6-methyl-4-azaspiro[2.5]octane-4-carboxamide (Compound 2).

[0144] Step 1: tert-Butyl 6-octane-4-carboxylate.80 58226332.1224990 / 23-003-PC / 554457

[0145] tert-Butyl 6- mg, 0.888 mmol, 1 equiv.)in THF (5 mL) under an gas was to - °C. Methyl magnesium bromide (3 M in diethyl ether, 1.5 equiv.) was added over 1 min and the mixture was stirred overnight allowing the cooling bath to expire. A saturated solution of ammonium chloride (15 mL) was added, and the mixture was extracted with EtOAc (20 mL). The organic layer was washed with brine (15 mL), dried over MgSO4, filtered, and the solvent removed to obtain the title compound (229 mg crude) as a yellow oil of sufficient purity for the next step.

[0146] Step 2: 6-Methyl-4-azaspiro[2.5]octan-6-ol 2,2,2-trifluoroacetate.

[0147] tert-Butyl 6-(2-1, 0.888 mmoltheo., 1 equiv.) was dissolved in a mixture of TFA (2 mL) in DCM (2 mL) and incubated for 30 min. The solvent was removed. The residue was suspended in MeCN and the solvent removed (2x) to obtain the title compound (crude yield 306 mg) as a brown oil that was used directly in the next step.

[0148] Step 3: 6-Hydroxy-N-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-6-methyl-4-azaspiro[2.5]octane-4-carboxamide (Compound 2).compound (21 mg, 25%).1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.75 (s, 1H), 9.19 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 4.32 (d, 2H), 4.08 (br s, 2H), 2.31 – 2.17 (m, 1H), 1.65 (br s, 2H), 1.20 (s, 3H), 1.07 (s, 3H), 0.94 – 0.81 (m, 7H), 0.71 (br s, 3H). LC-MS m / z 424 (M+H+). 81 58226332.1224990 / 23-003-PC / 554457 Scheme 31H- pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 3).

[0150] Step 1: tert-Butyloxy)-4-azaspiro[2.5]octane-4-carboxylate.

[0151] To a solution of tert-butyl 7-oxo-4-azaspiro [2.5] octane-4-carboxylate (25 g, 110mmol, 1 equiv.), CsF (84.3 g, 555 mmol, 5 equiv.) in THF (250 mL) was added dropwise TMSCF3 (39.4 g, 277 mmol, 2.5 equiv.) at 0 °C under N2. The resulting mixture was stirred at 70 °C for 24 hours. Then TMSCF3(10 g, 70.33 mmol, 0.634 equiv.) was added. The resulting mixture was stirred at 70 °C for another 24 hr. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4 x 200 mL). The mixture was filtered and concentrated under 82 58226332.1224990 / 23-003-PC / 554457 reduced pressure to give the title compound (40.3 g, 110 mmol, 99%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 3.80 (br d, 1H), 3.13 (br m, 1H), 2.04 (br d, 1H), 1.75 (br m, 1H), 1.55- 1.66 (m, 1H), 1.39 (s, 9H), 1.12-1.17 (m, 1H), 1.01 (m, 1H), 0.58-0.77 (m, 3H), 0.16 (s, 9H).

[0152] Step 2: Racemic 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol.

[0153] To a solution of4-azaspiro[2.5]octane-4-carboxylate (3-1, 35 g, 95 mmol, 1 equiv.) in MeOH (200 mL) was added HCl in MeOH (2 M, 184 mL, 3.87 equiv.) dropwise at 25 °C. The mixture was stirred at 25 °C for 6 hours. H2O (400 mL) was added, and the reaction mixture was washed with EtOAc (100 mL). The aqueous layer was carefully adjusted to pH to approximately 10 with solid Na2CO3. The solution was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (20 mL), and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM:MeOH, 10:1) to give the title compound (15 g, 77 mmol, 81%).1H NMR (400 MHz, DMSO-d6) δ 5.56 (br s, 1H), 2.85 (m, 1H), 2.64-2.76 (m, 1H), 1.93-2.01 (m, 1H), 1.50-1.57 (m, 2H), 1.01-1.10 (m, 1H), 0.52-0.58 (m, 1H), 0.31-0.42 (m, 2H), 0.20-0.26 (m, 1H). LC-MS m / z 196 (M+H+).

[0154] Step 3: Enantiopure 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol.

[0155] Racemic 7-g, 76.8 mmol) wasfurther purified by SFC (column: DAICEL CHIRALPAK®-IC (250 mm x 50 mm,10 μm); mobile phase: [CO2-EtOH(0.1%NH3H2O)]; B%:15%, isocratic elution mode), Mobile phase: A: Supercritical CO2, B: CO2-EtOH(0.1%NH3H2O)(A:B =85:15 at 200 ml / min (Volume ratios,Isocratic)), (Column Temp: 38 °C, Nozzle Pressure: 100 Bar, Nozzle Temp: 60 °C, EvaporatorTemp: 20 °C, Trimmer Temp: 25 °C, Wavelength: 220 nm) to yield the title compound as Peak 1 (3.57 g, 18.3 mmol, 30%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 5.56 (s, 1H), 83 58226332.1224990 / 23-003-PC / 554457 2.78-2.91 (m, 1H), 2.61-2.75 (m, 1H), 1.97 (d, 1H), 1.47-1.59 (m, 2H), 1.03-1.11 (m, 1H), 0.51- 0.58 (m, 1H), 0.31-0.41 (m, 2H), 0.19-0.26 (m, 1H). LC-MS m / z 196 (M+H+).

[0156] Step 4: Enantiopure 7-hydroxy-N-(3-(1-isobutyl-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4- carboxamide(Compound 3).pyrazol-4-yl)-7-oxa-4-azaspiro[2.5]octane-4-carboxamide Compound 4. 84 58226332.1224990 / 23-003-PC / 554457

[0158] Step 1: 1-(6-Chloro-1H- 1-yl)-2-methylpropan-2-ol.

[0159] 6- g, was dissolved inNMP (20 mL) in a 40 mL vial. Potassium carbonate (6.95 g, 50.3 mmol, 2 equiv.) and 2,2- dimethyloxirane (3.35 mL, 37.7 mmol, 1.5 equiv.) were added and the mixture was heated to 120 °C for 90 min. The mixture was cooled, poured into water (100 mL), and extracted with EtOAc (2 x 75 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent removed. The residue was subjected to FCC (EtOAc:hexanes, 30:70 to 100:0) to obtain the title compound (3.03 g, 53%) as a thick yellow oil that solidifies on standing.

[0160] Step 2: 2-Methyl-1-(6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)propan-2-ol.

[0161] 1-2.22 mmol, 1equiv.), 4-nitro-1-tetrahydropyran-2-yl-pyrazole (524 mg, 2.66 mmol, 1.2 equiv.), cesium carbonate (1.80 g, 5.54 mmol, 2.5 equiv.), pivalic acid (249 mg, 2.44 mmol, 1.1 equiv.), and XPhos (317 mg, 0.665 mmol, 0.3 equiv.) were added to a 40 mL vial. Dioxane (10 mL) was added, the mixture was sparged with nitrogen gas, palladium diacetate (50 mg, 0.22 mmol, 0.1 equiv.) was added, and the mixture was heated to 110 °C overnight. Palladium diacetate (100 mg, 0.44 mmol, 0.2 equiv.) and copper iodide (127 mg, 0.665 mmol, 0.3 equiv.) were added and the mixture was stirred at 140 °C for 75 min. The reaction mixture was filtered, and the solvent 85 58226332.1224990 / 23-003-PC / 554457 removed. The residue was subjected to FCC (EtOAc:hexanes, 0:100 to 100:0) to obtain the title compound (42.4 mg, 5%).

[0162] Step 3: 1-(6-(4-Amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-methylpropan-2-ol.

[0163] 2-[4,3-c]pyridin-1-yl]propan-2-ol (42.4 mg, 0.110 mmol, 1 equiv.) was dissolved in EtOAc (10 mL) and sparged with nitrogen gas. Palladium on carbon (10%, 500 mg) was added, the mixture was sparged with hydrogen gas then stirred overnight under a balloon of hydrogen. The mixture was sparged with nitrogen gas, filtered, rinsed with DCM, and the solvent removed to obtain the title compound of sufficient purity for the next step.

[0164] Step 4: 1-(6-(4-Amino-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-methylpropan-2-ol.

[0165] c]pyridin-1-yl]-2-methyl-propan-2-ol (0.110 mmol) was dissolved in a solution of HCl in dioxane (4 M, 2 mL, 8 mmol), sonicated briefly, and stirred at room temperature for 10 min. The solvent was removed. The solid was suspended in MeCN / DCM then dried twice to yield the title compound (22 mg, 65%) of sufficient purity for the next step.

[0166] Step 5: N-(3-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-oxa-4-azaspiro[2.5]octane-4-carboxamide (Compound 4). 58226332.1224990 / 23-003-PC / 554457

[0167] Compound 4 was synthesized in the same fashion as Compound 1 to afford the titlecompound (4.2 mg, 14%).1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.82 (s, 1H), 9.17 (s, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 6.58 (minor, s, 0.3H), 4.77 (s, 1H), 4.37 (s, 2H), 3.62 (major, m, 5.7H), 1.15 (m, 10H). LC-MS m / z 412.2 (M+H+). Scheme 5 EXAMPLE4-yl)-7-(2,2,2- trifluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 5).

[0168] Step 1: tert-Butyl 7-[2.5]octane-4-carboxylate.

[0169] tert-Butylmmol, 1 equiv.),MeCN (1 mL), DIPEA (4.8 equiv.), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.8 equiv.) were added to a microwave vial and heated to 120 °C for 30 min. The mixture was diluted with a saturated solution of sodium bicarbonate (20 mL) and extracted with EtOAc (20 87 58226332.1224990 / 23-003-PC / 554457 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed to obtain the title compound (474 mg, 77%) as a white oily semisolid.

[0170] Step 2: 7-(2,2,2-Trifluoroethyl)-4,7-diazaspiro[2.5]octane bis(2,2,2-trifluoroacetate).

[0171] tert-Butyl 7-4-carboxylate (5-1, 474mg, 1.61 mmol, 1 equiv.) was dissolved in a mixture of DCM (2 mL) and TFA (2 mL) in a loosely capped 40 mL vial and incubated at rt for 30 min. The solvent was removed, water was added, and the mixture was lyophilized to yield the title compound (572 mg, 84%) as a clear, light brown oil.

[0172] Step 3: N-(3-(1-Isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(2,2,2-trifluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxamide.titlecompound (49 mg, 53%).1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.83 (s, 1H), 9.22 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 4.32 (d, 2H), 3.15 (q, 2H), 2.60 (br s, 6H), 2.30 – 2.18 (m, 1H), 1.13 (br s, 4H), 0.88 (d, 6H). LC-MS m / z 477 (M+H+). 88 58226332.1224990 / 23-003-PC / 554457 Scheme 6 6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 6).

[0174] Step 1. 7-hydroxy-N-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide.1-5 to yield the title compound (351 mg, 81%) as a tan foam.

[0176] Step 2. Enantiopure 7-hydroxy-N-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 6). 89 58226332.1224990 / 23-003-PC / 554457

[0177] Racemic 7- 6-yl)-1H-pyrazol-4-yl)-7- - mg, 0.735 mmol) was subjected to chiral SFC (Mobile phase: 75:25, CO2 / Methanol, flow rate 2.5 mL / min, back pressure 100 bar, UV 214 nm) with peak 2 collected to obtain the title compound (142 mg, 40%).1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 10.87 (s, 1H), 9.24 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 6.05 (s, 1H), 4.32 (d, 2H), 4.16 – 4.07 (m, 1H), 3.24 (t, 1H), 2.30 – 2.18 (m, 2H), 1.66 (d, 1H), 1.61 – 1.52 (m, 1H), 1.37 – 1.22 (m, 3H), 1.14 – 1.10 (m, 1H), 0.88 (d, 6H), 0.83 – 0.78 (m, 1H). LC-MS m / z 478 (M+H+). Scheme 7cubane- 1-carboxamide (Compound 7).

[0178] Cubane-1-carboxylic acid (0.319 mmol, 1.5 equiv.) was dissolved in DMF (1 mL) andDIPEA (6 equiv.). [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl- ammonium;hexafluorophosphate (HBTU, 1.1 equiv.) was added, the mixture was sonicated until dissolution, then incubated for 15 min. 3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H- pyrazol-4-amine (1-5, 0.212 mmol, 1 equiv.) was added and the mixture was incubated for 30 min. The solution diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to obtain the title compound (68 mg, 83%).1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 11.19 (s, 1H), 9.23 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 4.36 – 4.28 (m, 5H), 4.11 – 4.04 (m, 4H), 2.29 – 2.21 (m, 1H), 0.88 (d, 6H). LC-MS m / z 387 (M+H+). 90 58226332.1224990 / 23-003-PC / 554457 EXAMPLE 8: 7-Hydroxy-N-(3-(1-neopentyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol- 4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 8).

[0179] Compound 8 was as Compound 1 beginning withneopentyl bromide to yield the title compound (9.1 mg, 13%).1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.86 (s, 1H), 9.24 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 6.02 (s, 1H), 4.31 (s, 2H), 4.11 (d, 1H), 3.30 – 3.19 (m, 1H), 2.22 (d, 1H), 1.72 – 1.51 (m, 2H), 1.39 – 1.20 (m, 3H), 1.18 – 1.08 (m, 1H), 0.98 (s, 9H), 0.87 – 0.75 (m, 1H). LC-MS m / z 492 (M+H+). EXAMPLE 9: 7-Hydroxy-N-(3-(4-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 9).

[0180] Compound 9 wasas Compound 1 beginning with 2-bromo-4-(methylsulfonyl)pyridine and using 3-2 to obtain the title compound (13%).1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.48 (s, 1H), 9.11 (d, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 7.91 (d, 1H), 6.14 (s, 1H), 4.19 (d, 1H), 3.49 (s, 3H), 3.32 (t, 1H), 2.27 (d, 1H), 1.80 – 1.60 (m, 2H), 1.42 – 1.30 (m, 3H), 1.23 – 1.17 (m, 1H), 0.92 – 0.88 (m, 1H). LC-MS m / z 460 (M+H+). 91 58226332.1224990 / 23-003-PC / 554457 Scheme 84-yl)-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 10).

[0181] Step 1: 2-Chloro-4-58226332.1224990 / 23-003-PC / 554457

[0182] 2,4-Dichloro-5-methyl-pyridine (2.01 g, 12.4 mmol, 1 equiv.), potassium hydroxide (2equiv.), and 2-methylpropan-1-ol (10 mL, 8.7 equiv.) were added to a 40 mL vial and heated to 90 °C for 1.5 hr. The reaction mixture was cooled, poured into ether (50 mL), washed with water (50 mL) then brine (50 mL), dried over MgSO4, filtered, and the solvent removed. The oil was subjected to FCC (Hexanes:EtOAc, 100:0 to 90:10) to obtain the title compound (680 mg, 28%) as a clear and colorless oil.

[0183] Steps 2 to 4: 7-Hydroxy-N-(3-(4-isobutoxy-5-methylpyridin-2-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 10).

[0184] Compound 10 wasas Compound 1 to obtain the titlecompound (28%).1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.81 (s, 1H), 8.33 (s, 1H), 8.06 (s, 1H), 7.49 (s, 1H), 6.03 (s, 1H), 4.09 (d, 1H), 3.93 (d, 2H), 3.22 (t, 1H), 2.25 – 2.01 (m, 5H), 1.65 (d, 1H), 1.56 (t, 1H), 1.34 – 1.14 (m, 3H), 1.13 – 1.07 (m, 1H), 1.03 (d, 6H), 0.82 – 0.73 (m, 1H). LC-MS m / z 468 (M+H+). Scheme 9pyrazol-4-yl)amino)nicotinamide (Compound 11). 93 58226332.1224990 / 23-003-PC / 554457

[0185] Step 1: Methyl 6-

[0186] A g, 3.99 mmol, 1equiv.), potassium cyclopropyltrifluororate (709 mg, 4.79 mmol, 1.2 equiv.), Pd(dppf)Cl2.DCM (326 mg, 399 μmol, 0.1 equiv.) and Cs2CO3 (3.90 g, 12.0 mmol, 3 equiv.) in THF (15 mL) and H2O (5 mL) was degassed and purged with N23 times then the mixture was stirred at 80 °C for 12 hours under an atmosphere of nitrogen gas. The mixture was concentrated, and the residue was purified by flash silica gel chromatography (0 to 5% ethyl acetate in petroleum ether) to give the title compound (387 mg, 46%) as colorless liquid.1H NMR (400 MHz, CDCl3) δ 8.79 (d, 1H), 7.84 (d, 1H), 3.95 (s, 3H), 2.20 (m, 1H), 1.10-1.19 (m, 2H), 0.74-0.81 (m, 2H). LC-MS m / z 212 (M+H+).

[0187] Step 2: 6-Chloro-5-cyclopropylnicotinamide.

[0188] A solution(11-1, 387 mg,1.83 mmol, 1 equiv.) in NH3 / MeOH (7 M, 5 mL) was stirred at 30 °C for 36 hours. The mixture was concentrated, and the residue was purified by flash silica gel chromatography (0 to 50% ethyl acetate in petroleum ether) to give the title compound (265 mg, 74%) as a white solid. LC- MS m / z 197 (M+H+).

[0189] Step 3: 5-Cyclopropyl-6-((3-(1-neopentyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)amino)nicotinamide. (Compound 11). 94 58226332.1224990 / 23-003-PC / 554457

[0190] mg, 0.31mmol, , - 2-yl- pyrazol-4-amine (prepared in a similar fashion to 4-3, 100 mg, 282 μmol, 1 equiv.) in n-BuOH (2 mL) was added TsOH (5.0 mg, 29 μmol, 0.1 equiv.). The mixture was stirred at 120 °C for 12 hours. The mixture was diluted with water (10 mL), extracted with EtOAc (2 x 10 mL). The organic layers were concentrated, and the residue was purified by prep-HPLC ([water (0.1% HCl) - ACN]; gradient: 20% - 50% B) to give the title compound (25 mg, 19%).1H NMR (400 MHz, DMSO-d6) δ 10.81 (br s, 1H), 9.28 (s, 1H), 8.51 (br s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.88-8.00 (m, 1H), 7.87 (s, 1H), 7.13-7.35 (m, 1H), 4.29 (s, 2H), 1.94-2.01 (m, 1H), 1.13-1.21 (m, 2H), 0.95 (s, 9H), 0.74-0.80 (m, 2H). LC-MS m / z 431 (M+H+). Scheme 102,7- naphthyridin-1(2H)-one (Compound 12). 58226332.1224990 / 23-003-PC / 554457

[0191] Step 1: tert-Butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate.

[0192] To a 101H-2,7-naphthyridine-2-carboxylate (500 mg, 1.86 mmol, 1 equiv.), NaIO4(1190 mg, 5.58 mmol, 3 equiv.), RuCl3(126 mg, 0.56 mmol, 0.3 equiv.) and MeCN (5 mL) at room temperature. The mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (petroleum ether:EtOAc, 1:3) to afford the title compound (400 mg, 76%).

[0193] Step 2: 6-((3-(1H-Benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)amino)-3,4-dihydro-2,7-naphthyridin-1(2H)-one. (Compound 12).

[0194] To a2,7-naphthyridine-2-carboxylate (12-1, 200 mg, 0.71 mmol, 1 equiv.), 3-(1H-1,3-benzodiazol-2-yl)- 1H-pyrazol-4-amine (42 mg, 0.21 mmol, 0.3 equiv.), n-BuOH (2 mL) and TsOH (24 mg, 0.14 mmol, 0.2 equiv.) at room temperature. The resulting mixture was stirred overnight at 120 °C. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Prep- HPLC (C18, water (0.1% FA) with MeCN (8% to 18%)) to obtain the title compound (13 mg, 5%).1H NMR (400 MHz, DMSO-d6) δ 13.09 (d, 2H), 9.96 (s, 1H), 8.64 (s, 1H), 8.47 (s, 1H), 96 58226332.1224990 / 23-003-PC / 554457 7.74 (s, 2H), 7.50 (s, 1H), 7.23 (dt, 2H), 6.88 (s, 1H), 3.37 (dt, 2H), 2.91 (t, 2H). LC-MS m / z 346 (M+H+). Scheme 11c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 13).

[0195] Step 1. 6-Chloro-2-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridine.

[0196] To a solution of 6-chloro-2-methyl-1H-pyrrolo[3,2-c] pyridine (1.8 g, 11 mmol, 1equiv.) in DMF (20 mL) was added sodium hydride (60% in oil, 860 mg, 2 equiv.) at 0 °C. The mixture was stirred for 15 min.2,2,2-Trifluoroethyl trifluoromethanesulfonate (3.76 g, 16.2 mmol, 1.5 equiv.) was added and the mixture was allowed to warm to room temperature and 97 58226332.1224990 / 23-003-PC / 554457 stirred for 2 hours. The reaction mixture was quenched with ice water (100 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc, 10:1) to afford the title compound (2.5 g, 93%) as light-yellow solid.

[0197] Step 2. 2-Methyl-6-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridine.

[0198] To a[3,2-c]pyridine (13-1, 500 mg, 2.01 mmol, 1 equiv.) and 4-nitro-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole (587 mg, 2.41 mmol, 1.2 equiv.) in dioxane (10 mL) was added Cs2CO3 (1.64 g, 5.03 mmol, 2.5 equiv.), pivalic acid (411 mg, 4.02 mmol, 2 equiv.), CuI (230 mg, 1.20 mmol, 0.6 equiv.), XPhos (478 mg, 1.00 mmol, 0.5 equiv.) and Pd(OAc)2 (45 mg, 0.20 mmol, 0.1 equiv.) and the reaction mixture was sparged with nitrogen gas. The resulting mixture was stirred overnight at 120 °C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc, 3:1) to afford the title compound (600 mg, 68%) as yellow oil.

[0199] Step 3. 3-(2-Methyl-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine. 98 58226332.1224990 / 23-003-PC / 554457

[0200] To a 6-yl] -4-nitro-1-{[(trimethylsilyl)methoxy] methyl} pyrazole (13-2, 1.20 g, 2.72 mmol, 1 equiv.) in MeOH (20 mL) was added Pd / C (10%, 1.2 g) in a pressure reactor. The mixture was stirred at room temperature under an atmosphere of hydrogen (30 psi) for 2 hours. The mixture was filtered through Celite®and concentrated under reduced pressure to obtain the title compound (1.1 g, 98%) as yellow solid.

[0201] Step 4. 7-Hydroxy-N-(3-(2-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)- 4-azaspiro[2.5]octane-4-carboxamide.

[0202] yl] -1-{[(trimethylsilyl)methoxy] methyl} pyrazol-4-amine (13-3, 450 mg, 1.09 mmol, 1 equiv.) and CDI (343 mg, 2.12 mmol, 2 equiv.) in DCM (18 mL) was stirred for 1 hour at room temperature. To the above mixture was added DIPEA (410 mg, 3.17 mmol, 3 equiv.) and 7- (trifluoromethyl)-4-azaspiro[2.5]octan-7-ol hydrochloride (3-2 HCl, 490 mg, 2.12 mmol, 2 equiv.) in portions at 0 °C. The resulting mixture was stirred for additional 2 hours at room temperature. The solvent was removed, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc, 3:1) to afford the title compound (570 mg, 82%) as light-yellow solid. 99 58226332.1224990 / 23-003-PC / 554457

[0203] Step 5. 7-Hydroxy-N-(3-(2-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 13).

[0204] c]pyridin-6-yl]-1-{[(trimethylsilyl)methoxy] methyl} pyrazol-4-yl}-7-(trifluoromethyl)-4- azaspiro [2.5] octane-4-carboxamide (13-4, 200 mg, 0.316 mmol, 1 equiv.) and HCl in 1,4- dioxane (4 M, 5 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: MeCN; Gradient: 52% B to 82% B) to afford the title compound (59 mg, 37%).1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.00 (s, 1H), 8.83 (d, 1H), 8.17 (s, 1H), 8.07 (d, 1H), 6.51 (s, 1H), 6.01 (s, 1H), 5.31 (q, 2H), 4.10 (d, 1H), 3.23 (t, 1H), 2.48 (s, 2H), 2.22 (d, 1H), 1.66 (d, 1H), 1.57 (s, 1H), 1.28 (s, 3H), 1.17 – 1.07 (m, 1H), 0.79 (s, 1H). LC-MS m / z 517 (M+H+). Scheme 12pyrazol-4-yl)urea (Compound 14). 58226332.1224990 / 23-003-PC / 554457

[0205] Step 1. 1,1-dicyclopropyl-3-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)urea.

[0206] To 2-yl-pyrazol-4- a to mg, , CDI (380 mg, 2.4 mmol, 4 equiv.) in THF (3 mL), was added mixture solution of Et3N (180 mg, 1.8 mmol, 3 equiv.) and N-cyclopropylcyclopropanamine hydrochloride (94 mg, 0.7 mmol, 1.2 equiv.) in THF (1 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (0 to 50% ethyl acetate in petroleum ether) to give the title compound (250 mg, 78%) as a white oil of sufficient purity for the next step. LC-MS m / z 464 (M+H+).

[0207] Step 2: 1,1-Dicyclopropyl-3-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)urea. (Compound 14).

[0208] A mixture of 1,1-dicyclopropyl-3-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1-tetrahydropyran-2-yl-pyrazol-4-yl]urea (200 mg, 0.4 mmol, 1 equiv.) in HCl / MeOH (3 M, 4 mL), was degassed, purged with N2(3 times), and then the mixture was stirred at 25 °C for 16 hours under an atmosphere of N2. The reaction mixture was concentrated, the crude product was triturated with MeCN (5 mL) at 25 °C for 1 hour, then filtered to obtain the title compound (157 mg, 95%).1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 4.25 (d, 2H), 2.55 (m, 2H), 2.16-2.25 (m, 1H), 0.81-0.90 (m, 10H), 0.69-0.75 (m, 4H). LC- MS m / z 380 (M+H+). 101 58226332.1224990 / 23-003-PC / 554457 Scheme 136-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 15).

[0209] Step 1. 2-Chloro-N-isobutyl-5-nitropyridin-4-amine.

[0210] A solution ofequiv.), isobutylamine(5.68 g, 77.7 mmol, 1.5 equiv.) and DIPEA (22.6 mL, 130 mmol, 2.5 equiv.) in THF (100 mL) was stirred for 4 hours at 70 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether in EtOAc, 100 to 50%) to afford the title compound (10 g, 84%) as light-yellow oil.

[0211] Step 2. 6-Chloro-N4-isobutylpyridine-3,4-diamine.102 58226332.1224990 / 23-003-PC / 554457

[0212] A solution (15-1, 10.0 g, 43.5mmol, 1 equiv.), iron g, (23.3 g, 435 mmol, 10 equiv.) in EtOH (400 mL) and H2O (200 mL) was stirred for 3 hours at 75 ℃. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 500 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (pet ether in EtOAc, 100 to 50%) to afford the title compound (3.8 g, 44%) as a brown solid.

[0213] Step 3. 6-Chloro-1-isobutyl-1H-[1,2,3]triazolo[4,5-c]pyridine.

[0214] A solution of 6-(15-2, 1.0 g, 5.0mmol, 1 equiv.) and NaNO2(0.41 g, 6.0 mmol, 1.2 equiv.) in HCl(aq)(1 M, 32.6 mL) was stirred for 1 hour at room temperature. The mixture was basified to pH 9 with a saturated solution of Na2CO3 (aq.). The resulting mixture was diluted with water (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:EtOAc, 5:1) to afford the title compound (0.80 g, 76%) as a brown solid.

[0215] Step 4. 1-Isobutyl-6-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine. 103 58226332.1224990 / 23-003-PC / 554457

[0216] (15-3,600 mg, (832 mg, 3.41 mmol, 1.2 equiv.) in 1,4-dioxane (60 mL) was added Cs2CO3 (4.64 g, 14.2 mmol, 5 equiv.), PivOH (3.65 g, 14.2 mmol, 5 equiv.), CuI (832 mg, 6.82 mmol, 2.4 equiv.), XPhos (1.36 g, 2.84 mmol, 1 equiv.) and Pd(OAc)2 (130 mg, 0.57 mmol, 0.2 equiv.) under an atmosphere of nitrogen gas. The mixture was stirred for 12 h at 120 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:EtOAc, 5:1) to afford the title compound (300 mg, 76%) as light-yellow oil.

[0217] Step 5. 3-(1-Isobutyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine.

[0218] To apyridin-6-yl]-4-nitro-1-([2-(trimethylsilyl) ethoxy] methylpyrazole (15-4, 100 mg, 0.23 mmol, 1 equiv.) and B2(OH)4(107 mg, 1.19 mmol, 5 equiv.) in DMF (5 mL) was added 1-octyl-4-(1- octylpyridin-1-ium-4-yl) pyridin-1-ium dibromide (0.65 mg, 0.001 mmol, 0.005 equiv.) at room temperature. The resulting mixture was stirred for 20 min at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:EtOAc, 1:1) to afford the title compound (200 mg, 76%) as light-yellow solid. 104 58226332.1224990 / 23-003-PC / 554457

[0219] Step 6. 7-Hydroxy-N-(3-(1-isobutyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane- 4-carboxamide.

[0220] A -1-([2-(trimethylsilyl) ethoxy] methylpyrazol-4-amine (15-5, 100 mg, 0.25 mmol, 1 equiv.) and CDI (105 mg, 0.63 mmol, 2.5 equiv.) in DMF (5 mL) was stirred for 30 min at room temperature. 7- (Trifluoromethyl)-4-azaspiro [2.5] octan-7-ol (3-2, 75.5 mg, 0.38 mmol, 1.5 equiv.) in DMF (5 mL) was added at room temperature. The resulting mixture was stirred for additional 3 hours at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:EtOAc, 1:1) to afford the title compound (200 mg, 55%) as light-yellow solid.

[0221] Step 7. 7-Hydroxy-N-(3-(1-isobutyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide.

[0222] Ac] pyridin-6-yl]-1-([2-(trimethylsilyl) ethoxy] methylpyrazol-4-yl-7-(trifluoromethyl)-4-azaspiro [2.5] octane-4-carboxamide (15-6, 100 mg, 0.16 mmol, 1 equiv.), HCl (gas) in 1,4-dioxane (4 M, 2.4 mL), and MeOH (5 mL) was stirred for 2 hours at room temperature. The mixture was basified to pH to approximately 9 with a saturated solution of NaHCO3(aq.). The resulting mixture was 105 58226332.1224990 / 23-003-PC / 554457 diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether:EtOAc, 1:1) to afford the title compound (100 mg, 55%) as white solid.

[0223] Step 8. Enantiopure 7-hydroxy-N-(3-(1-isobutyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compund 15).4-yl}-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (15-7, 100 mg, 0.16 mmol) was purified by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK®IA, 2 x 25 cm, 5 μm; Mobile Phase A: (Hex:DCM, 3:1, with 0.5% 2 M NH3-MeOH), Mobile Phase B: IPA; isocratic 20%) with peak 2 collected to afford the title compound (12 mg, 11%).1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 10.65 (s, 1H), 9.65 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 6.02 (s, 1H), 4.66 (d, 2H), 4.11 (d, 1H), 3.33 – 3.18 (m, 1H), 2.38 – 2.21 (m, 2H), 1.72 – 1.54 (m, 2H), 1.45 – 1.26 (m, 2H), 1.31 – 1.20 (m, 2H), 1.17 – 1.08 (m, 1H), 0.92 (d, 7H). LC-MS m / z 479 (M+H+). 106 58226332.1224990 / 23-003-PC / 554457 Scheme 14 4-yl)spiro[cyclopropane-1,3'-indoline]-1'-carboxamide (Compound 16).

[0225] Step 1: 7'-Fluorospiro-2'-one.

[0226] A solution ofequiv.) in THF (15 mL) wascooled to -40 °C, then a solution of LDA (2 M in THF / heptane / ethylbenzene, 9.92 mL, 3 equiv.) under N2 atmosphere. The mixture was stirred at 0 °C for 30 min. 1,2-Dibromoethane (1.49 g, 7.94 mmol, 1.2 equiv.) was added dropwise and stirred at 25 °C for 4 hours. The mixture was poured into sat. aq. NH4Cl (50 mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated, and the residue was purified by flash silica gel chromatography (0 to 20% ethyl acetate in petroleum ether) to give the title compound (508 mg, 43%) as a pink solid.1H NMR 107 58226332.1224990 / 23-003-PC / 554457 (400 MHz, CDCl3) δ 7.97 (s, 1H), 6.94-7.00 (m, 2H), 6.61-6.65 (m, 1H), 1.81 (m, 2H), 1.57 (m, 2H). LC-MS m / z 178 (M+H+).

[0227] Step 2. 7'-fluorospiro[cyclopropane-1,3'-indoline].

[0228] A mixture of 7'- 2'-one (16-1, 508 mg, 2.87mmol, 1 equiv.) in THF (8 was (3 times) then cooled on an ice bath. LiAlH4(2.5 M in THF, 4.59 mL, 4 equiv.) was added at 0 °C, then the mixture was warmed to 60 °C and stirred for 4 hours under N2. The reaction mixture was cooled to 0 °C, diluted with THF (20 mL), then quenched by the careful addition of water (0.5 mL), aqueous NaOH (1 M, 0.5 mL), then water (1.5 mL). A white precipitate was formed which was filtered off through Celite®. The filtered cake was washed with EtOAc (2 x 20 mL). The combined filtrates were evaporated under reduced pressure and the residue was purified by flash silica gel chromatography (EtOAc in petroleum ether, 0 to 3%) to give the title compound (310 mg, 43%, 65% purity) as yellow liquid, which was used directly in the next step. LC-MS m / z 164 (M+H+).

[0229] Steps 3 and 4: 7'-Fluoro-N-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)spiro[cyclopropane-1,3'-indoline]-1'-carboxamide. (Compound 16).titlecompound (13 mg, 9%).1H NMR (400 MHz, DMSO-d6) δ 10.13-10.63 (m, 1H), 9.14 (s, 1H), 8.46 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 6.99-7.14 (m, 2H), 6.70 (d, 1H), 4.31 (d, 2H), 4.22 (s, 2H), 2.20-2.31 (m, 1H), 1.17 (s, 2H), 1.08 (s, 2H), 0.85 (d, 6H). LC-MS m / z 446 (M+H+). EXAMPLE 17: N-(3-(1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4- yl)-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 17). 108 58226332.1224990 / 23-003-PC / 554457

[0231] Compound 17 was as Compound 1 beginning with(bromomethyl)cyclobutane and to (27.7 mg, 36%).1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.85 (s, 1H), 9.22 (s, 1H), 8.31- 8.12 (m, 3H), 6.02 (s, 1H), 4.51 (d, 2H), 4.11 (d, 1H), 3.24 (t, 1H), 2.91 – 2.80 (m, 1H), 2.22 (d, 1H), 2.02 – 1.76 (m, 6H), 1.72 – 1.49 (m, 2H), 1.29 (s, 3H), 1.12 (p, 1H), 0.80 (s, 1H). LC-MS m / z 490 (M+H+). Scheme 15- 7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 18). 109 58226332.1224990 / 23-003-PC / 554457

[0232] Step 1. 6-Chloro-3-(2- [1,2-a]pyrazine.

[0233] 3-, MeCN (10mL), H2O (2 mL), 2-methylprop-1-en-1-ylboronic acid (0.86 g, 8.6 mmol, 1 equiv.), Na2CO3(2.74 g, 25.8 mmol, 3 equiv.) and Pd(dppf)Cl2(0.63 g, 0.86 mmol, 0.1 equiv.) were combined under an atmosphere of nitrogen gas. The resulting mixture was stirred for 2 hours at 70 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether in EtOAc, 100 to 50%) to afford the title compound (1.5 g, 84%) as yellow solid.

[0234] Step 2. 3-(2-Methylprop-1-en-1-yl)-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-a]pyrazine.

[0235] 7.22 mmol,1 equiv.), DMF (15 mL), 4-nitro-1-(oxan-2-yl)pyrazole (1.42 g, 7.22 mmol, 1 equiv.), 2,2- dimethylpropanoic acid (0.18 g, 1.8 mmol, 0.25 equiv.), K2CO3 (2.99 g, 21.7 mmol, 3 equiv.), bis(adamantan-1-yl)(butyl)phosphane (0.39 g, 1.1 mmol, 0.15 equiv.) and Pd(OAc)2110 58226332.1224990 / 23-003-PC / 554457 (0.16 g, 0.72 mmol, 0.1 equiv.) were combined under an atmosphere of nitrogen gas and the resulting mixture was stirred for 2 hours at 120 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:EtOAc, 2:1) to afford the title compound (200 mg, 8%) as white solid.

[0236] Step 3. 3-(3-Isobutylimidazo[1,2-a]pyrazin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.

[0237] 3-[3-(2-1-(oxan-2-yl)pyrazole (18-2, 150 mg, 0.41 mmol, 1 equiv.), MeOH (3 mL) and Pd(OH)2on carbon (10%, 25 mg) were combined. The resulting mixture was stirred for 2 hours under at atmosphere of hydrogen at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0238] Steps 4 and 5. 7-Hydroxy-N-(3-(3-isobutylimidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 18).obtain the title compound (3.6 mg, 5%).1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.29 (s, 1H), 9.25 (s, 1H), 8.78 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 6.03 (s, 1H), 4.09 (d, 1H), 3.25 (s, 1H), 2.93 (d, 2H), 2.18 (d, 1H), 2.07 (t, 1H), 1.66 (d, 1H), 1.56 (t, 1H), 1.36 (s, 2H), 1.22 (d, 2H), 1.14 – 1.07 (m, 1H), 0.96 (d, 6H), 0.79 (s, 1H). LC-MS m / z 478 (M+H+). 111 58226332.1224990 / 23-003-PC / 554457 Scheme 16 -5-.

[0240] Step 1: 6-[[3-(1-6-yl)-1H-pyrazol-4-yl]amino]-5-methyl-pyridine-3-carbonitrile.pyrazol-4-amine(prepared by the same method as 1-5, 39.2 mg, 0.16 mmol), 6-fluoro-5-methyl-pyridine-3- carbonitrile (20 mg, 0.15 mmol), 4-methylbenzenesulfonic acid monohydrate (2.8 mg, 0.015 mmol) and n-BuOH (1.5 mL) was stirred at 120 °C. After 18 h, the mixture was filtered and washed with MeCN (2 x 1 mL) to afford the title compound (42 mg, 78%) as a white powder. LC-MS m / z 359 (M+H+).

[0242] Step 2: 6-[[3-(1-Isopropylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl]amino]-5-methyl-pyridine-3-carboxamide (Compound 19). 58226332.1224990 / 23-003-PC / 554457

[0243] A mixture of 6-[[3-(1-isopropylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl]amino]-5-methyl-pyridine-3-carbonitrile (42 mg, 0.12 mmol), lithium hydroxide monohydrate (15.0 mg, 0.35 mmol), hydrogen peroxide (30 wt%, 0.036 mL, 0.35 mmol), EtOH (1.5 mL) and water (1.5 mL) was stirred at 90 °C. After 20 h, the resulting mixture was concentrated and purified by PrepHPLC to afford the title compound (38 mg, 86%) after lyophilization.1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 10.96 (s, 1H), 9.24 (s, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.19 (s, 1H), 5.15 (p, 1H), 2.41 (s, 3H), 1.52 (d, 6H). LC-MS m / z 377.2 (M+H+). Scheme 17 EXAMPLEpyrazol-4- yl]-7-fluoro-indoline-1-carboxamide (Compound 20).

[0244] A mixture of 3-[1-(2,2-dimethylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-amine dihydrochloride (17 mg, 0.050 mmol), bis(2,5-dioxopyrrolidin-1-yl) carbonate (14 mg, 0.054 mmol). DIPEA (0.0345 mL, 0.20 mmol) and dichloromethane (0.4 mL) was stirred at room temperature. After 15 min, a mixture of 7-fluoroindoline hydrochloride (10.3 mg, 0.059 mmol) and DMF (0.5 mL) was added. After 18 h, the resulting mixture was purified by PrepHPLC to provide the title compound (4.0 mg, 17%).1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.77 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.24 – 7.09 (m, 3H), 4.30 (s, 2H), 4.25 (t, 2H), 3.18 (t, 2H), 0.97 (s, 9H). LC-MS m / z 434 (M+H+). 113 58226332.1224990 / 23-003-PC / 554457 Scheme 18(2- methylimidazo[1,2-a]pyridin-3-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 21).

[0245] Step 1: tert-Butyl3-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0246] To a solution ofacid (400 mg, 2.27mmol, 1 equiv.) tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (482 mg, 2.27 mmol, 1 equiv.), DIPEA (0.395 mL, 2.27 mmol, 1 equiv.) and DMF (4 mL) was added HATU (863 mg, 114 58226332.1224990 / 23-003-PC / 554457 2.27 mmol, 1 equiv.). The mixture was stirred at room temperature for 15 hr. The resulting mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography (dichloromethane:MeOH = 10:1) to give the title compound (763 mg, 91%) as a yellow oil. LC- MS m / z 371.1 (M+H+).

[0247] Step 2: 4, 7-Diazaspiro[2.5]octan-7-yl-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone.

[0248] A mixture of3-carbonyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (763 mg, 2.06 mmol, 1 equiv.), HCl in MeOH (2 M, 10 mL). was stirred at room temperature for 2 hr. The resulting mixture was concentrated in vacuo to give the title compound (500 mg, 90%) as a yellow oil.

[0249] Step 3: 3-(4, 7-Diazaspiro [2.5] octan-7-ylmethyl)-2-methyl-imidazo [1, 2-a]pyridine.

[0250] To a solution of[1,2-a]pyridin-3-yl)methanone (300 mg, 1.11 mmol, 1 equiv.) and THF (10 mL) was added dropwise LAH (2.5 M, 0.444 mL, 1 equiv.) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 hr. Water (0.2 mL), 15% aqueous sodium hydroxide (0.2 mL) and water (0.6 mL) were sequentially and slowly added dropwise, and the resulting mixture was stirred at room temperature for 2 hr. MgSO4was added, and the precipitates were removed by filtration. The filtrate was purified by PrepHPLC to give the title compound (80 mg, 28%) as a yellow solid. LC-MS m / z 257 (M+H+). 115 58226332.1224990 / 23-003-PC / 554457

[0251] Step 4: N-[3-(1-Isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl]-7-[(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 21).toafford the title compound (9.5 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.82 (s, 1H), 9.19 (s, 1H), 8.43 (d, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.44 (d, 1H), 7.21 (t, 1H), 6.91 (t, 1H), 4.32 (d, 2H), 4.12 (bs, 1H), 3.76 (s, 2H), 3.04 (bs, 1H), 2.42 (bs, 4H), 2.30 - 2.21 (m, 1H), 2.26 (s, 3H), 1.34 (bs, 2H), 0.88 (d, 6H), 0.73 (bs, 2H). LC-MS m / z 539 (M+H+). Scheme 19 EXAMPLE4- yl]indane-1-carboxamide (Compound 22). OF

[0253] dihydrochloride (1-5, 20 mg, 0.060 mmol), 7-fluoroindane-1-carboxylic acid (9.0 mg, 0.050 mmol), EDCI hydrochloride (12 mg, 0.065 mmol), 1-hydroxybenzotriazole hydrate (9.2 mg, 116 58226332.1224990 / 23-003-PC / 554457 0.060 mmol), DIPEA (0.017 mL, 0.10 mmol) and DMF (0.5 mL) was stirred at room temperature. After 18 h, the resulting mixture was purified by PrepHPLC to provide the title compound (4.5 mg, 22%).1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 10.96 (s, 1H), 8.76 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.42 (q, 1H), 7.28 (d, 1H), 7.11 (t, 1H), 4.33 - 4.27 (m, 1H), 4.30 (d, 3H), 3.13 (dt, 1H), 3.04 - 2.96 (m, 1H), 2.41 - 2.33 (m, 1H), 2.28 – 2.17 (m, 1H), 0.86 (d, 6H). LC-MS m / z 419 (M+H+). Scheme 204- yl]-2H-pyrazolo[4,3-b]pyridin-5-amine (Compound 23).

[0254] Step 1: 6-Chloro-5-3-amine.58226332.1224990 / 23-003-PC / 554457

[0255] A mixture of 5-bromo-6-chloro-2-methylpyridin-3-amine (3.0 g, 13.6 mmol, 1 equiv.),cyclopropylboronic acid (1.28 g, 14.9 mmol, 1.2 equiv.), Pd(OAc)2 (304 mg, 1.36 mmol, 0.1 equiv.), tricyclohexylphosphine (760 mg, 2.71 mmol, 0.2 equiv.), K3PO4 (8.63 g, 40.6 mmol, 3 equiv.), 1,4-dioxane (20 mL) and water (10 mL) was stirred at 100 °C. After overnight, the resulting mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 600 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and purified by silica gel column chromatography (MeOH / dichloromethane, 0 to 20% in 30 min) to afford the title compound (1.3 g, 53%) as a yellow solid.

[0256] Step 2: 5-Chloro-6-cyclopropyl-1H-pyrazolo[4,3-b]pyridine.

[0257] To aamine (500 mg,2.74 mmol, 1 equiv.), AcOK (537.32 mg, 5.47 mmol, 2 equiv.), acetic acid (5 mL) and toluene (5 mL) at 0 °C was added isoamyl nitrite (481 mg, 4.11 mmol, 1.5 equiv.) dropwise. The resulting mixture was stirred at 60 °C for 4 h and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and purified by PrepHPLC to provide the title compound (274 g, 51%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 8.22 (s, 1H), 7.72 (s, 1H), 2.19 (tt, 1H), 1.12 – 1.00 (m, 2H), 0.86 – 0.78 (m, 2H). LC-MS m / z 194 (M+H+).

[0258] Step 3: 6-Cyclopropyl-N-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl]-2H-pyrazolo[4,3-b]pyridin-5-amine (Compound 23). 118 58226332.1224990 / 23-003-PC / 554457

[0259] - (1-5, 14mg, 0.055 mmol), 5-chloro-6-cyclopropyl-2H-pyrazolo[4,3-b]pyridine (9.7 mg, 0.050 mmol), 4- methylbenzenesulfonic acid monohydrate (0.95 mg, 0.0050 mmol) and n-BuOH (0.5 mL) was stirred at 120 °C. After 3 d, the mixture was concentrated in vacuo and purified by PrepHPLC to afford the title compound (3.0 mg, 14%).1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 12.85 (s, 1H), 11.01 (s, 1H), 9.25 (s, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 4.33 (d, 2H), 2.31 - 2.22 (m, 1H), 2.08 - 2.01 (m, 1H), 1.25 (d, 2H), 0.89 (d, 6H), 0.79 (d, 2H). LC-MS m / z 414 (M+H+). Scheme 21-1H- pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 24). 119 58226332.1224990 / 23-003-PC / 554457

[0260] Step 1: 1-Benzyl-

[0261] To a stirred one g, 14.8 mmol, 1 equiv.) inTHF (15 mL) was added NaH (60% purity, 1.18 g, 29.61 mmol, 2 equiv.) at 0 °C. After 30 min, benzyl bromide (2.5 mL, 21.1 mmol, 1.4 equiv.) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 h, quenched by adding water (30 mL) and saturated aqueous NH4Cl (40 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo, and purified by silica gel column chromatography (EtOAc / petroleum ether, 0 to 20%) to give the title compound (2.6 g, 73%) as a yellow oil. LC-MS m / z 226.1 (M+H+).

[0262] Step 2: 4-Benzyl-6,6-difluoro-4-azaspiro[2.5]octane.

[0263] To a stirred solution of EtMgBr (3 M, 14.4 mL, 42.6 mmol, 4 equiv.) in THF (20 mL)was added a solution of Ti(Oi-Pr)4(6.3 mL, 21.4 mmol, 2 equiv.) in THF (4 mL) under N2atmosphere at ˗67 °C. After 10 min, a solution of 1-benzyl-5,5-difluoro-piperidin-2-one (2.4 g, 10.67 mmol, 1 equiv.) in THF (4 mL) was added dropwise at ˗67 °C. The resulting mixture was stirred at room temperature for 16 h, quenched by adding water (100 mL), and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo, and purified by silica gel column chromatography (EtOAc / petroleum ether, 0 to 10%) to give the title compound (1.7 g, 61%) as a colorless oil. LC-MS m / z 238.2 (M+H+). 120 58226332.1224990 / 23-003-PC / 554457

[0264] Step 3: 6,6-Difluoro-4-azaspiro[2.5]octane

[0265] To a solution of (450 mg, 1.90 mmol, 1equiv.), HCl (12 M, 0.5 mL, 6.08 mmol, 3.2 equiv.) and MeOH (4 mL) was added Pd / C (10%, 0.5 g). The mixture was stirred under H2 (15 psi) at room temperature for 16 h. The resulting mixture was filtered, concentrated in vacuo to give the title compound (HCl salt form, 390 mg, used as a crude in the next step without further purification).

[0266] Step 4: 6,6-Difluoro-N-[3-[1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 24).20 toobtain the title compound (8.0 mg, 17%).1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 10.86 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 5.64 (q, 2H), 4.33 (bs, 2H), 2.24 - 2.13 (m, 2H), 1.67 - 0.72 (m, 6H). LC-MS m / z 456 (M+H+). EXAMPLE 25.1-Cyclopropyl-3-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4- yl]-1-(1H-pyrazol-3-ylmethyl)urea (Compound 25). 58226332.1224990 / 23-003-PC / 554457

[0268] Compound 25 was synthesized following the same procedure as Compound 20 toobtain the title compound (15 mg, 74%).1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 12.60 (s, 1H), 10.87 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 6.14 (d, 1H), 4.57 (s, 2H), 4.35 (d, 2H), 2.76 - 2.71 (m, 1H), 2.32 - 2.25 (m, 1H), 1.10 (d, 2H), 0.92 (d, 8H). LC-MS m / z 420 (M+H+). Scheme 22- - methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 26).

[0269] Step 1: tert-Butyl 7-[(3-methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxylate. 122 58226332.1224990 / 23-003-PC / 554457

[0270] A mixture of(63 mg, 0.30 mmol),5-(bromomethyl)-1-methyl-imidazole (119 mg, 0.68 mmol), DIPEA (0.16 mL, 0.89 mmol) and dichloromethane (1 mL) was stirred at room temperature. After 1 d, the resulting mixture was concentrated in vacuo and purified by PrepHPLC to afford the title compound (29 g, 32%).

[0271] Step 2: 7-[(3-Methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane.

[0272] A mixture of tert-butyl 7-[(3-methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxylate (29 mg, 0.095 mmol) and 4N HCl in 1,4-dioxane (1 mL) was stirred at room temperature. After 2 h, the resulting mixture was concentrated in vacuo to afford the title compound (20 mg, used as a crude in the next step without further purification).

[0273] Step 3: N-[3-(1-Isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl]-7-[(3-methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 26).

[0274] Compound 26 was synthesized following the same procedure as Compound 20 toobtain the title compound (12.5 mg, 37%).1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 123 58226332.1224990 / 23-003-PC / 554457 10.81 (s, 1H), 9.20 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.61 (s, 1H), 6.75 (s, 1H), 4.31 (d, 2H), 4.13 (bs, 2H), 3.65 (s, 3H), 3.42 (s, 2H), 2.40 (bs, 4H), 2.28 – 2.22 (m, 1H), 1.32 (bs, 2H), 0.88 (d, 6H), 0.80 (bs, 2H). LC-MS m / z 489 (M+H+). EXAMPLE 27.1-Cyclopropyl-1-(3-thienylmethyl)-3-[3-[1-(2,2,2- trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]urea (Compound 27).

[0275] Compound 27 wasas Compound 20 toobtain the title compound (23 mg, 64%).1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.78 (s, 1H), 9.22 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.48 (t, 1H), 7.33 (s, 1H), 7.05 (d, 1H), 5.62 (q, 2H), 4.53 (s, 2H), 2.63 (dq, 1H), 1.09 (d, 2H), 0.88 (q, 2H). LC-MS m / z 462 (M+H+). EXAMPLE 28. N-[3-[1-(2,2,2-Trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4- yl]spiro[2.5]octane-8-carboxamide (Compound 28).

[0276] Compound 28 was synthesized following the same procedure as Compound 22 toobtain the title compound (17 mg, 67%).1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 11.31 (s, 1H), 9.25 (s, 1H), 8.48 (s, 1H), 8.431H), 8.36 (s, 1H), 5.64 (q, 2H), 2.24 (d, 1H), 1.98 (s, 1H), 1.86 (t, 1H), 1.62 – 1.53 (m, 3H), 1.44 (q, 1H), 1.36 – 1.21 (m, 1H), 0.96 (d, 1H), 0.84 (t, 2H), 0.41 (t, 2H). LC-MS m / z 419 (M+H+). 124 58226332.1224990 / 23-003-PC / 554457 Scheme 23(Compound 29).

[0277] Step 1: 1-(6-Chloro-1-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidin-2-one.

[0278] To a solution of 6-chloro-3-iodo-1-isobutyl-pyrazolo[4,3-c]pyridine (925 mg, 2.76mmol, 1.0 equiv.) in anhydrous 1,4-dioxane (25 mL) was added 2-pyrrolidinone (235 mg, 2.76 mmol, 1.0 equiv.), Xantphos (160 mg, 0.28 mmol, 0.10 equiv.), Pd2(dba)3(65 mg, 0.071 mmol, 0.026 equiv.) and Cs2CO3 (1.80 g, 5.52 mmol, 2.0 equiv.). The mixture was degassed with N2 for 10 min and then heated to 90 °C for 2 hours. Upon completion, the reaction was cooled to rt and filtered through Celite®. The Celite®pad was washed with EtOAc (approximately 30 mL) and the filtrate concentrated to a crude oil. Purification via automated flash column chromatography (80 g Redisep®column, 0-50% EtOAc-hexanes) afforded the title compound (763 mg, 2.61 mmol, 95%) as a colorless solid. LC-MS m / z 294 (M+H+).

[0279] Step 2: 1-[1-Isobutyl-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridin-3-yl]pyrrolidin-2-one.

[0280] To a solution of 1-(6-chloro-1-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidin-2-one(742 mg, 2.54 mmol, 1.0 equiv.) and 4-nitro-1-tetrahydropyran-2-yl-pyrazole (750 mg, 3.80 mmol, 1.50 equiv.) in anhydrous DMF (25 mL) under N2 was added K2CO3 (1.05 g, 7.61 mmol, 3.0 equiv.) and 2,2-dimethylpropanoic acid (65 mg, 0.64 mmol, 0.25 equiv.). Diacetoxypalladium (57 mg, 0.25 mmol, 0.10 equiv.) and di(1-adamantyl)-n-butylphosphine 125 58226332.1224990 / 23-003-PC / 554457 hydriodide (cataCXium®AHI, CAS: 714951-87-8) (185 mg, 0.38 mmol, 0.15 equiv.) were added and the mixture degassed with N2 for 5 mins. The reaction was then heated to 120 °C for 16 hours. Upon completion, the reaction was cooled, poured into water (75 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (2 × 75 mL), brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (80 g Redisep®column, 10- 100% EtOAc–Hexanes) afforded the title compound (660 mg, 1.46 mmol, 57%) as a yellow solid. LC-MS m / z 454 (M+H+).

[0281] Step 3: 1-[6-(4-Amino-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1-isobutyl-pyrazolo[4,3-c]pyridin-3-yl]pyrrolidin-2-one.

[0282] To a solution of 1-[1-isobutyl-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridin-3-yl]pyrrolidin-2-one (660 mg, 1.46 mmol, 1.0 equiv.) in MeOH (40 mL) was added satd. aqueous NH4Cl solution (3 mL) and zinc powder (952 mg, 14.56 mmol, 10.0 equiv.). The reaction was stirred at rt for 10 min. Upon completion, the reaction was filtered through Celite®and the Celite®pad washed with MeOH (approximately 10 mL). The filtrate was concentrated in vacuo to give the title compound (310 mg, 0.73 mmol, 50%), which was sufficiently pure to be carried through to the next step without further purification. LC-MS m / z 424 (M+H+).

[0283] Step 4: 7-Hydroxy-N-[3-[1-isobutyl-3-(2-oxopyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide.

[0284] 1-[6-(4-amino-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1-isobutyl-pyrazolo[4,3-c]pyridin-3-yl]pyrrolidin-2-one (75 mg, 0.18 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (600 µL) and DIPEA (92.4 µL, 0.53 mmol, 3.0 equiv.). Bis(2,5-dioxopyrrolidin-1-yl) carbonate (113 mg, 0.44 mmol, 2.5 equiv.) was added and the mixture sonicated until complete dissolution and the reaction stirred for 15 min at rt. Racemic 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol (234 mg, 0.44 mmol, 2.5 equiv.) ) in DMF (2 mL) and DIPEA (154 µL, 0.89 mmol, 5.0 equiv.) was added and the mixture stirred for 10 min at rt. Upon completion, the mixture was concentrated to remove CH2Cl2, resuspended in EtOAc (15 mL) and washed with water (20 mL). The aqueous layer was back-extracted with EtOAc (3 × 75 mL) and the combined organic layers washed with brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced 126 58226332.1224990 / 23-003-PC / 554457 pressure to a crude residue. Purification via automated flash column chromatography (12 g Redisep®column, 30-100% EtOAc–hexanes) afforded the title compound (96.5 mg, 0.15 mmol, 85%) as an off-white solid. LC-MS m / z 645 (M+H+).

[0285] Step 5: 7-Hydroxy-N-[3-[1-isobutyl-3-(2-oxopyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 29).

[0286] 7-Hydroxy-N-[3-[1-isobutyl-3-(2-oxopyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (83.7 mg, 0.13 mmol, 1.0 equiv.) was triturated in hydrogen chloride (4.0 M solution in dioxane) (2 mL, 8 mmol, 61.6 equiv.) and stirred at rt with occasional sonication for 10 min. Upon completion, the reaction was concentrated in vacuo and subjected to azeotropic distillation with CH2Cl2 (3 × 5 mL) to give a crude residue. Purification via preparative HPLC (10-100% MeCN–water + 0.1% formic acid) afforded the title compound (32.8 mg, 0.059mmol, 45%). 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, minor tautomer), 12.84 (s, 1H), 10.81(s, 1H), 10.60minor tautomer), 9.54 (s, 1H), 8.04 (d, 2H), 7.97 (s, minor tautomer), 5.96 (s, 1H), 4.15 (d, 2H), 4.03 (d, 1H), 3.92 (t, 2H), 3.16 (t, 1H), 2.54 (t, 2H), 2.21 – 2.06 (m, 4H), 1.63 – 1.45 (m, 2H), 1.30 – 1.22 (m, 2H), 1.19 (d, 1H), 1.11 – 1.01 (m, 1H), 0.87 – 0.70 (m, 7H); LC-MS m / z 561 (M+H+). 127 58226332.1224990 / 23-003-PC / 554457 Scheme 23methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 30).

[0287] Step 1: 6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine.

[0288] To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.02 g, 13.2 mmol, 1.0 equiv.)in DMF (30 mL) was added 1-iodopyrrolidine-2,5-dione (3.94 g, 17.5 mmol, 1.3 equiv.) and the mixture stirred at 60 °C for 4 hours. Upon completion, the reaction was quenched by addition of water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (0-60% EtOAc–hexanes) afforded the title compound (2.53 g, 9.04 mmol, 69%) as a light brown solid. LC-MS m / z 280 (M+H+).

[0289] Step 2: 6-chloro-3-iodo-1-isobutyl-pyrazolo[4,3-c]pyridine.

[0290] To a solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2.05 g, 7.32 mmol, 1.0equiv.) in NMP (20 mL) was added K2CO3 (1.42 g, 10.24 mmol, 1.4 equiv.) followed by 1- bromo-2-methyl-propane (875 uL, 8.05 mmol, 1.1 equiv.) and the mixture stirred at 100 °C for 128 58226332.1224990 / 23-003-PC / 554457 30 min. Upon completion, the reaction was poured into water (75 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (0-15% EtOAc–Hexanes) afforded the title compound (2.46 g, 5.41 mmol, 74%) as a colorless solid. LC-MS m / z 336 (M+H+).

[0291] Step 3: 6-Chloro-1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridine.

[0292] To a solution of 6-chloro-3-iodo-1-isobutyl-pyrazolo[4,3-c]pyridine (940 mg, 2.8mmol, 1.0 equiv.) in anhydrous 1,4-dioxane (15 mL) was added 3-methoxyazetidine hydrochloride (346 mg, 2.80 mmol, 1.0 equiv.), Xantphos (162 mg, 0.28 mmol, 0.10 equiv.), Pd2(dba)3(66 mg, 0.072 mmol, 0.03 equiv.) and Cs2CO3(1.83 g, 5.62 mmol, 2.01 equiv.). The mixture was degassed with N2for 10 min then heated to 90 °C for 16 hours. Upon completion, the reaction was cooled to rt, filtered through Celite®with the Celite®pad washed with EtOAc (approxmiately 30 mL) and the filtrate concentrated to a crude oil. Purification via automated flash column chromatography (80 g Redisep®column, 0-50% EtOAc-hexanes) afforded the title compound (733 mg, 2.49 mmol, 89%) as a colorless solid. LC-MS m / z 295 (M+H+).

[0293] Step 4: 6-(1-Benzyl-4-nitro-pyrazol-3-yl)-1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridine.

[0294] To a solution of 6-chloro-1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridine (870 mg, 2.66 mmol, 1.0 equiv.) and 4-nitro-1-tetrahydropyran-2-yl-pyrazole (810 mg, 3.99 mmol, 1.50 equiv.) under N2in anhydrous DMF (25 mL) was added K2CO3(1.10 g, 7.97 mmol, 3.0 equiv.) and 2,2-dimethylpropanoic acid (68 mg, 0.67 mmol, 0.25 equiv.). Diacetoxypalladium (60 mg, 0.27 mmol, 0.10 equiv.) and di(1-adamantyl)-n-butylphosphine hydriodide (cataCXium®AHI, CAS: 714951-87-8) (194 mg, 0.40 mmol, 0.15 equiv.) were added and the mixture degassed with N2for 5 mins. The reaction was heated to 120 °C for 1 hour, followed by heating to 130 °C for 3 hours. Upon completion, the mixture was poured into water (75 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (2 × 75 mL), brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (80 g Redisep®column, 0-60% EtOAc–Hexanes) afforded the title compound (790 mg, 1.71 mmol, 64%) as a yellow solid. LC-MS m / z 462 (M+H+). 129 58226332.1224990 / 23-003-PC / 554457

[0295] Step 5: 3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-amine.

[0296] To a solution of 6-(1-benzyl-4-nitro-pyrazol-3-yl)-1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridine (870 mg, 1.89 mmol, 1.0 equiv.) in EtOH (15 mL) under N2wasadded Pd(OH)2 / C (20 wt. %)( 935 mg, 3.10 mmol, 1.64 equiv.) and the mixture degassed withN2 for 10 mins. A balloon of H2 was affixed and the reaction heated to 80 °C for 16 hours. The following day, the reaction was cooled and filtered through Celite®. The Celite®pad was washed with EtOH (approximately 30 mL) and the filtrate concentrated in vacuo to a crude residue. Purification via automated flash column chromatography (40 g Redisep®column, 0- 10% MeOH–CH2Cl2) afforded the title compound (285 mg, 0.83 mmol, 44%) as a yellow glassy solid. LC-MS m / z 342 (M+H+).

[0297] Step 5: 7-Hydroxy-N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 30).

[0298] 3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-amine (30 mg, 0.09 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (600 µL) and DIPEA (45.8 µL, 0.26 mmol, 3.0 equiv.). Bis(2,5-dioxopyrrolidin-1-yl) carbonate (25 mg, 0.10 mmol, 1.11 equiv.) was added and the mixture sonicated until complete dissolution. The reaction was stirred for 15 min at rt before a solution of enantiopure 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol (3-3, 25 mg, 0.13 mmol, 1.46 equiv.) in DMF (2 mL) and DIPEA (76.4 µL, 0.44 mmol, 5.0 equiv.) was added and the mixture stirred for 10 min at rt. Upon completion, the mixture was passed through a 45 μm filter and purified via preparative HPLC (10-100% MeCN–water + 0.1% formic acid) to afford the title compound (5.2 mg, 0.01 mmol, 11%).1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, minor tautomer), 12.77 (s, 1H), 10.72 (s, 1H), 10.52 (s, minor tautomer), 8.80 (s, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 5.96 (s, 1H), 4.35 – 4.25 (m, 3H), 4.04 – 3.87 (m, 4H), 3.27 – 3.14 (m, 6H), 2.11 (d, 1H), 1.65 – 1.44 (m, 2H), 1.36 – 1.11 (m, 1H), 1.01 (s, 1H), 0.78 (d, 6H), 0.72 (s, 1H). LC-MS m / z 563 (M+H+). 130 58226332.1224990 / 23-003-PC / 554457 Scheme 24c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 31).

[0299] Step 1: 1-Isobutyl-3-(3-methoxyazetidin-1-yl)-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine.

[0300] To a solution of 6-chloro-1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridine (713 mg, 2.42 mmol, 1.0 equiv.) and 4-nitro-1-tetrahydropyran-2-yl-pyrazole (715 mg, 3.63 mmol, 1.5 equiv.) in anhydrous DMF (25 mL) under N2 was added K2CO3 (1.00 g, 7.25 mmol, 3.0 equiv.) and 2,2-dimethylpropanoic acid (62 mg, 0.61 mmol, 0.25 equiv.). Diacetoxypalladium (54 mg, 0.24 mmol, 0.10 equiv.) and di(1-adamantyl)-n-butylphosphine hydriodide (cataCXium®AHI CAS Number: 714951-87-8) (176 mg, 0.36 mmol, 0.15 equiv.) were added and the mixture degassed with N2for 5 mins. The reaction was then heated to 120 °C for 16 hours. Upon completion, the reaction was cooled, poured into water (75 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (2 × 75 mL), brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (80 g Redisep®column, 20-100% EtOAc-Hexanes) afforded the title compound (560 mg, 1.30 mmol, 54%) as a yellow solid. LC-MS m / z 456 (M+H+).

[0301] Step 2: 3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-amine. 131 58226332.1224990 / 23-003-PC / 554457

[0302] To a solution of 1-isobutyl-3-(3-methoxyazetidin-1-yl)-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (590 mg, 1.30 mmol, 1.0 equiv.) (660 mg, 1.46 mmol, 1.0 equiv.) in MeOH (40 mL) was added satd. aqueous NH4Cl solution (3 mL) and zinc powder (847 mg, 12.95 mmol, 10.0 equiv.). The reaction was stirred at rt for 10 min. Upon completion, the reaction was filtered through Celite®and the Celite®pad washed with MeOH (approximately 10 mL). The filtrate was concentrated in vacuo to give the title compound (310 mg, 0.73 mmol, 56%), which was sufficiently pure to be carried through to the next step without further purification. LC-MS m / z 426 (M+H+).

[0303] Step 3: N-[3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide.

[0304] 3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-amine (60 mg, 0.14 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (600 µL) and DIPEA (73.5 µL, 0.42 mmol, 3.0 equiv.). Bis(2,5-dioxopyrrolidin-1-yl) carbonate (40 mg, 0.16 mmol, 1.11 equiv.) was added and the mixture sonicated until complete dissolution before the reaction was stirred for 25 min at rt.4-Azaspiro[2.5]octane hydrochloride in DMF (2 mL) and DIPEA (123 µL, 0.71 mmol, 5.0 equiv.) was added and the mixture stirred for 10 min at rt. Upon completion, the reaction mixture was concentrated to remove CH2Cl2, resuspended in EtOAc (15 mL) and washed with water (20 mL). The aqueous layer was back- extracted with EtOAc (3 × 20 mL) and the combined organic layers washed with brine (1 × 30 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (12 g Redisep®column, 5-100% EtOAc–hexanes) afforded the title compound (20.3 mg, 0.036 mmol, 26%) as a colorless solid. LC-MS m / z 563 (M+H+).

[0305] Step 4: N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 31).

[0306] To a stirred solution of N-[3-[1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (37 mg, 0.066 mmol, 1.0 equiv.) in anhydrous MeOH (3 mL) under N2, was added 4- methylbenzenesulfonic acid hydrate (6.0 mg, 0.032 mmol, 0.48 equiv.) and the reaction stirred at 65 °C for 10 min. The reaction mixture was then cooled, passed through a 45 um filter and purified via preparative HPLC (10-100% MeCN–water + 0.1% formic acid) to afford the title 132 58226332.1224990 / 23-003-PC / 554457 compound (20.3 mg, 0.042 mmol, 65%).1H NMR (400 MHz, DMSO-d6) δ 13.13 (s, minor tautomer), 12.73 (s, 1H), 10.65 (s, 1H), 10.46 (s, minor tautomer), 8.76 (s, 1H), 8.02 (s, 2H), 7.86 (s, 1H), 4.37 – 4.26 (m, 4H), 4.00 – 3.87 (m, 5H), 3.20 (s, 6H), 2.11 (p, 1H), 1.67 (s, 2H), 1.37 (s, 2H), 0.90 (br. s, 1H), 0.79 (d, 7H). LC-MS m / z 479 (M+H+). EXAMPLE 32: N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2-methylpropyl)pyrazolo[4,3- c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-methyl-4-azaspiro[2.5]octane-4-carboxamide (Compound 32).

[0307] Compound 32 wasprocedure as Compound 31 togive the title compound (20.9 mg, 58%).1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, minor tautomer), 12.80 (s, 1H), 10.72 (s, 1H), 10.54 (s, minor tautomer), 8.84 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 4.42 – 4.33 (m, 2H), 4.18 – 4.11 (m, 1H), 4.07 – 3.95 (m, 3H), 3.28 (s, 4H), 2.85 (s, 0.5 H), 2.18 (t, 0.5 H), 1.85 (s, 1H), 1.65 – 1.54 (m, 2H), 1.45 – 1.39 (m, 1H), 1.32 – 1.11 (m, 1H), 1.05 – 0.97 (m, 1H), 0.86 (s, 12H), 0.67 (t, 1H). LC-MS m / z 493 (M+H+). EXAMPLE 33: 6,6-Difluoro-N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2- methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4- carboxamide (Compound 33). H N N F

[0308] Compound 33 wasprocedure as Compound 31 withthe following modification: the reaction was left to stir at rt for 72 hours to afford the title compound (3.1 mg, 8%).1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, minor tautomer), 12.86 (s, 133 58226332.1224990 / 23-003-PC / 554457 1H), 10.86 (s, 1H), 10.65 (s, minor tautomer), 8.85 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 4.41 – 4.33 (m, 2H), 4.05 (d, 2H), 4.02 – 3.94 (m, 4H), 3.28 (s, 3H), 2.25 – 2.10 (m, 1H), 1.46 (s, 1H), 1.26 – 1.22 (m, 1H), 1.02 (s, 1H), 0.86 (d, 6H). LC-MS m / z 515 (M+H+). Scheme 25trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 34).

[0309] Step 1: 6-Chloro-3-iodo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine.

[0310] To a solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2.05 g, 7.32 mmol, 1.0equiv.) in DMF (15 mL) was added K2CO3(2.50 g, 18.1 mmol, 2.0 equiv.) followed by 2,2,2- trifluoroethyl trifluoromethanesulfonate (2.61 mL, 18.07 mmol, 2.0 equiv.) and the mixture stirred at 80 °C for 30 min. Upon completion, the reaction was poured into water (100 mL) and extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a crude residue. Purification via automated flash column chromatography (120 g Redisep®column, 0-20% EtOAc–Hexanes, desired regioisomer elutes first at 17% EtOAc) afforded the title compound (1.90 g, 5.26 mmol, 58%) as a colorless solid. LC-MS m / z 362 (M+H+).

[0311] Step 2: 6-Chloro-3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine.

[0312] To a solution of 6-chloro-3-iodo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (900mg, 2.49 mmol, 1.0 equiv.) in anhydrous 1,4-dioxane (10 mL) was added 3-methoxyazetidine hydrochloride (308 mg, 2.49 mmol, 1.0 equiv.), Xantphos (144 mg, 0.25 mmol, 0.10 equiv.), 134 58226332.1224990 / 23-003-PC / 554457 Pd2(dba)3(59 mg, 0.064 mmol, 0.026 equiv.) and Cs2CO3(1.62 g, 4.97 mmol, 2.0 equiv.). The mixture was degassed with N2 for 10 min before being heated to 90 °C for 16 hours. Upon completion, the reaction was cooled to rt and filtered through Celite®. The Celite®pad was washed with EtOAc (approximately 30 mL) and the filtrate concentrated to a crude oil. Purification via automated flash column chromatography (80 g Redisep®column, 0-50% EtOAc-hexanes) afforded the title compound (761 mg, 2.37 mmol, 95%) as a colorless solid. LC-MS m / z 321 (M+H+).

[0313] Step 3: 6-(1-Benzyl-4-nitro-pyrazol-3-yl)-3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine.

[0314] To a solution of 6-chloro-3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (761 mg, 2.37 mmol, 1.0 equiv.) and 4-nitro-1- tetrahydropyran-2-yl-pyrazole (724 mg, 3.56 mmol, 1.50 equiv.) in anhydrous dioxane (20 mL) under N2 was added Cs2CO3 (1.93 g, 5.94 mmol, 2.5 equiv.) and 2,2-dimethylpropanoic acid (485 mg, 4.75 mmol, 2.0 equiv.). Diacetoxypalladium (53 mg, 0.24 mmol, 0.10 equiv.) and XPhos (566 mg, 1.19 mmol, 0.5 equiv.) were added and the mixture degassed with N2 for 10 mins before being heated to 120 °C for 8 hours and 100 °C for 48 hours. Upon completion, the reaction was cooled to rt and filtered through Celite®. The Celite®pad was washed with CH2Cl2(approximately 30 mL), EtOAc (approxmately 10 mL) and the filtrate concentrated to a crude oil. Purification via automated flash column chromatography (80 g Redisep®column, 0-70% EtOAc-hexanes) afforded the title compound (1.02 g, 2.09 mmol, 88%) as a colorless solid. LC- MS m / z 488 (M+H+).

[0315] Step 5: 3-[3-(3-Methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-amine.

[0316] To a solution of 6-(1-benzyl-4-nitro-pyrazol-3-yl)-3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 1.0 equiv.) in EtOH (15 mL)under N2 was added Pd(OH)2 / C (20 wt. %) (2.10 g, 2.99 mmol, 1.43 equiv.) and the mixturedegassed with N2for 10 mins. A balloon of H2was affixed and the reaction heated to 80 °C for 16 hours. The following day, the reaction was cooled and filtered through Celite®. The Celite®pad was washed with EtOH (approximately 30 mL) and the filtrate concentrated in vacuo to a crude residue. Purification via automated flash column chromatography (40 g Redisep®column, 135 58226332.1224990 / 23-003-PC / 554457 0-10% MeOH–CH2Cl2) afforded the title compound (292 mg, 0.79 mmol, 38%) as a yellow solid. LC-MS m / z 368 (M+H+).

[0317] Step 6: 7-Hydroxy-N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 34).

[0318] 3-[3-(3-Methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-amine (40 mg, 0.12 mmol, 1.0 equiv.) was dissolved in CH2Cl2(600 µL) and DIPEA (56.8 µL, 0.33 mmol, 3.0 equiv.). Bis(2,5-dioxopyrrolidin-1-yl) carbonate (31 mg, 0.12 mmol, 1.11 equiv.) was added and the mixture sonicated until complete dissolution and the reaction stirred for 15 min at rt. Enantiopure 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol (30 mg, 0.15 mmol, 1.41 equiv.) in DMF (2 mL) and DIPEA (94.7 µL, 0.54 mmol, 5.0 equiv.) was added and the mixture stirred for 10 min at rt. Upon completion, the mixture was passed through a 45 um filter and purified via preparative HPLC (20-100% MeCN-water + 0.1% formic acid) to afford the title compound (35.0 mg, 0.06 mmol, 55%).1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, minor tautomer), 12.93 (s, 1H), 10.72 (s, 1H), 10.52 (s, minor tautomer), 8.94 (s, 1H), 8.15 (d, 2H), 6.04 (s, 1H), 5.33 (q, 2H), 4.46 – 4.36 (m, 3H), 4.07 – 3.99 (m, 2H), 3.31 – 3.22 (m, 5H), 2.18 (d, 1H), 1.71 – 1.56 (m, 2H), 1.39 – 1.31 (m, 1H), 1.24 (s, 1H), 1.09 (s, 1H), 0.80 (s, 1H). LC-MS m / z 589 (M+H+). EXAMPLE 35: N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3- c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-methyl-4-azaspiro[2.5]octane-4-carboxamide (Compound 35).

[0319] Compound 35 wasprocedure as Compound 34 toafford the title compound (21.3 mg, 60%).1H NMR (400 MHz, DMSO-d6) δ 13.28 (s, minor tautomer), 12.89 (s, 1H), 10.65 (s, 1H), 10.47 (s, minor tautomer), 8.90 (s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 5.33 (q, 2H), 4.42 (s, 2H), 4.15 (d, 1H), 4.06 – 4.00 (m, 2H), 3.31 – 3.26 (m, 5H), 136 58226332.1224990 / 23-003-PC / 554457 1.86 (s, 1H), 1.65 – 1.54 (m, 2H), 1.44 (s, 1H), 1.27 (s, 1H), 1.17 (d, 1H), 1.08 – 0.98 (m, 1H), 0.87 (d, 3H), 0.67 (s, 2H). LC-MS m / z 519 (M+H+). EXAMPLE 36: 6,6-Difluoro-N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2,2,2- trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4- carboxamide (Compound 36).

[0320] Compound 36 wasprocedure as Compound 34 toafford the title compound (4.5 mg, 12%).1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, minor tautomer), 12.94 (s, 1H), 10.78 (s, 1H), 10.57 (s, minor tautomer), 8.91 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 5.33 (q, 2H), 4.41 (d, 3H), 4.03 (d, 2H), 3.28 (s, 3H), 2.25 – 2.13 (m, 1H), 1.87 – 0.57 (m, 1H). LC-MS m / z 541 (M+H+). EXAMPLE 37: N-[3-[3-(3-methoxyazetidin-1-yl)-1-(2-methylpropyl)pyrazolo[4,3- c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-oxa-4-azaspiro[2.5]octane-4-carboxamide (Compound 37).

[0321] Compound 37 wasprocedure as Compound 30 togive the title compound (19.8 mg, 56%).1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, minor tautomer), 12.77 (s, 1H), 10.67 (s, 1H), 10.47 (s, minor tautomer), 8.76 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 4.38 – 4.26 (m, 3H), 4.00 – 3.87 (m, 5H), 3.66 – 3.41 (m, 5H), 3.21 (s, 5H), 2.11 (p, 1H), 1.16 (s, 1H), 1.05 (s, 1H), 0.78 (d, 6H). LC-MS m / z 481 (M+H+). 137 58226332.1224990 / 23-003-PC / 554457 Scheme 26methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 38).

[0322] Step 1: 7-Hydroxy-N-[3-[1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide.

[0323] Intermediate 38-6 was synthesized following the same procedure as Compound 31 togive the title compound (209 mg, 69%). LC-MS m / z 647 (M+H+).

[0324] Step 2: 7-Hydroxy-N-[3-[3-(3-hydroxyazetidin-1-yl)-1-isobutyl-pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide

[0325] To a stirred solution of 7-hydroxy-N-[3-[1-isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (78.3 mg, 0.12 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) under N2 at 0 °C, was added tribromoborane (5 equiv., 0.61 mmol, 5.0 equiv.) dropwise. The reaction was gradually warmed to rt and stirred for 3 hours. Upon completion, the reaction was reverse quenched in an ice-cold satd. NaHCO3solution and EtOAc (60 mL) was added. The layers were separated, and the aqueous layer was back-extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine (1 x 100 mL), dried (MgSO4), filtered and concentrated in vacuo to a crude residue. Purification via automated flash column chromatography (12 g 138 58226332.1224990 / 23-003-PC / 554457 Redisep®column, 0-10% MeOH-CH2Cl2) afforded the title compound (46.7 mg, 0.07 mmol, 61%) as a colorless solid. LC-MS m / z 633 (M+H+).

[0326] Step 3: 7-Hydroxy-N-[3-[3-(3-hydroxyazetidin-1-yl)-1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 38).

[0327] To a stirred solution of 7-hydroxy-N-[3-[3-(3-hydroxyazetidin-1-yl)-1-isobutyl-pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (46.7 mg, 0.074 mmol, 1.0 equiv.) in anhydrous MeOH (3mL) under N2, was added 4-methylbenzenesulfonic acid hydrate (7.0 mg, 0.04 mmol, 0.50equiv.) and the reaction stirred at 65 °C for 25 min. An additional portion of 4-methylbenzenesulfonic acid hydrate (11 mg, 0.058 mmol, 0.78 equiv.) was added and thereaction stirred at 65 °C for 4 hours. The mixture was cooled, passed through a 45 μm filter andpurified via preparative HPLC (10-100% MeCN–water + 0.1% formic acid) to afford the title compound (1.4 mg, 0.003 mmol, 3.5%). LC-MS m / z 549 (M+H+); Analytical HPLC purity 98% at 254 nm. Scheme 27pyrazol-4-yl]-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 39). 139 58226332.1224990 / 23-003-PC / 554457

[0328] Step 1: 6-Chloro-1-( 1H-pyrazolo[4,3-c]pyridine.

[0329] To a 1 equiv.) and(3-fluorooxetan- g, 1.83 equiv.) in DMAc (20 mL) was added NaOH (260.4 mg, 6.51 mmol, 2 equiv.). The mixture was stirred at 100 °C for 12hr. Then, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with aqueous NaCl 60 mL (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, Eluent of 0 to approximately 30% EtOAc in petroleum ether / Ethyl acetate ether, gradient at 40 mL / min). The title compound 6-chloro-1-[(3-fluorooxetan-3- yl)methyl]pyrazolo[4,3-c]pyridine (400 mg, 1.66 mmol, 50.84%) was obtained as a yellow liquid.1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, 1H), 8.41 (s, 1H), 7.91 (d, 1H), 5.02-5.11 (m, 2H), 4.53-4.69 (m, 4H).

[0330] Step 2: 1-((3-Fluorooxetan-3-yl)methyl)-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.

[0331] (39-1,400 mg, 1.66 mmol, 1 equiv.), 4-nitro-1-tetrahydropyran-2-yl-pyrazole (326.4 mg, 1.66 mmol, 1 140 58226332.1224990 / 23-003-PC / 554457 equiv.), CuI (315.2 mg, 1.66 mmol, 1 equiv.), XPhos (473.5 mg, 993.25 μmol, 0.6 equiv.) and Cs2CO3 (1.62 g, 4.97 mmol, 3 equiv.), Pd(OAc)2 (92.9 mg, 413.79 μmol, 0.25 equiv.), 2,2- dimethylpropanoic acid (507.2 mg, 4.97 mmol, 3 equiv.) in dioxane (7 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 120 °C for 12h under N2atmosphere. LC-MS showed to approximately 34% of desired compound was detected. The reaction mixture was then diluted with H2O (20 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, Eluent of 0 to approximately 100% Ethyl acetate / Petroleum ether gradient at 50 mL / min) to provide the title compound 1-[(3- fluorooxetan-3-yl)methyl]-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3- c]pyridine (285 mg, 42.79%).1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.20 (s, 1H), 5.40 (m, 1H), 5.07-5.17 (m, 2H), 4.79-4.93 (m, 2H), 4.60-4.71 (m, 2H), 3.78 (br d, 1H), 3.27 (br d, 1H), 2.21-2.29 (m, 1H), 1.89 (br s, 1H), 1.44 (br d, 4H).

[0332] Step 3: 3-(1-((3-Fluorooxetan-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.

[0333] 2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (1-2, 285 mg, 708.29 μmol, 1 equiv.) in MeOH (2 mL) was added Pd / C (100 mg, 93.97 μmol, 10% purity, 0.133 equiv.) and NH3 / MeOH (7 M, 2 mL, 19.77 equiv.) under a nitrogen atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 psi) at 25 °C for 5hr. LC-MS showed to approximately 82% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. The title compound 3-[1-[(3-fluorooxetan-3- yl)methyl]pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-amine (1-3, 196 mg, 74.31%) was obtained as a black brown solid.1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 141 58226332.1224990 / 23-003-PC / 554457 8.38 (s, 1H), 7.76 (s, 1H), 7.19 (s, 1H), 5.71 (m, 1H), 4.99-5.15 (m, 2H), 4.80-4.93 (m, 2H), 4.56-4.72 (m, 4H), 3.87 (br d, 1H), 3.46-3.55 (m, 1H), 2.34-2.40 (m, 1H), 1.80-1.88 (m, 1H), 1.46-1.68 (m, 4H). LC-MS m / z 373.1 (M+H+).

[0334] Step 4: 3-(1-((3-Fluorooxetan-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine.-1-tetrahydropyran-2-yl-pyrazol-4-amine (39-3, 50 mg) in dioxane (5 mL) was added HCL in dioxane (4 N, 0.5 mL) under N2 atmosphere. The mixture was stirred under N2 for 2 hr. LC- MS showed completion of reaction. The reaction mixture was filtered and concentrated under reduced pressure and then diluted with acetonitrile and lyophilized to give title compound as brown residue which was used into the next step without further purification.

[0336] Step 5: [3-[1-[(3-Fluorooxetan-3-yl)methyl]pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 39).

[0337] pyrazol-4-amine (39-4, 29 mg, 0.1 mmol, 1 equiv.), DCM (0.5 mL) and DIPEA (87 μL, 0.5 mmol, 5 equiv.) were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 7- (trifluoromethyl)-4-azaspiro[2.5]octan-7-ol (3-2, 30 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution 142 58226332.1224990 / 23-003-PC / 554457 was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (10.5 mg, 20%).1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 10.90 (s, 1H), 9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 6.11 (s, 1H), 5.22 (d, 2H), 4.93 (m, 2H), 4.72 (m, 2H), 4.17 (d, 1H), 2.28 (d, 1H), 1.84 – 1.58 (m, 2H), 1.35 (m, 4H), 1.19 (d, 1H), 0.89 (d, 1H). LC-MS m / z 510 (M+H+). Scheme 28- - .

[0338] Step 1: 6-Bromo-1- [4,3-c]pyridine.

[0339] To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (1.2 g, 6.06 mmol, 1 equiv.) inDMAc (10 mL) was added NaOH (484.8 mg, 12.12 mmol, 2 eq.) and bromomethylcyclopropane (1.64 g, 12.12 mmol, 1.16 mL, 2 eq.). The mixture was stirred at 100 °C for 12 hours. The mixture was diluted with water (100 mL), extracted with EtOAc (3 X 80 mL). The organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated to give the residue. The residue was purified by flash silica gel 143 58226332.1224990 / 23-003-PC / 554457 chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 0 to approximately 30% Ethyl acetate / Petroleum ether gradient at 50 mL / min) to give the title compound 6- bromo-1-(cyclopropylmethyl)pyrazolo[4,3-c]pyridine (730 mg, 47.78%).1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.12 (s, 1H), 7.57 (d, 1H), 4.22 (d, 2H), 1.29-1.38 (m, 1H), 0.62-0.69 (m, 2H), 0.41-0.47 (m, 2H). LC-MS m / z 254 (M+H+).

[0340] Step 2: 1-(Cyclopropylmethyl)-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.

[0341] mg, 2.90mmol, 1 , mg, , Pd(OAc)2 (65 mg, 289.52 μmol, 0.1 eq.), XPhos (276 mg, 578.96 μmol, 0.2 eq.) and CuI (331 mg, 1.74 mmol, 0.6 eq.), Cs2CO3 (2.36 g, 7.24 mmol, 2.5 eq.), pivalic acid (739 mg, 7.24 mmol, 2.5 eq.) in dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 48 hours under N2atmosphere. LCMS showed the desired MS. The mixture was concentrated to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 0 to approximately 30% Ethyl acetate / Petroleum ether) to give the title compound (580 mg, 54%).1H NMR (400 MHz, CDCl3) δ .21 (d, 1H), 8.29 (s, 1H), 8.26 (d, 1H), 7.79 (s, 1H), 5.47 (m, 1H), 4.33 (d, 2H), 3.95 (br d, 1H), 3.37 (m, 1H), 2.41-2.51 (m, 1H), 2.07-2.12 (m, 1H), 2.03 (br d, 1H), 1.61 (br m, 2H), 1.48-1.54 (m, 1H), 1.34-1.40 (m, 1H), 0.65 (m, 2H), 0.45 (m, 2H). LC-MS m / z 369 (M+H+).

[0342] Step 3: 3-(1-(Cyclopropylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine. 58226332.1224990 / 23-003-PC / 554457

[0343] A mixture of 1-(cyclopropylmethyl)-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (40-2, 580 mg, 1.57 mmol, 1 eq.), Pd / C (10%, 0.1 g) in MeOH (8 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 12 hours under H2(15 psi) atmosphere. The mixture was filtered, and the filtrate was concentrated to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 0 to approximately 65% Ethyl acetate / Petroleum ether) to give the title compound (252 mg, 44%).1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.16 (s, 1H), 7.77 (s, 1H), 7.35 (s, 1H), 5.41 (d, 1H), 4.31-4.43 (m, 1H), 4.14-4.27 (m, 2H), 3.60-3.72 (m, 1H), 2.71-3.01 (m, 2H), 2.60 (d, 1H), 2.11 (d, 1H), 1.90 (d, 1H), 1.78 (d, 1H), 1.61 (s, 2H), 1.36 (s, 1H), 0.63 (s, 2H), 0.44 (s, 2H). LC-MS m / z 339 (M+H+).

[0344] Step 4: 3-(1-(Cyclopropylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine.

[0345] tetrahydropyran-2-yl-pyrazol-4-amine (2-3, 50 mg) in dioxane (1 mL) was added HCL in dioxane (4 N, 1 mL) under N2 atmosphere. The mixture was stirred under nitrogen for 2 hr. LC-MS showed completion of reaction. The reaction mixture was filtered and concentrated under reduced pressure and then diluted with acetonitrile and lyophilized to give title compound as brown residue which was used into the next step without further purification.

[0346] Step 5: N-(3-(1-(Cyclopropylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 40).224990 / 23-003-PC / 554457

[0347] To 3-(1-(cyclopropylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine(40-4, 26 mg, 0.1 mmol, 1 equiv.), DCM (0.5 mL) and DIPEA (87 μL, 0.5 mmol, 5 equiv.) were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 7-(trifluoromethyl)-4- azaspiro[2.5]octan-7-ol (3-2, 30 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (13.2 mg, 28%).1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 10.92 (s, 1H), 9.30 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 6.11 (s, 1H), 4.46 (d, 2H), 4.17 (d, 1H), 3.30 (m, 1H), 2.28 (d, 1H), 1.73 (d, 1H), 1.64 (m, 1H), 1.36 (m, 4H), 1.18 (m, 1H), 0.86 (s, 1H), 0.57 (d, 2H), 0.49 (d, 2H). LC-MS m / z 476 (M+H+). Scheme 29 4-yl)carbamoyl)-4-azaspiro[2.5]octan-7-yl)acetate (Compound 41).

[0348] Step 1: 6-Bromo-1-pyridine.58226332.1224990 / 23-003-PC / 554457

[0349] To a solution of 6-bromo-1H-pyrazolo [4, 3-c] pyridine (7 g, 35.35 mmol, 1 equiv.) inCH3CN (100 mL) was added Cs2CO3 (34.6 g, 106 mmol, 3 equiv.) and 1-bromo-2-methyl- propane (14.55 g, 106.16 mmol, 11.54 mL, 3 equiv.). The solution was stirred at 30 °C for 24 hr. Then 1-bromo-2-methyl-propane (14.53 g, 106.05 mmol, 11.53 mL, 3 equiv.) was added. The resulting mixture was stirred at 30 °C for 24 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate 3 / 1) to give 6-bromo-1-isobutyl-pyrazolo [4, 3- c] pyridine (5.5 g, 61%).1H NMR (400 MHz, CDCl3) 9.04 (s, 1H), 8.74-8.80 (m, 1H), 7.68 (s, 1H), 4.30 (d, 2H), 2.29 (m, 1H), 0.85 (d, 6H). LC-MS m / z 254 (M+H+).

[0350] Step 2: 1-Isobutyl-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.

[0351] mmol, 1equiv.), 4-nitro-1-tetrahydropyran-2-yl-pyrazole (4.27 g, 21.64 mmol, 1 equiv.), Pd(OAc)2 (1.21 g, 5.41 mmol, 0.25 equiv.), Cs2CO3(21.15 g, 64.93 mmol, 3 equiv.), CuI (1.03 g, 5.41 mmol, 0.25 equiv.), 2,2-dimethylpropanoic acid (6.63 g, 64.93 mmol, 7.46 mL, 3 equiv.), dimethylpropanoic acid (1.05 g, 10.23 mmol, 1.18 mL, 2.7 equiv.) and XPhos (6.19 g, 12.99 mmol, 0.6 equiv.) in dioxane (33 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 120 °C for 3 hr under N2atmosphere. The reaction mixture was quenched by addition NH3.H2O (60 mL) at 25 °C, then diluted with water (40 mL) and extracted with EtOAc (300 mL). The combined organic layers were washed with brine (10 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1) to give 1-isobutyl-6-(4-nitro- 1-tetrahydropyran-2-yl-pyrazol-3-yl) pyrazolo [4, 3-c] pyridine (4.89 g, 61%) as a yellow solid. LC-MS m / z 371 (M+H+).

[0352] Step 3: 3-(1-Isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine. 147 58226332.1224990 / 23-003-PC / 554457

[0353] To yl) pyrazolo[4, 3-c]Pd / C (815.00 mg, 765.83 μmol, 10% purity, 0.058 equiv.). The mixture was stirred under H2 (15 psi) at 25 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1-tetrahydropyran-2-yl-pyrazol-4-amine (3.73 g, 10.96 mmol, 83%).1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, 1H), 8.32 (d, 1H), 7.75 (s, 1H), 7.20 (s, 1H), 5.67 (m, 1H), 4.61 (s, 2H), 4.22-4.28 (m, 2H), 3.93 (br d, 1H), 3.51-3.61 (m, 1H), 2.34-2.45 (m, 1H), 2.16-2.31 (m, 1H), 1.94-2.03 (m, 1H), 1.76-1.89 (m, 1H), 1.58-1.69 (m, 1H), 1.47-1.56 (m, 2H), 0.88 (m, 6H). LC-MS m / z 341 (M+H+).

[0354] Step 4: 3-(1-Isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine.

[0355] To a2-yl-pyrazol-4-amine (41-3, 500 mg, 1.47 mmol, 1 equiv.) in MeOH (10 mL) was added HCl / MeOH (2 M, 5 mL, 6.81 equiv.).The mixture was stirred at 25 °C for 5hr. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(1-isobutylpyrazolo[4,3-c]pyridin-6- yl)-1H-pyrazol-4-amine (326 mg, 1.27 mmol, 87%) as a yellow solid. LC-MS m / z 257 (M+H+).

[0356] Step 5: Methyl 2-(4-((3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)carbamoyl)-4-azaspiro[2.5]octan-7-yl)acetate (Compound 41). 148 58226332.1224990 / 23-003-PC / 554457

[0357] 4, 26 mg,0.1 mmol,, added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and methyl 2-(4- azaspiro[2.5]octan-7-yl)acetate (28 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (16.40 mg, 35%).1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.71 (s, 1H), 9.14 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 4.23 (d, 2H), 4.09 (s, 1H), 3.49 (s, 3H), 2.81 (s, 1H), 2.43 (s, 1H), 2.18 (s, 1H), 2.13 (d, 1H), 1.67 (d, 1H), 1.54 (d, 1H), 1.33 (s, 1H), 1.28 – 1.22 (m, 1H), 1.11 (s, 1H), 1.09 – 0.99 (m, 1H), 0.81 (d, 6H), 0.63 (s, 2H). LC-MS m / z 466 (M+H+). Scheme 304- yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 42). 149 58226332.1224990 / 23-003-PC / 554457 mmol, 1 equiv.) inwas g, 0 °C. The mixture was stirred for 30 min. isobutyl bromide (8.98 g, 65.5 mmol, 2 equiv.) was added and the mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to afford 6-chloro-1-(2-methylpropyl) pyrrolo[3,2- c] pyridine (5 g, 73%) as yellow oil.

[0360] Step 2: 1-Isobutyl-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridine

[0361] 4.792mmol, 1 equiv.) and 4-nitro-1-(oxan-2-yl) pyrazole (1417.37 mg, 7.188 mmol, 1.5 equiv.) in DMF (15 mL) were added K2CO3(1986.75 mg, 14.376 mmol, 3 equiv.), Trimethylacetic acid (122.35 mg, 1.198 mmol, 0.25 equiv.), Pd(OAc)2 (107.69 mg, 0.480 mmol, 0.1 equiv.) and bis(adamantan-1-yl) (butyl)phosphane (257.71 mg, 0.719 mmol, 0.15 equiv.). After stirring for 150 58226332.1224990 / 23-003-PC / 554457 2 h at 120 °C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to afford 3-[1-(2-methylpropyl) pyrrolo[3,2-c] pyridin-6-yl]-4-nitro-1-(oxan-2-yl) pyrazole (800 mg, 45.19%) as yellow oil.

[0362] Step 3: 3-(1-Isobutyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine

[0363] (2-methylpropyl) pyrrolo[3,2-c]yl]-4-nitro-1-(oxan-2-yl) pyrazole (790 mg, 2.138 mmol, 1 equiv.) in DMF (10 mL) was added B2(OH)4(575 mg, 6.414 mmol, 3 equiv.) and 4-(pyridin-4-yl) pyridine (16.70 uL, 0.011 mmol, 0.005 equiv.). The mixture was stirred for 5 min at rt. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to afford 3-[1-(2- methylpropyl) pyrrolo[3,2-c] pyridin-6-yl]-1-(oxan-2-yl) pyrazol-4-amine (440 mg, 60.6%) as yellow oil.

[0364] Step 4: 3-(1-Isobutyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazol-4-amine

[0365] 2-yl)pyrazol-4-amine (440 mg, 1.296 mmol, 1 equiv.) was added HCl(gas)in 1,4-dioxane (8 mL). The mixture was stirred overnight at rt. The precipitated solids were collected by filtration and 151 58226332.1224990 / 23-003-PC / 554457 washed with MeOH (3 x 3 mL). This resulted in 3-[1-(2-methylpropyl) pyrrolo[3,2-c] pyridin- 6-yl]-1H-pyrazol-4-amine (218 mg, 63%) as yellow solid.1H NMR (300 MHz, DMSO-d6) δ 14.00 (s, 1H), 11.00 (m, 2H), 9.20 (s, 1H), 8.91 (s, 1H), 8.16 (s, 1H), 7.98 (d, 1H), 7.07 (d, 1H), 4.31 (d, 2H), 2.29 – 2.16 (m, 1H), 0.90 (d, 6H). LC-MS m / z 255 (M+H+).

[0366] Step 5: 7-Hydroxy-N-(3-(1-isobutyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 42).

[0367] 26 mg, 0.1mmol, 1 , were followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 7-(trifluoromethyl)-4-azaspiro[2.5]octan- 7-ol (3-2, 30 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (15.0 mg, 63%).1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.97 (s, 1H), 8.86 (s, 1H), 8.00 (d, 2H), 7.46 (d, 1H), 6.58 (d, 1H), 5.97 (s, 1H), 3.99 (d, 3H), 2.20 – 2.02 (m, 2H), 1.59 (d, 1H), 1.50 (m, 1H), 1.22 (m, 3H), 1.09 – 0.99 (m, 1H), 0.80 (d, 6H), 0.76 – 0.67 (m, 1H). LC-MS m / z 478 (M+H+). Scheme 31224990 / 23-003-PC / 554457 EXAMPLE 43.7-Fluoro-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)- 1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 43).

[0368] Step 1: 7-Fluoro-4-H NMorpholinosulfur trifluorideN DCM, -35OC to rt, 24 h TFA, DCM, H2O, r.t. (2 h)

[0369] Tert-butyl 6-[2.5]octane-4-carboxylate (227 mg, 1 mmol, 1.0 equiv.)and dry DCM (2 mL) were added to a 5 mL vial, and the mixture was cooled to -35OC followed by drop-wise addition of morpholino sulfur trifluoride (526 mg, 0.36 mL, 3 mmol, 3 equiv.). The vial was vigorously stirred under a balloon of N2. The reaction was warmed to room temperature and was further stirred for further 24 h. Then the reaction was quenched by addition of water (5 mL) and extracted with EtOAc (2 x 10 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and the solvent was removed to obtain desired product in good purity which was used for next step deprotection. The resulting product was dissolved in DCM (2 mL), TFA (2 mL) and water (0.2 mL) and the mixture was stirred for 2 h. LC-MS indicated completion of reaction. The mixture was extracted with EtOAc (2 x 10 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and the solvent was removed and lyophilized by adding 1 mL of acetonitrile to obtain desired product in good purity which was used for next step reaction.

[0370] Step 2: 7-Fluoro-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 43). 153 58226332.1224990 / 23-003-PC / 554457

[0371] To 3-(1- 1H-pyrazol-4-amine(24-5, 29 mg, 0.1, mmol, 5 equiv.) were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 7-fluoro-4- azaspiro[2.5]octane (43-1, 20 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (15.5 mg, 35%).1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 10.74 (s, 1H), 9.21 (s, 1H), 8.38 (d, 2H), 8.05 (s, 1H), 5.56 (d, 2H), 4.90 (d, 1H), 3.61 (s, 2H), 1.91 (s, 2H), 1.22 – 0.57 (m, 6H). LC-MS m / z 439 (M+H+). Scheme 32pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 44).

[0372] Step 1: Tert-butyl (4-[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)carbamoyl)-4-azaspiro[2.5]octan-7-yl)carbamate. 154 58226332.1224990 / 23-003-PC / 554457

[0373] 5, 26 mg,0.1 mmol,, added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. THF (0.5 mL) and tert-butyl (4- azaspiro[2.5]octan-7-yl)carbamate (34 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, and the resulting product was used as such for next-step reaction.

[0374] Step 2: 7-Amino-N-[3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 44).

[0375] To tert-1H-pyrazol-4-yl)carbamoyl)-4-azaspiro[2.5]octan-7-yl)carbamate (44-5, 50 mg, 0.1 mmol, 1 equiv.), DCM (1.0 mL) and TFA (1 mL) were added, and the mixture was incubated at room temperature for 2 hr. The solvent was removed, and the resulting product was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (19.3 mg, 41%).1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 10.93 (s, 1H), 9.33 (s, 1H), 8.46 (d, 2H), 8.29 (s, 1H), 8.20 (d, 1H), 4.40 (d, 2H), 4.27 (d, 1H), 3.39 (d, 1H), 2.34 (m, 1H), 2.05 (d, 1H), 1.93 (d, 1H), 1.53 (s, 2H), 1.39 (m, 3H), 0.97 (d, 6H), 0.81 (s, 2H). LC-MS m / z 409 (M+H+). 155 58226332.1224990 / 23-003-PC / 554457 Scheme 33 pyrazol-4-yl)indoline-1-carboxamide (Compound 45).

[0376] To 3-(1-isobutyl-1H- pyrazol-4-amine (1-5, 26 mg,0.1 mmol, 1 equiv.), DCM (0.5 mmol, 5 equiv.) were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 5,7-difluoroindoline (24 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (15.5 mg, 30%).1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 10.63 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 8.14 (d, 1H), 8.05 (s, 1H), 7.21 – 7.11 (m, 1H), 7.04 (m,1H), 4.21 (m, 4H), 3.11 (m, 2H), 2.17 (m, 1H), 0.80 (d, 6H). LC-MS m / z 438.2 (M+H+). Scheme 34 EXAMPLE 46.4-yl)-7- methylene-4-azaspiro[2.5]octane-4-carboxamide (Compound 46). 156 58226332.1224990 / 23-003-PC / 554457

[0377] To 3-(1-isobutyl-1H- -1H-pyrazol-4-amine (1-5, 26 mg,0.1 mmol, 1 equiv.), DCM (0.5mmol, 5 equiv.) were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 7-methylene-4- azaspiro[2.5]octane (19 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (20.5 mg, 51%).1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.81 (s, 1H), 9.16 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.05 (d, 1H), 4.73 (s, 1H), 4.66 (s, 1H), 4.24 (d, 2H), 2.44 (m, 4H), 2.18 (dt, 1H), 2.09 (d, 2H), 0.99 – 0.94 (m, 4H), 0.81 (d, 6H). LC-MS m / z 406 (M+H+). Scheme 351H-pyrazol- 4-yl)-7-oxa-4-azaspiro[2.5]octane-4-carboxamide (Compound 47).

[0378] To 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine(24-5, 29 mg, 0.1 mmol, 1 equiv.), DCM (0.5 mL) and DIPEA (87 μL, 0.5 mmol, 5 equiv.) were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 7-oxa-4- azaspiro[2.5]octane (17 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (15.0 mg, 36%).1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 10.66 (s, 1H), 9.18 157 58226332.1224990 / 23-003-PC / 554457 (s, 1H), 8.37 (d, 2H), 8.06 (s, 1H), 5.56 (d, 2H), 3.77 – 3.42 (m, 6H), 1.12 (d, 4H). LC-MS m / z 422 (M+H+). Scheme 364- yl)-6-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 48).

[0379] Step 1: 6-(Trifluoromethyl)-4-azaspiro[2.5]octan-6-ol. Tert-butyl 6-oxo-4-azaspiro[2.5]octane-4-carboxylate (225 mg, 1 mmol, 1.0 equiv.) and cesium fluoride (225 mg, 1.5 mmol, 1.5 equiv.) were added to a 20 mL vial, followed by addition of THF (5 mL). The vial was vigorously stirred under a balloon of N2 with cooling on an ice-bath. Trimethyl(trifluoromethyl)silane (426 mg, 3 mmol, 0.45 mL, 3 equiv.,) was added in two portions over 5 min. The reaction was warmed to room temperature and was further stirred for further 4 h. Then excess of TMSCF3 was quenched by careful addition of water (5 mL) and extracted with EtOAc (2x 10 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and the solvent removed to obtain desired product in good purity which was used for next step deprotection. The resulting product was dissolved in DCM (2 mL), TFA (2 mL) and water (0.2 mL) was added, and the mixture was stirred overnight at rt then at 65 °C for 2 h. The mixture was extracted with EtOAc (2x 10 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and the solvent removed and lyophilized by adding 1 mL of acetonitrile to obtain desired product in good purity which was used for next step reaction. 158 58226332.1224990 / 23-003-PC / 554457

[0380] Step 2: 6-Hydroxy-N-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-6-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 48).

[0381] To 3- (1-5, 26 mg,0.1 mmol, 1, were added followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (28 mg, 0.11 mmol, 1.1 equiv.) and the mixture was sonicated then stirred for 15 min. DMF (0.5 mL) and 6-(trifluoromethyl)-4- azaspiro[2.5]octan-6-ol (48-1, 30 mg, 0.15 mmol, 1.5 equiv.) were added and the mixture was incubated at room temperature for 2 hr. The solvent was removed, the solution was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to yield the title compound (10.5 mg, 22%).1H NMR (400 MHz, DMSO-d6) 12.78 (s, 1H), 10.79 (s, 1H), 9.15 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 5.78 (s, 1H), 4.24 (d, 2H), 2.97 (s, 1H), 2.22 – 2.14 (m, 1H), 1.90 (s, 1H), 1.82 (d, 1H), 1.35 (s, 1H), 1.17 (s, 1H), 1.04 (s, 1H), 0.81 (d, 6H), 0.67 (s, 2H). LC-MS m / z 478 (M+H+). EXAMPLE 49.7-Hydroxy-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)- 1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 49). CF3NNH

[0382] Compound 49 wasprocedure as Compound 1. ChiralSFC (Column Chiralcel®OD, 4.6 mm x 150 mm, 5 μm, flow 2.5 mL / min, back pressure 100 bar, gradient 70:30 CO2 / isopropanol) where peak 1 afforded the title compound (2.6 mg, 6%). 159 58226332.1224990 / 23-003-PC / 5544571H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 10.80 (s, 1H), 9.29 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 6.05 (s, 1H), 5.63 (q, 2H), 4.11 (d, 1H), 3.23 (s, 1H), 2.21 (d, 1H), 1.66 (d, 1H), 1.58 (d, 1H), 1.32 (d, 3H), 1.12 (s, 1H), 0.80 (s, 1H). LC-MS m / z 504 (M+H+). EXAMPLE 50.7-Hydroxy-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)- 1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 50).

[0383] Compound 50 wasprocedure as Compound 1. ChiralSFC (Column Chiralcel®OD, 4.6 mm x 150 mm, 5 μm, flow 2.5 mL / min, back pressure 100 bar, gradient 70:30 CO2 / isopropanol) where peak 2 afforded the title compound (3.9 mg, 8%).1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 10.80 (s, 1H), 9.29 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 6.05 (s, 1H), 5.63 (q, 2H), 4.11 (d, 1H), 3.23 (s, 1H), 2.21 (d, 1H), 1.66 (d, 1H), 1.58 (d, 1H), 1.32 (d, 3H), 1.12 (s, 1H), 0.80 (s, 1H). LC-MS m / z 504 (M+H+). EXAMPLE 51.7-(Difluoromethyl)-7-hydroxy-N-(3-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 51).

[0384] Compound 51 wasprocedure as Compound 1. ChiralSFC (Column Chiralpak®IC, 4.6 mm x 150 mm, 5 μm, flow 2.5 mL / min, back pressure 100 bar, gradient 75:25 CO2 / methanol) where peak 1 afforded the title compound (14.4 mg, 16%).1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.77 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 8.40 160 58226332.1224990 / 23-003-PC / 554457 (s, 1H), 8.12 (s, 1H), 5.66 – 5.57 (m, 2H), 5.28 (s, 1H), 4.04 (s, 1H), 3.60 (d, 1H), 2.13 (d, 1H), 1.47 (s, 2H), 1.23 (s, 3H), 1.15 (s, 1H), 1.10 (s, 2H), 0.79 (s, 2H). LC-MS m / z 486 (M+H+). EXAMPLE 52.7-(Difluoromethyl)-7-hydroxy-N-(3-(1-(2,2,2-trifluoroethyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 52). CF3NNH

[0385] Compound 52 wasprocedure as Compound 1. ChiralSFC (Column Chiralpak®IC, 4.6 mm x 150 mm, 5 μm, flow 2.5 mL / min, back pressure 100 bar, gradient 75:25 CO2 / methanol) where peak 2 afforded the title compound (15.3 mg, 17%).1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.77 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 5.66 – 5.57 (m, 2H), 5.28 (s, 1H), 4.04 (s, 1H), 3.60 (d, 1H), 2.13 (d, 1H), 1.47 (s, 2H), 1.23 (s, 3H), 1.15 (s, 1H), 1.10 (s, 2H), 0.79 (s, 2H). LC-MS m / z 486 (M+H+). EXAMPLE 53. (R)-N-(3-(1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H- pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 53).

[0386] Compound 53 wasas Compound 1 using chiral SFC(Column Chiralpak®IC, 4.6 mm x 150 mm, 5 μm, flow 2.5 mL / min, back pressure 100 bar, gradient 70:30 CO2 / methanol) where peak 1 afforded the title compound (23.7 mg, 21%).1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.87 (s, 1H), 9.25 (s, 1H), 8.38 (s, 1H), 8.22 (s, 161 58226332.1224990 / 23-003-PC / 554457 1H), 8.12 (s, 1H), 6.05 (s, 1H), 4.73 (d, 2H), 4.11 (d, 1H), 3.24 (s, 1H), 2.22 (d, 1H), 1.67 (d, 1H), 1.59 (d, 1H), 1.36 (d, 9H), 1.12 (s, 1H), 0.81 (s, 1H). EXAMPLE 54. N-(3-(1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H- pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 54).

[0387] Compound 54 was as Compound 1. Chiral®SFC (Column Chiralpak IC, 2.5 mL / min, back pressure 100 bar, gradient 70:30 CO2 / methanol) where peak 2 afforded the title compound (12.5 mg, 11%).1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.85 (s, 1H), 9.24 (s, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 6.03 (s, 1H), 4.75 (s, 1H), 4.69 (s, 1H), 4.10 (d, 1H), 3.23 (t, 1H), 2.21 (d, 1H), 1.66 (d, 1H), 1.58 (d, 1H), 1.31 (dd, 10H), 1.11 (s, 1H), 0.79 (s, 1H). LC-MS m / z 496 (M+H+). EXAMPLE 55.7,7-Difluoro-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)- 1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 55).

[0388] Compound 55 wasprocedure as Compound 1 using7,7-difluoro-4-azaspiro[2.5]octane hydrochloride. The residue was concentrated, dissolved in DMF, and subjected to preparatory HPLC (H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (5.2 mg, 10%).1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 10.86 (s, 1H), 9.28 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 5.63 (q, 2H), 1.95 (s, 3H), 1.22 (d, 5H). LC-MS m / z 456 (M+H+). 162 58226332.1224990 / 23-003-PC / 554457 EXAMPLE 56.7-Hydroxy-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)- 1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 56).

[0389] Compound 56 was procedure as Compound 1 using6-chloro-1H-pyrazolo[4,3-c] was dissolved in DMF, and subjected to preparatory HPLC (H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (4.3 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.99 (s, 1H), 8.97 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 6.75 (d, 1H), 6.03 (s, 1H), 5.40 – 5.33 (m, 2H), 4.10 (d, 1H), 3.22 (s, 1H), 2.22 (d, 1H), 2.08 (d, 1H), 1.65 (d, 1H), 1.57 (d, 1H), 1.31 (d, 4H), 1.11 (s, 1H), 0.79 (s, 1H). LC-MS m / z 503 (M+H+). Scheme 376-yl)- 1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 57). 163 58226332.1224990 / 23-003-PC / 554457

[0390] Step 1: Tert-butyl 7- 4-carboxylate.

[0391] To a solution of tert-4-carboxylate (800.0 mg, 3.55mmol, 1 equiv.) in EtOH (8 mL) at 0° C was added NaBH4 (200.0 mg, 5.29 mmol, 1.49 equiv.) portionwise. The reaction was stirred under an atmosphere of nitrogen at 0° C for 1 hour. It was then allowed to reach 25°C and stirred for a further 2 hours. The reaction mixture was added into aq. saturated NH4Cl (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over with anhyd. Na2SO4, filtered and concentrated under reduced pressure to give the title compound (730.0 mg, 3.21 mmol, 90%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ: 3.86-4.05 (m, 2H), 2.91-3.03 (m, 1H), 1.87-1.99 (m, 1H), 1.73-1.84 (m, 1H), 1.53 (br d, 2H), 1.47 (s, 9H), 1.38-1.43 (m, 1H), 1.13-1.25 (m, 1H), 0.78-0.91 (m, 1H), 0.54-0.66 (m, 1H), 0.42-0.52 (m, 1H).

[0392] Step 2: Tert-butyl 7-(p-tolylsulfonyloxy)-4-azaspiro[2.5]octane-4-carboxylate.

[0393] To a solution of 57-2 mg, and DMAP (0.25 g, 2.05 mmol,0.93 equiv.) in DCM (5 mL) and TEA (1.5 mL) were added 4-methylbenzenesulfonyl chloride (0.84 g, 4.41 mmol, 2 equiv.) at 25°C. After the reaction mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (EtOAc:Petroleum ether, 0:100 to 20:80) to give 57-3 (820 mg, 2.15 mmol, 98%) obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ: 7.79 (d, 2H), 7.35 (d, 2H), 4.77 (m, 1H), 3.74-3.87 (m, 1H), 2.98-3.13 (m, 1H), 2.46 (s, 3H), 164 58226332.1224990 / 23-003-PC / 554457 1.78-1.91 (m, 2H), 1.60-1.70 (m, 1H), 1.48-1.55 (m, 1H), 1.44 (s, 9H), 1.04-1.13 (m, 1H), 0.79 (m, 1H), 0.61-0.71 (m, 1H), 0.42-0.50 (m, 1H). LC-MS m / z 282 (M+H+).

[0394] Step 3: Tert-butyl 7-phenoxy-4-azaspiro[2.5]octane-4-carboxylate.

[0395] To a solution of 57- in THF (10 mL) was addedpotassium phenoxide (1.60 g,. was stirred at 25°C for 12 hr. Then the reaction mixture was stirred under 80°C for 12 hr. LCMS showed the desired MS and the compound 3 was consumed completely. The reaction mixture was diluted with 30 mL H2O and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over with anhyd. Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (EtOAc:Petroleum ether, 0:100 to 2:98) to give 57-4 (370.0 mg, 0.72 mmol, 35.52%, 75% purity) obtained as a colorless oil. LC-MS m / z 204 (M+H+).

[0396] Step 4. Tert-butyl 7-(p-tolylsulfonyloxy)-4-azaspiro[2.5]octane-4-carboxylate.

[0397] To a solution of 57-4 mg, in DCM (3 mL) was addedTFA (552.6 mg, 4.85 mmol, 360 μL, 4.90 equiv.). The mixture was stirred at 25 °C for 1 hr. LCMS showed the desired MS and the compound 57-4 was consumed completely. The reaction mixture was diluted with EtOAc (30 mL) and extracted with H2O (3 x 20 mL). Then the combined water layers were washed with EtOAc (3 x 5 mL) and concentrated under reduced pressure to give 57-5 (110.0 mg, 35%, TFA) as a yellow gum.1H NMR (400 MHz, CDCl3) δ: 9.05-9.70 (m, 2H), 7.27-7.33 (m, 2H), 6.99 (m, 1H), 6.86-6.92 (m, 2H), 4.68-4.75 (m, 1H), 3.45-3.59 (m, 1H), 3.13-3.29 (m, 1H), 2.23-2.35 (m, 2H), 2.13-2.22 (m, 1H), 1.81 (br d, 1H), 1.22-1.30 (m, 1H), 1.09-1.16 (m, 1H), 0.77 (m, 1H), 0.63 (m, 1H). LC-MS m / z 204 (M+H+). 165 58226332.1224990 / 23-003-PC / 554457

[0398] Step 5: 7-Phenoxy-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 57).

[0399] Compound 1 usingamine 24-5. The residue was concentrated, dissolved in DMF, and subjected to preparatory HPLC (H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (5.8 mg, 12%).1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 10.84 (s, 1H), 9.26 (s, 1H), 8.42 (d, 2H), 8.13 (s, 1H), 7.26 (t, 2H), 6.98 – 6.87 (m, 3H), 5.62 (q, 2H), 4.76 (s, 1H), 4.22 (s, 1H), 3.01 (s, 1H), 1.93 (s, 2H), 1.73 (s, 1H), 1.37 (s, 4H), 0.95 (s, 2H), 0.80 (s, 1H). LC-MS m / z 512 (M+H+). EXAMPLE 58. N-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7- phenoxy-4-azaspiro[2.5]octane-4-carboxamide (Compound 58).

[0400] Compound 58 wasprocedure as Compound 1 usingamine 57-5. The residue was concentrated, dissolved in DMF, and subjected to preparatory HPLC (H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (15.0 mg, 31%).1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.22 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 7.27 (t, 2H), 6.96 (s, 1H), 6.96 – 6.87 (m, 2H), 4.76 (s, 1H), 4.30 (d, 2H), 2.24 (dt, 1H), 2.03 (s, 2H), 1.36 (s, 2H), 0.87 (d, 5H). LC-MS m / z 486 (M+H+).

[0401] COMPOUNDS 59-164. Compound 59-164 were synthesized following similarprocesses as in Examples 1-58. Analytical data for the compounds is included in Table 2. 166 58226332.1224990 / 23-003-PC / 554457 Scheme 38 H N F3CNNBnNBnHCl OH(2,2,2- trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 165).

[0402] Step 1: 1-(6-(1-Benzyl-4- yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(trifluoromethyl)azetidin-3-ol.

[0403] pyrazolo[4,3-c]pyridine (100 mg, 0.189 mmol, 1 equiv.), Xantphos (11 mg, 0.019 mmol, 0.1 equiv.), cesium carbonate (185 mg, 0.568 mmol, 3 equiv.), and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (50.4 mg, 0.284 mmol, 1.5 equiv.) and dioxane (2 mL) were added to a vial and sparged with nitrogen gas. Pd2(dba)3(8.7 mg, 0.0095 mmol, 0.05 equiv.) was added, the vial 167 58226332.1224990 / 23-003-PC / 554457 was sealed, and the mixture was heated to 100 °C for 1 hr. The reaction mixture was allowed to cool, loaded onto Celite®, and subjected to FCC (silica, Hex:EtOAc, 100:0 to 0:100) to obtain the titled compound as a brown oil which was used without further purification.

[0404] Step 2: 1-(6-(4-Amino-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(trifluoromethyl)azetidin-3-ol.

[0405] 1-(6- pyrazolo[4,3-c]pyridin-3-yl)-3-yl)-1-(2,2,2- trifluoroethyl)pyrazolo[4,3-c]pyridin-3-yl]-3-(trifluoromethyl)azetidin-3-ol (0.189 mmol, 1 equiv.) was suspended in ethanol (10 mL) and sparged with nitrogen gas. 20% Pd(OH)2on carbon (500 mg) was added, the reaction mixture was sparged with hydrogen gas, then stirred for 14h at 70 °C under a balloon of hydrogen gas. The reaction mixture was allowed to cool, sparged with nitrogen gas, filtered through Celite®, rinsed with DCM:EtOH (4:1, 25 mL), and the solvent removed to yield the titled compound as a brown oil which was used without further purification.

[0406] Step 3: 7-Hydroxy-N-(3-(3-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide. (Compound 165).

[0407] Thedescribed inScheme 1 for compound 1 using 1-(6-(4-amino-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H- pyrazolo[4,3-c]pyridin-3-yl)-3-(trifluoromethyl)azetidin-3-ol (0.189 mmol, 1 equiv.) and 168 58226332.1224990 / 23-003-PC / 554457 enantiopure 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol (Intermediate 3-3, 2 equiv.) to yield the titled compound (42 mg, 35% yield over 3 steps). LC-MS m / z 643 (M+H+).1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 10.71 (s, 1H), 9.00 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.43 (s, 1H), 6.05 (s, 1H), 5.37 (q, 2H), 4.56 (dd, 2H), 4.22 (d, 2H), 4.15 – 4.03 (m, 1H), 3.30 – 3.19 (m, 2H), 2.18 (d, 1H), 1.68 (d, 1H), 1.58 (t, 1H), 1.45 (s, 1H), 1.36 (d, 1H), 1.26 – 1.19 (m, 1H), 1.11 – 1.07 (m, 1H), 0.80 (s, 1H). Scheme 39- 1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 166). F3CNNH

[0408] The compound was synthesized following the same procedure as Compound 165using 3-(trifluoromethyl)azetidin-3-amine hydrochloride to yield the titled compound (42 mg,38% yield over 3 steps). LC-MS m / z 642 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s,169 58226332.1224990 / 23-003-PC / 554457 1H), 10.72 (s, 1H), 8.98 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 6.04 (s, 1H), 5.36 (q, 2H), 4.47 (t, 2H), 4.20 – 4.04 (m, 3H), 3.24 (s, 1H), 2.83 (s, 2H), 2.18 (d, 1H), 1.72 – 1.30 (m, 4H), 1.23 (s, 1H), 1.09 (s, 1H), 0.79 (s, 1H).EXAMPLE 61. N-(3-(3-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 167).

[0409] The compound was synthesized following the same procedure as Compound 166using (3-fluoroazetidin-3-yl)methanol hydrochloride to yield the title compound (20 mg, 18% yield over 3 steps). LC-MS m / z 607 (M+H+).1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.73 (s, 1H), 8.97 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 6.04 (s, 1H), 5.43 – 5.30 (m, 3H), 4.38 (dd, 2H), 4.26 (dt, 2H), 4.11 (d, 1H), 3.80 (d, 1H), 3.75 (d, 1H), 3.24 (t, 1H), 2.18 (d, 1H), 2.08 (s, 1H), 1.68 (d, 1H), 1.58 (t, 1H), 1.43 – 1.31 (m, 2H), 1.24 (s, 1H), 1.09 (s, 1H), 0.80 (s, 1H).EXAMPLE 62. N-(3-(3-(3-Ethylazetidin-1-yl)-1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 168).

[0410] The compound was same procedure as Compound 166using 6-(1-benzyl-4-nitro-1H-pyrazol-3-yl)-1-(2-fluoro-2-methylpropyl)-3-iodo-1H- pyrazolo[4,3-c]pyridine and 3-ethylazetidine to yield the titled compound (8.8 mg, 2% over 3 170 58226332.1224990 / 23-003-PC / 554457 steps). LC-MS m / z 579 (M+H+).1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.79 (s, 1H), 8.87 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 6.03 (s, 1H), 4.46 (s, 1H), 4.41 (s, 1H), 4.26 (q, 2H), 4.17 – 4.01 (m, 1H), 3.80 (q, 2H), 3.29 – 3.17 (m, 1H), 2.79 – 2.70 (m, 1H), 2.18 (d, 1H), 1.73 – 1.49 (m, 4H), 1.35 (d, 8H), 1.28 – 1.19 (m, 1H), 1.13 – 1.03 (m, 1H), 0.91 (t, 3H), 0.85 – 0.72 (m, 1H). Scheme 40224990 / 23-003-PC / 554457

[0411] EXAMPLES 63 and 64: (R)-N-(3-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 169) and (R)-N-(3-(2-((1- fluorocyclopropyl)methyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 170). Step 1: (6-

[0412] To a25.2 mmol, 1 equiv.) inanhydrous THF (60 mL) was added sodium hydride (1.20 g, 30.0 mmol, 1.2 equiv, 60% oil dispersion) at 0oC. The reaction mixture was stirred for 30 min, then chloromethyl 2,2- dimethylpropanoate (4.4 mL, 31 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 14 hours at room temperature, then diluted with water (80 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to an oil. The residue was purified by silica gel column chromatography (Hexanes:EtOAc, 100:00-60:40) to give the title compound (7.5 g, 95%) as a viscous oil that solidified upon standing. LC-MS m / z 312 / 314.

[0413] Step 2: (6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl pivalate. 172 58226332.1224990 / 23-003-PC / 554457

[0414] Ac]pyridin-1-yl)methyl pivalate (169-1, 7.5 g, 24 mmol, 1 equiv.), 4-nitro-1-tetrahydropyran-2-yl-pyrazole (7.1 g, 36.01 mmol, 1.5 equiv.), potassium carbonate (4.3 g, 31.11 mmol, 1.3 equiv.), pivalic acid (740 mg, 7.25 mmol, 0.3 equiv.), CuI (5.5 g, 28.88 mmol, 1.2 equiv.), and PdCl2(PPh3)2 (840 mg, 1.20 mmol, 0.05 equiv). The flask was evacuated and refilled with nitrogen. Degassed anhydrous DMF (90 mL) was added, and the reaction mixture was heated at 120oC for 17 hours. The reaction mixture was allowed to come to room temperature, diluted with EtOAc and filtered through a Celite®pad. To the filtrate was added water, and the solid precipitate was removed by filtration. The two layers from filtrate were separated, and the aqueous layer was extracted with more EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The residual oil was purified by silica gel column chromatography (Hexanes:EtOAc, 95:5 to 40:60) to give the title compound (4.75 g, 46%) as a light yellow foam. LC-MS m / z 429.

[0415] Step 3: 6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.

[0416] A mixture of (6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl pivalate (169-2, 4.75 g, 11.1 mmol, 1 equiv.) and 2M aqueous NaOH (25 mL, 50 mmol, 4.5 equiv.) in methanol (35 mL) was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (100 mL) and extracted 173 58226332.1224990 / 23-003-PC / 554457 with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (3.5 g, 100%) as a light green foam. LC-MS m / z 315.

[0417] Step 4: 3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.

[0418] A 2502-yl-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine (169-3, 3.5 g, 11 mmol, 1 equiv.), 1,2-dichloroethane (50 mL) and N-iodosuccinimide (3800 mg, 16.89 mmol, 1.5 equiv.), and the reaction mixture was stirred at 90oC for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (4 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give a reddish oil. Purification of the residue by silica gel column chromatography (DCM:EtOAc, 100:0 to 75:25) afforded the title compound (1.5 g, 31%) as a light orange solid. LC-MS m / z 441.

[0419] Step 5: 1-((1-fluorocyclopropyl)methyl)-3-iodo-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.

[0420] To a mixture of 3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine (169-4, 500 mg, 1.14 mmol, 1 equiv.) and potassium carbonate (471 mg, 3.41 mmol, 3 equiv) in 1-methylpyrrolidin-2-one (6.0 mL) was added (1- fluorocyclopropyl)methyl methanesulfonate (250 mg, 1.49 mmol, 1.3 equiv.), and the resulting 174 58226332.1224990 / 23-003-PC / 554457 mixture was heated at 80oC for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After filtration and concentration, the residue was purified by silica gel column chromatography (Hexanes:EtOAc, 95:5 to 20:80) to give the title compound (359 mg, 62%) as a white foam. LC-MS m / z 513 (M+H+).

[0421] Step 6: 3-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine and 3-(2-((1-fluorocyclopropyl)methyl)- 2H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (169-5, 250 mg, 0.488 mmol, 1 equiv.) in methanol (5 mL) was added saturated NH4Cl aq. solution (1 mL) and zinc (320 mg, 4.89 mmol, 10 equiv.). The resulting suspension was stirred at room temperature for 20 minutes. Mixture was filtered through a Celite®pad, and the filter cake was washed with MeOH. The filtrate was concentrated to dryness, and the residue was partitioned between DCM and water. The aqueous layer was extracted with more DCM (2 x 25 mL), and the organic layers were combined, dried over MgSO4, filtered, and concentrated to give the title compounds (171 mg, 98%, 72 / 28 mixture of 169-6 / 169-7). LC-MS m / z 357 (M+H+).

[0423] Step 7: (7R)-N-(3-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide and (7R)-N-(3-(2-((1-fluorocyclopropyl)methyl)-2H- pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-hydroxy-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. 175 58226332.1224990 / 23-003-PC / 5544576-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine (169-6) and 3-(2-((1- fluorocyclopropyl)methyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-amine (169-7) (72:28 mixture, 171 mg, 0.480 mmol, 1 equiv.) in anhydrous dichloromethane (4.80 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (147 mg, 0.574 mmol, 1.20 equiv.), and the resulting orange solution was sonicated for approximately 1 minute, followed by stirring for 20 minutes. To this mixture was added a solution of (7R)-7- (trifluoromethyl)-4-azaspiro[2.5]octan-7-ol HCl salt (3-3a, 189 mg, 0.816 mmol, 1.70 equiv.), DIPEA (0.25 mL, 1.4 mmol, 3.0 equiv.) and anhydrous N,N-dimethylformamide (3.2 mL). After stirring for 30 minutes, reaction mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title compounds (285 mg, 103%, 69 / 31 mixture of 169-8 / 169-9). LC-MS m / z 578 (M+H+).

[0425] Step 8: (R)-N-(3-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide and (R)-N-(3-(2-((1-fluorocyclopropyl)methyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1H- pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide.a- -c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-hydroxy-7-(trifluoromethyl)- 4-azaspiro[2.5]octane-4-carboxamide (169-8) and (7R)-N-(3-(2-((1-fluorocyclopropyl)methyl)- 2H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-hydroxy-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (169-9) (69:31 mixture, 277 mg, 0.48 176 58226332.1224990 / 23-003-PC / 554457 mmol, 1 equiv.) in methanol (4.8 mL) was added 4-methylbenzenesulfonic acid monohydrate (45 mg, 0.24 mmol, 0.49 equiv.), and the resulting mixture was stirred at 50oC for 15 minutes. The reaction mixture was concentrated dryness, and residue was redissolved in DMSO, filtered, and subjected to preparative HPLC (0.1% FA, Water:MeCN, 90:10 to 5:95) to obtain Compound 169 (85 mg, 36%) and Compound 170 (36 mg, 15%).

[0427] Compound 169:

[0428] 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 10.86 (s, 1H), 9.25 (s, 1H), 8.38 (s,1H), 8.28 (s, 1H), 8.11 (s, 1H), 6.04 (s, 1H), 4.97 (d, 2H), 4.10 (d, 1H), 3.23 (t, 1H), 2.22 (d, 1H), 1.74 – 1.50 (m, 2H), 1.43 – 1.25 (m, 3H), 1.21 – 0.97 (m, 5H), 0.91 – 0.74 (m, 1H). LC- MS m / z 494 (M+H+).

[0429] Compound 170:

[0430] 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 10.60 (s, 1H), 8.66 (s, 1H), 8.08 (s,1H), 7.53 – 7.37 (m, 2H), 6.02 (s, 1H), 4.07 (d, 1H), 3.75 (dd, 2H), 3.22 (t, 1H), 2.12 (d, 1H), 1.71 – 1.47 (m, 2H), 1.38 – 1.22 (m, 2H), 1.20 – 0.97 (m, 4H), 0.91 – 0.71 (m, 3H). LC-MS m / z 494 (M+H+). Scheme 41-- -(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 171) 177 58226332.1224990 / 23-003-PC / 554457

[0431] Step 1: To a solution of 5-chloro-3H-imidazo[4,5-b]pyridine (418.0 mg, 2.72 mmol,1.00 equiv) in anhydrous THF (10 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (131 mg, 3.28 mmol, 1.20 equiv) The mixture was stirred for 30 min at 0 °C before chloromethyl 2,2-dimethylpropanoate (471 μL, 3.27 mmol, 1.20 equiv) was added slowly and the mixture gradually warmed to rt and stirred for 16 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 150 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification via automated flash column chromatography (first regioisomer eluted with 26% EtOAc–Hexanes and second regioisomer eluted with 56% EtOAc–Hexanes) afforded regioisomer one (254.9 mg, 0.95 mmol, 35%) and regioisomer two (374.5 mg, 1.40 mmol, 51%) as colorless and pale orange solids, respectively. LC-MS m / z 248.2 (M+H+).

[0432] Step 2: To a stirred solution of (5-chloroimidazo[4,5-b]pyridin-3-yl)methyl 2,2-dimethylpropanoate (regioisomer two, 300 mg, 1.12 mmol, 1.00 equiv) and 4-nitro-1- tetrahydropyran-2-yl-pyrazole (276 mg, 1.40 mmol, 1.25 equiv) under N2in anhydrous DMF (11.0 mL) was added K2CO3 (464.0 mg, 3.36 mmol, 3.00 equiv) and 2,2-dimethylpropanoic acid (29.0 mg, 0.28 mmol, 0.25 equiv). The mixture was degassed with N2 for 5 min before Pd(OAc)2(25.0 mg, 0.11 mmol, 0.10 equiv) and bis(1-adamantyl)-butyl-phosphane (cataCXium®A) (60.0 mg, 0.17 mmol, 0.15 equiv) were added. The reaction was degassed for 5 min with N2 before being stirred at 120 °C for 5 h. Upon completion, the reaction was poured into water (30 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (2 × 30 mL), brine (1 × 75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a residue. Purification via automated flash column chromatography (25g Redisep®column, 0-100% EtOAc–Hexanes) afforded (5-(4-nitro-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl pivalate (191.0 mg, 0.45 mmol, 40%) as a pale yellow solid. LC-MS m / z 429.2 (M+H+).

[0433] Step 3: To a solution of (5-chloroimidazo[4,5-b]pyridin-3-yl)methyl 2,2-dimethylpropanoate (200.9 mg, 0.469mmol, 1.00 equiv) in MeOH (5 mL) was added satd. aqueous NH4Cl solution (1 mL) and zinc dust (305.0 mg, 4.66 mmol, 9.94 equiv) in two portions. The reaction was stirred at rt for 10 min. Upon completion, the reaction was filtered through a disposable Celite®funnel and the filter cake washed with MeOH (approximately 10 178 58226332.1224990 / 23-003-PC / 554457 mL). The filtrate was concentrated in vacuo to give [5-(4-nitro-1-tetrahydropyran-2-yl-pyrazol- 3-yl)imidazo[4,5-b]pyridin-3-yl]methyl 2,2-dimethylpropanoate (231.3 mg, 0.58 mmol) as a dark yellow solid that was carried through to the next step without further purification. LC-MS m / z 399.2 (M+H+).

[0434] Step 4: To a stirred solution of [5-(4-amino-1-tetrahydropyran-2-yl-pyrazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl 2,2-dimethylpropanoate (200.9 mg, 0.050 mmol, 1.00 equiv) in methanol (10 mL) was added p-toluenesulfonic acid monohydrate (44.0 mg, 0.23 mmol, 0.46 equiv) and the mixture stirred at 65 °C for 1 h. Upon completion, the reaction was cooled to rt and concentrated in vacuo to a residue. Purification using automated flash column chromatography (eluting with 0-20% MeOH–CH2Cl2+ 0.7 N NH3) afforded [5-(4-amino-1- tetrahydropyran-2-yl-pyrazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl 2,2-dimethylpropanoate (140.8 mg, 0.045 mmol, 0.89 equiv) as a yellow semi-solid. LC-MS m / z 315.2 (M+H+).

[0435] Step 5: Synthesized using general procedure described for compound 1 to afford [5-(4-amino-1H-pyrazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl 2,2-dimethylpropanoate (104.5 mg, 0.195 mmol, 76%) as a colorless foamy solid. LC-MS m / z 536.2 (M+H+).

[0436] Step 6: (7R)-7-hydroxy-N-[3-(3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 171)

[0437] A solution of [5-(4-amino-1H-pyrazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl 2,2-dimethylpropanoate (50.0 mg, 0.93 mmol, 1.00 equiv) and 2 N NaOH (0.5 mL, 1.0 mmol, 10 equiv) in MeOH (0.5 mL) was stirred at 60 °C for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 60 mL), dried (MgSO4), filtered and concentrated in vacuo to a residue. Purification via preparative HPLC (0-100% MeCN–water + 0.1% formic acid) afforded (7R)-7- hydroxy-N-[3-(3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-4- azaspiro[2.5]octane-4-carboxamide (14.0 mg, 0.03 mmol, 36%).1H NMR (400 MHz, DMSO- d6) δ 12.75 (d, 2H), 10.98 (s, 1H), 8.42 (s, 1H), 8.02 (s, 2H), 7.91 (s, 1H), 5.93 (s, 1H), 4.05 (d, 1H), 3.23 – 3.11 (m, 1H), 2.32 – 2.16 (m, 1H), 1.55 (s, 2H), 1.39 – 1.25 (m, 1H), 1.09 (s, 3H), 0.70 (s, 1H);19F NMR (376 MHz, DMSO-d6) δ -83.3; LC-MS m / z 422.2 (M+H+). 179 58226332.1224990 / 23-003-PC / 554457

[0438] Compounds 172-234 in Table 3 were synthesized using (7R)-7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol hydrochloride (3-3a) and a functionalized 1H-pyrazol-4-amine, such as a 3-(pyrazolopyridinyl)-1H-pyrazol-4-amine prepared according to the general procedure of Scheme 40 or a 3-(imidazopyridinyl)-1H-pyrazol-4-amine prepared according to the general procedure of Scheme 41. 180 58226332.1224990 / 23-003-PC / 554457 Table 3 Compound Structure LC-MS m / z 1H NMRNo.181 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , , 3 , , , ,182 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , , (s, 2 , 7 d, 78 , ,183 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , s, 7 , , 39 (s, , , 7 , , 7 (s, , 0184 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO-d6) δ , 1 , ), ), s, , , , , , 94 m, 10 – , , 96 m, 30 – , ), , 30185 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO-d6) δ , , , 1 d, , , 49 – , 1 65 ), 5 , , 6 , 9 ), 1186 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 8 , , 4 33 , 1 , 8 , 0 , 4187 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , 2 , 3 , , , , , , δ 3 72188 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , 6 , , , d, 31 - , 9 , q, ,189 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , 95 s, 53 δ 4 – δ 8 , , , 4190 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , , 65 ), 7 δ 0 , δ 6 δ ,191 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z H δ – , , d, 31 – δ 44 , 59 δ 7 ,192 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ 38 , δ 8 d, 10 – δ 44 s, 85 δ 43 ,193 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ 38 m, 64 – δ 9 - , 0 m, 23 , 5 30194 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 , , 09 – , 9 , 5 3 , 1 7195 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO-d6) δ , ), , (s, 11 , 8 , , , 5 8196 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , d, , 3 , , , 3 , , 58 (s, , 4 6 , , 1 1 (t, ),197 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z , 2 45 , 7 9 , ), 2 , , 1 , 7 . , 0 07198 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO-d6) δ , 7 11 , 14 –199 58226332.1224990 / 23-003-PC / 554457 Scheme 42Example 66.6,6-Difluoro-N-(3-(3-(3-(methoxy-d3)azetidin-1-yl)-1-((tetrahydrofuran-3- yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4- carboxamide (Compound 253).

[0439] pyran- - 3-yl)-1H-pyrazolo[4,3-c]pyridine.3-Iodo-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H- 200 58226332.1224990 / 23-003-PC / 554457 pyrazolo[4,3-c]pyridine (850.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in DMF (10 mL). Potassium carbonate (670.0 mg, 4.8 mmol, 2.5 equiv.) and 3-(bromomethyl)tetrahydrofuran (0.3 mL, 3.0 mmol, 1.0 equiv.) were added, and reaction stirred at 100 °C for 4 hours. The reaction mixture was filtered and concentrated to dryness. The residue was purified via flashsilica gel chromatography (0-80% Hex:EtOAc) to give the title compound (721.4 mg, 71.3%) asa pale yellow oil. LC-MS m / z 525 (M+H+).2-yl)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridine.3-iodo-6- (4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine (200.0 mg, 0.38 mmol, 1.0 equiv.), 3-(methoxy-d3)azetidine TFA (114.5 mg, 0.57 mmol, 1.5 equiv.), cesium carbonate (497.1 mg, 1.5 mmol, 4.0 equiv.), Pd2(dba)3 (9.0 mg, 0.025 equiv.), and XantPhos (22.1 mg, 0.04 mmol, 0.1 equiv.) were added to a pressure flask and flushed with nitrogen. Anhydrous dioxane (0.5 M) was added, reaction sparged with nitrogen, sealed, and stirred at 100 °C for 16 hours. The solution was then cooled, filtered through Celite®, and concentrated to dryness. The residue was purified via flash silica gel chromatography (0-100%Hex:EtOAc) to give the title compound (181.4 mg, 97.7%) as a yellow solid. LC-MS m / z 487(M+H+).224990 / 23-003-PC / 554457

[0441] Step 3: 3-(3-(3-(methoxy-d3)azetidin-1-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.3-(3- (methoxy-d3)azetidin-1-yl)-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1- ((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (181.4 mg, 0.37 mmol, 1.0 equiv.) was dissolved in anhydrous methanol (3 mL) and Zn powder (195.1 mg, 3.0 mmol, 8.0 equiv.) was added, followed by saturated aqueous ammonium chloride (0.6 mL). The reaction was stirred at 50 °C for 5 minutes. The solution was cooled, filtered through Celite®, and the filter pad washed with MeOH (3 x 10 mL). The solution was concentrated to dryness and titlecompound (160.4 mg, 94.7%) was taken forward without further purification. LC-MS m / z 457(M+H+).3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)-4-azaspiro[2.5]octane-4-carboxamide. A mixture of 3-(3-(3-(methoxy-d3)azetidin-1-yl)-1- ((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-amine (179.0 mg, 0.39 mmol, 1.0 equiv.) and DSC (105.5 mg, 0.41 mmol, 1.05 equiv.) in DCM (0.2 M), was sonicated for 2 min. Once a mostly homogenous solution was obtained, a solution of 24-4 (180.0 mg, 0.78 mmol, 2.0 equiv.) and Hunig’s base (0.2 mL, 1 mmol, 3.0 equiv.) in DCM (0.3 M) was added. The resulting solution was sonicated for 2 minutes, then stirred for 16 hours. The solution was then concentrated to dryness and purifiedvia flash silica gel chromatography (0-100% Hex:EtOAc) to give the title compound (122.4 mg,49.6%). LC-MS m / z 630 (M+H+). 202 58226332.1224990 / 23-003-PC / 554457

[0443] Step 5: 6,6-difluoro-N-(3-(3-(3-(methoxy-d3)azetidin-1-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4- carboxamide (Compound 253) 6,6-difluoro-N-(3-(3-(3-(methoxy-d3)azetidin-1-yl)-1- ((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (122.4 mg, 0.16 mmol, 1.0 equiv.) wasdissolved in methanol (0.3 M), and p-toluenesulfonic acid monohydrate (17.0 mg, 0.09 mmol, 0.6 equiv.) added. The reaction mixture was stirred at 50 °C for 30 minutes. The reaction mixture was concentrated to dryness and purified via chiral SFC (Column ChiralPak®AD, 4.6 mm x 150 mm, 5 μm, flow 2.5 mL / min, back pressure 100 bar, gradient 55:45 CO2 / methanol) where peak 1 afforded Compound 253 (13.5 mg, 11%).1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.85 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 4.39 (d, 4H), 4.24 (t, 2H), 3.99 (d, 2H), 3.81 (q, 1H), 3.64 (t, 2H), 3.48 (t, 1H), 2.77 – 2.71 (m, 1H), 2.18 (s, 3H), 1.97 – 1.87 (m, 2H), 1.65 (dd, 2H). LC-MS m / z 546 (M+H+).Example 67. 2-Ethyl-5,5- 1-yl)-1- ((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4- yl)piperidine-1-carboxamide (Compound 254). 203 58226332.1224990 / 23-003-PC / 554457

[0444] Further purification via reverse-phase chromatography (EZ Thermo Fisher HypersilGOLD™ C18; H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) gave 254-5.1H NMR (400 MHz, DMSO-d6) δ 9.61 (br s, 1H), 3.49 (m, 2H), 2.13 (m, 2H), 1.75 (m, 4H), 1.29 (dd, 1H), 1.15 (s, 1H), 0.87 (t, 3H), 0.80 (s, 1H). LC-MS m / z 150 (M+H+).

[0445] Compound 254 was synthesized following the same procedure as Compound 253using 254-5. The residue was concentrated, dissolved in DMF, and subjected to preparatory HPLC (H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (9.6 mg, 11%).1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.69 (s, 1H), 8.87 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 4.38 (m, 4H), 4.23 (s, 2H), 4.02 (s, 1H), 3.97 (m, 2H), 3.80 (q, 1H), 3.62 (q, 2H), 3.47 (t, 1H), 3.24 (d, 1H), 3.15 (d, 1H), 2.73 (s, 1H), 2.23 – 1.97 (m, 2H), 1.84 (m, 4H), 1.66 (m, 2H), 0.91 (t, 3H).LC-MS m / z 548 (M+H+). Scheme 43(methylsulfonyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4- azaspiro[2.5]octane-4-carboxamide (Compound 255). 204 58226332.1224990 / 23-003-PC / 554457

[0446] 2H-pyran-2-yl)- - a vial 3- iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine (255-1, 200 mg, 0.454 mmol, 1.0 equiv.), (1-fluorocyclopropyl)methanol (57 mg, 0.632 mmol, 1.4 equiv.) and 2-(tributyl-λ⁵-phosphanylidene)acetonitrile (220 mg, 0.911 mmol, 2.0 equiv) was dissolved in toluene (5 mL) and stirred overnight at 100oC. After 15h the mixture was cooled and poured into water (20 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and the solvent removed. The residue was purified by silica gel column chromatography (24g, Hexanes:EtOAc, 100:0 to 60:40 ) to obtain title compound (255-2, 120 mg, 51.55%) as light yellow solid. First peak obtained during column chromatography was the desired regioisomer. LCMS m / z 513.0 (M+H+).

[0447] 1-yl)-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine. In a 40 mL vial 1-[(1-fluorocyclopropyl)methyl]-3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3- yl)pyrazolo[4,3-c]pyridine (255-2, 155 mg, 0.302 mmol, 1 equiv.), 3- methylsulfonylazetidine;hydrochloride (81 mg, 0.471 mmol, 1.55 equiv.), dicesium carbonate (468 mg, 1.436 mmol, 3 equiv.), and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)- 205 58226332.1224990 / 23-003-PC / 554457 diphenyl-phosphane (28 mg, 0.048 mmol, 0.1 equiv.) and 1,5-diphenylpenta-1,4-dien-3- one;palladium (27 mg, 0.029 mmol, 0.05 equiv.) were suspended in 1,4-dioxane (3 mL) in a 40 mL vial and degassed with N2. The reaction mixture was heated to 100oC. After 15h, water (15 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 15 mL), washed with brine (10 mL), dried over anhy. sodium sulfate and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography (12G Redisep®column) using DCM:MeOH( 0-15%) as eluent to obtain title compound (255-3, 165 mg, 90% pure, 94.46%) as yellow solid. LC-MS m / z 520.0 (M+H+).

[0448] 1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-amine. A solution of 1- [(1-fluorocyclopropyl)methyl]-3-(3-methylsulfonylazetidin-1-yl)-6-(4-nitro-1-tetrahydropyran- 2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (255-3, 165 mg, 0.285 mmol, 1 equiv.), zinc (130 mg, 1.987 mmol, 8 equiv.) in methanol (3 mL) and satd. ammonium hydrochloride (1 mL)^in water was stirred for 1h at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15^mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain title compound (255-4, 150 mg, 96.476 %) as yellow solid. LC-MS m / z 490.2 (M+H+). 206 58226332.1224990 / 23-003-PC / 554457(methylsulfonyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide. To a solution of 3-[1-[(1- fluorocyclopropyl)methyl]-3-(3-methylsulfonylazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1- tetrahydropyran-2-yl-pyrazol-4-amine (255-4, 150 mg, 0.275 mmol, 1 equiv.) in anhydrous N,N-dimethylformamide (2 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (78 mg, 0.30 mmol, 1.1 equiv.) and N-ethyl-N-isopropyl-propan-2-amine (0.1 mL, 0.6 mmol, 2 equiv.), and the resulting orange solution was sonicated for a min and allowed to stir at rt for 15 mins. To this mixture was then added a solution of 6,6-difluoro-4-azaspiro[2.5]octane hydrochloride (75 mg, 0.408 mmol, 1.5 equiv.), N-ethyl-N-isopropyl-propan-2-amine (0.2 mL, 1 mmol, 4 equiv.) and anhydrous N,N-dimethylformamide (1 mL), and solution immediately turned light yellow and stirred for 14h at rt. The reaction mixture was cooled in ice bath and 10 mL water was added to it and it was extracted with ethyl acetate (2 x 20 mL). Combined organic layer washed with water (15 mL), dried over anhy. sodium sulfate and concentrated under reduced pressure to obtain title compound (255-5, 175 mg, 96.25% Yield) as yellow solid and used directly for next step. LC-MS m / z 663.3 (M+H+). 207 58226332.1224990 / 23-003-PC / 554457(methylsulfonyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4- azaspiro[2.5]octane-4-carboxamide. A mixture of 6,6-difluoro-N-(3-(1-((1- fluorocyclopropyl)methyl)-3-(3-(methylsulfonyl)azetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (255- 5, 175 mg, 0.264 mmol, 1 equiv.) and 4-methylbenzenesulfonic acid monohydrate (40.0 mg, 0.210 mmol, 0.8 equiv.) in methanol (3 mL) was stirred at 60°C for 4h. The reaction mixture was cooled to rt and saturated NaHCO3solution (0.25 mL) was added and filtered through a syringe filter. The filtrate was purified by reverse phase (RP)-HPLC (10-100% ACN / water / 1mM HCl), product out at 65-70%). After lyophilization, obtained the title compound (55 mg, 33.86% yield) as pale yellow solid in the form of HCl salt.

[0451] Compound 255-5, (25 mg) was dissolved in ethyl acetate (20 mL) and washed withsaturated NaHCO3 solution. The organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue product was resuspended in water / MeCN (1:1) and lyophilized to obtain Compound 255, (18 mg, 11.78%) as the free base. LC-MS m / z 579.3 (M+H+).1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.76 (s, 1H), 8.86 (d, 1H), 8.00 (d, 2H), 4.67 (d, 2H), 4.51 – 4.34 (m, 5H), 3.05 (s, 3H), 2.12 (t, 3H), 1.40 – 0.45 (m, 11H).

[0452] Compounds 253-255 were synthesized according to the above Examples. Compounds256-378 in Table 4 were synthesized using variously substituted 1H-pyrazol-4-amines and piperidines according to the general procedures of Scheme 42 and Scheme 43. 208 58226332.1224990 / 23-003-PC / 554457 Table 4 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph209 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz210 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz211 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Chiral Structure1H NMR No. m / z Chromatograph 2H) 1.36 (d 5H) 1.23 m m212 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz213 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz214 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz215 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz216 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1.71 (s 2H) 1.40 (s217 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 3H) 1.31 – 1.27 (m218 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz219 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz m, 0 Rtm, 0 Rt220 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Chiral Structure1H NMR No. m / z Chromatograph 1H NMR (400 MHz 6 m, 0 k221 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 6 m, 0 k222 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz223 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Chiral Structure1H NMR No. m / z Chromatograph 1H NMR (400 MHz 6 m, 5 2, m 5, ar n224 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Chiral Structure1H NMR No. m / z Chromatograph 1H NMR (400 MHz m 5, ar n225 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Chiral Structure1H NMR No. m / z Chromatograph 1H NMR (400 MHz e: : e: : m 5, ar n k226 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz m 5, ar n m, 0227 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz m, 0228 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph H1H NMR (400 MHz229 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Chiral Structure1H NMR No. m / z Chromatograph 1H NMR (400 MHz m 5, ar n m 5, ar n230 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz231 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz232 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz233 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 4H) 0.56 (dd 2H)234 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz235 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz236 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS1Chiral Structure H NMR No. m / z Chromatograph 1H NMR (400 MHz237 58226332.1224990 / 23-003-PC / 554457 Example 69. N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4- yl)-4-azaspiro[2.5]octane-5,5-d2-4-carboxamide (Compound 379).

[0453] 4-aluminum deuteride(262.0 mg, 6.24 mmol, 1.3 equiv.) was suspended in anhydrous THF (15 mL) and cooled to 0 °C under nitrogen.4-azaspiro[2.5]octan-5-one (600.0 mg, 4.8 mmol, 1.0 equiv.) in anhydrous THF (12 mL) was added dropwise, and reaction mixture allowed to warm to room temperature. After 5 hrs, the reaction mixture was cooled to 0 °C and carefully quenched with water (5 mL). DCM (25 mL) was added, and the reaction washed with 1 M HCl (2 x 15 mL). The aqueous layer was concentrated and the residue was purified via flash silica gel chromatography (0-10% DCM:0.7M MeOH / NH3) to give 379-1 (394.7 mg, 73%) as an oil. LC-MS m / z 114 (M+H+)

[0454] Compound 379 was synthesized following the same procedure as Compound 1using amine 379-1. The residue was concentrated, dissolved in DMF, and subjected to preparatory HPLC (H2O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (42.0 mg, 40%).1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.68 (s, 1H), 9.21 (s, 1H), 8.42 (d, 1H), 8.36 (s, 1H), 8.08 (d, 1H), 5.58 (d, 2H), 1.72 – 1.65 (m, 2H), 1.39 (m, 2H), 0.96 (m, 6H). LC-MS m / z 422 (M+H+).EXAMPLE 70. N-(3-(1-(2-Fluoro-2-methylpropyl)-3-(3-hydroxyazetidin-1-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 380). 238 58226332.1224990 / 23-003-PC / 554457

[0455] 2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)azetidin-3-ol. A mixture of 1-(2-fluoro-2- methyl-propyl)-3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (260 mg, 0.506 mmol), azetidin-3-ol (1.1 equiv., 40.6 mg, 0.56 mmol), Pd2(dba)3 (0.026 equiv., 12.0 mg, 0.013 mmol), Xantphos (0.1 equiv., 29.3 mg, 0.05 mmol), cesium carbonate (1.2 equiv., 198 mg, 0.607 mmol) and degassed 1,4-dioxane (2.5 mL) was stirred at 100 °C. After 1 d, the resulting mixture was filtered and washed with EtOAc (2 x 2 mL). The combined organic layers were concentrated in vacuo and purified by PrepHPLC (0.1% formic acid, 10% ACN in water to 100% ACN) to provide the title compound (40 mg, 17%) after lyophilization. LC-MS m / z 460.2 (M+H+).

[0456] Step 2: 1-[6-(4-Amino-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1-(2-fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-ol. A mixture of 1-[1-(2-fluoro-2- methyl-propyl)-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridin-3- 239 58226332.1224990 / 23-003-PC / 554457 yl]azetidin-3-ol (40 mg, 0.087 mmol), Pd(OH)2(0.1 equiv., 6.2 mg, 0.0087 mmol) and ethanol (3 mL) was subjected to H2 (1 atm balloon) with stirring. After 2.5 h, the mixture was filtered through Celite®and concentrated in vacuo to provide the title compound (36 mg, 96%). LC-MS m / z 430.2 (M+H+).yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-4- azaspiro[2.5]octane-4-carboxamide. A mixture of 1-[6-(4-amino-1-tetrahydropyran-2-yl- pyrazol-3-yl)-1-(2-fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-ol (15 mg, 0.035 mmol), bis(2,5-dioxopyrrolidin-1-yl) carbonate (1.2 equiv., 10.7 mg, 0.0419 mmol) and dichloromethane (0.4 mL) was stirred at room temperature. After 20 min, a mixture of 4- azaspiro[2.5]octane hydrochloride (1.3 equiv., 6.7 mg, 0.045 mmol), DIPEA (2.5 equiv., 0.015 mL, 0.087 mmol) and DMF (0.5 mL) was added. After 1 h, the resulting mixture was purified by PrepHPLC (0.1% formic acid, 10% ACN in water to 100% ACN) to provide the titlecompound (12 mg, 61%) after lyophilization. LC-MS m / z 567.3 (M+H+).240 58226332.1224990 / 23-003-PC / 554457yl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide. (Compound 380) A mixture of N-[3-[1-(2-fluoro-2-methyl-propyl)-3-(3-hydroxyazetidin-1- yl)pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]-4-azaspiro[2.5]octane-4- carboxamide (11 mg, 0.019 mmol), 4-methylbenzenesulfonic acid monohydrate (0.5 equiv., 1.8 mg, 0.0097 mmol) and methanol (0.5 mL) was stirred at 60 °C. After 1 h, the mixture was purified by PrepHPLC (0.1% formic acid, 10% ACN in water to 100% ACN) to provide titlecompound (5.0 mg, 53%) after lyophilization. 1H NMR (400 MHz, DMSO-d6) δ 12.82 (bs, 1H),10.68 (s, 1H), 8.84 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 5.72 (bs, 1H), 4.67 (p, 1H), 4.50 – 4.36 (m, 4H), 3.88 (t, 2H), 3.60 (bs, 2H), 1.77 – 1.69 (m, 2H), 1.52 (bs, 2H), 1.45 (s, 2H), 1.36 (d, 6H), 0.97 (s, 4H). LC-MS m / z 483.3 (M+H+). 241 58226332.1224990 / 23-003-PC / 554457 Scheme 44pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 381).

[0459] a were added 3-(3-iodo-1H-pyrrolo[3,2-c]pyridin-6-yl-4-nitro-1-(oxan-2-yl)pyrazole (2 g, 4.55 mmol, 1 242 58226332.1224990 / 23-003-PC / 554457 equiv), DMF (20 mL), 2-fluoro-2-methylpropyl trifluoromethanesulfonate (1.22 g, 5.47 mmol, 1.2 equiv) and K2CO3 (1.89 g, 13.66 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0-60% in 30 min) to afford compound 381-2, 3-[1-(2-fluoro-2-methylpropyl)-3-iodopyrrolo[3,2-c]pyridin-6-yl]-4-nitro-1- (oxan-2-yl)pyrazole (1.3 g, 55.62%).-3-iodopyrrolo[3,2-c]pyridin-6-yl]-4-nitro-1-(oxan-2-yl)pyrazole (150 mg, 0.29 mmol, 1 equiv), piperazine, 1-methyl- (292.70 mg, 2.92 mmol, 10 equiv), Cs2CO3(190.42 mg, 0.58 mmol, 2 equiv) and Pd-PEPPSI®-IHeptCl 3-chloropyridine (28.46 mg, 0.03 mmol, 0.1 equiv) in dioxane (4 mL) was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford compound 381-3, 1-[1-(2-fluoro-2- methylpropyl)-6-[4-nitro-1-(oxan-2-yl)pyrazol-3-yl]pyrrolo[3,2-c]pyridin-3-yl]-4- methylpiperazine (125 mg, 88.10%). 243 58226332.1224990 / 23-003-PC / 554457

[0461] methylpropyl)-6-[4-nitro-1-(oxan-2-yl)pyrazol-3-yl]pyrrolo[3,2-c]pyridin-3-yl]-4- methylpiperazine (120 mg, 0.25 mmol, 1 equiv) in MeOH (6 mL) and saturated NH4Cl (1.2 mL) were added Zn (161.58 mg, 2.50 mmol, 10 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The mixture was basified to pH 9 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 12:1) to afford compound 381-4, 3-[1-(2- fluoro-2-methylpropyl)-3-(4-methylpiperazin-1-yl)pyrrolo[3,2-c]pyridin-6-yl]-1-(oxan-2- yl)pyrazol-4-amine (90 mg, 79.94%).-3-(4-methylpiperazin-1-yl)pyrrolo[3,2-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-amine (45 mg, 0.10 mmol, 1 equiv) and CDI (32.03 mg, 0.20 mmol, 2 equiv) in DCM (1 mL) was stirred at room temperature for 1 h. To the above mixture were added DIPEA (63.83 mg, 0.50 mmol, 5 equiv) 244 58226332.1224990 / 23-003-PC / 554457 and 4-azaspiro[2.5]octane hydrochloride (29.17 mg, 0.20 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford compound 381-5, N-(3-[1-(2- fluoro-2-methylpropyl)-3-(4-methylpiperazin-1-yl)pyrrolo[3,2-c]pyridin-6-yl]-1-(oxan-2- yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (80 mg, 87.45%) as red semi-solid.(4-methylpiperazin-1-yl)pyrrolo[3,2-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4- azaspiro[2.5]octane-4-carboxamide (80 mg, 0.09 mmol, 1 equiv, 64%) and para-toluene sulfonate (7.44 mg, 0.04 mmol, 0.5 equiv) in MeOH (8 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 9 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 47% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.32 to afford Compound 381, N-(3-[1-(2-fluoro-2- methylpropyl)-3-(4-methylpiperazin-1-yl)pyrrolo[3,2-c]pyridin-6-yl]-1H-pyrazol-4-yl-4- azaspiro[2.5]octane-4-carboxamide (8.9 mg, 20.16%). LCMS:(ES, m / z):[M+1]=509.1H NMR (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.82 (s, 1H), 8.81 (s, 1H), 8.05 (d, 2H), 6.87 (s, 1H), 4.34 (d, 2H), 3.51 (s, 1H), 3.05 (s, 4H), 2.56 (d, 3H), 2.26 (s, 3H), 1.73 (s, 2H), 1.50 (d, 4H), 1.35 (s, 3H), 1.28 (s, 3H), 1.24 (s, 1H), 1.00 (s, 4H), 0.84 (d, 1H). 245 58226332.1224990 / 23-003-PC / 554457 Example 72. [1-[6-[4-(4-azaspiro[2.5]octane-4-carbonylamino)-1H-pyrazol-3-yl]-1-(2- fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]-methyl-carbamic acid (Compound 382).tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]-N-methyl- carbamate. To a 20-mL vial were added 1-(2-fluoro-2-methyl-propyl)-3-iodo-6-(4-nitro-1- tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (500 mg, 0.972 mmol, 500 mg), tert- butyl N-(azetidin-3-yl)-N-methyl-carbamate (272 mg, 1.46 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (44.5 mg, 0.0486 mmol, 0.05 equiv.), (5- diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (Xantphos) (56.3 mg, 0.0972 mmol, 0.1 equiv.), and 1,4-dioxane (5 mL). The mixture was de-gassed with nitrogen and heated at 110 °C overnight (16h). The reaction mixture was filtered though a Celite®pad, and the filtrate was concentrated. The residue was purified by ISCO®(0-50% EA / Hex) to provide compound 382-2 (640 mg, 1.1 mmol, 110%) as a yellow solid. LCMS: m / z = 573.400 [M+H]+(2-fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]-N-methyl-carbamate. A 246 58226332.1224990 / 23-003-PC / 554457 heterogeneous mixture of tert-butyl N-[1-[1-(2-fluoro-2-methyl-propyl)-6-(4-nitro-1-tetrahydropyran-2- yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]-N-methyl-carbamate (0.64 g, 1.1 mmol), zinc dust (730 mg, 11 mmol, 10 equiv.) in saturated ammonium chloride solution (2 mL) and methanol (10 mL) was stirred at room temperature for 1h. The reaction mixture was filtered through a Celite®pad, and the filtrate was concentrated. The residue was purified by ISCO®(0-10% MeOH / DCM) to provide compound 382-3 (650 mg, 1.2 mmol, 110%). LCMS: m / z = 543.400 [M+H]+- 3- yl]azetidin-3-yl]-N-methyl-carbamate. A mixture of tert-butyl N-[1-[6-(4-amino-1- tetrahydropyran-2-yl-pyrazol-3-yl)-1-(2-fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3- yl]azetidin-3-yl]-N-methyl-carbamate (100 mg, 0.184 mmol, 100 mg) and bis(2,5- dioxopyrrolidin-1-yl) carbonate (51.9 mg, 0.203 mmol, 1.1 equiv.) in dichloromethane (1 mL) was sonicated for 1 minute. To the resulting suspension, a solution of 4- azaspiro[2.5]octane;hydrochloride (40.8 mg, 0.276 mmol, 1.5 equiv.), and N-ethyl-N-isopropyl- propan-2-amine (71.5 mg, 0.553 mmol, 3 equiv.) in N,N-dimethylformamide (1 mL) was added. The resulting mixture was stirred at room temperature for 1h. The solvents were removed in vacuo and the residue was purified by ISCO®(0-100% EA / Hex) to provide compound 382-4 (220 mg, 0.32 mmol, 180%, containing some DMF). LCMS: m / z = 680.4 [M+H]+247 58226332.1224990 / 23-003-PC / 554457

[0467] 3-yl]-1-(2-fluoro-2-acid. tert-Butyl N-[1-[6-[4-(4-azaspiro[2.5]octane-4-carbonylamino)-1-tetrahydropyran-2-yl-pyrazol- 3-yl]-1-(2-fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]-N-methyl- carbamate (220 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL), and the solution was treated with trifluoroacetic acid (420 mg, 3.69 mmol, 20 equiv.) at room temperature. The mixture was stirred at room temperature overnight (16h). The reaction mixture was concentrated and the residue was purified by RP-prepHPLC (Phenomenex Gemini C18, 10-60% MeCN / water + 0.1% FA) to provide compound 382 (26.0 mg, 0.0482 mmol, 26.1%). LCMS: m / z = 540.3 [M+H+].1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.16 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 4.56 – 4.39 (m, 3H), 4.28 (dd, 1H), 4.10 (dd, 1H), 3.75 – 3.59 (m, 3H), 2.94 (s, 3H), 1.84 (t, 2H), 1.54 (s, 2H), 1.48 (s, 3H), 1.43 (s, 3H), 1.02 (d, 4H). Scheme 45 248 58226332.1224990 / 23-003-PC / 5544571H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide and N-(3-(3-(3-methoxyazetidin-1-yl)-2-((1-methylpyrrolidin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compounds 383 and 384).1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4- azaspiro[2.5]octane-4-carboxamide (383-3) and N-(3-(3-(3-methoxyazetidin-1-yl)-2-((1- methylpyrrolidin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (383-4). In a 40 mL vial, N-[3-[3- 249 58226332.1224990 / 23-003-PC / 554457 (3-methoxyazetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4- yl]-4-azaspiro[2.5]octane-4-carboxamide (383-1, 300 mg, 0.592 mmol, 1 equiv.), (1- methylpyrrolidin-3-yl)methanol (383-2, 100 mg, 0.868 mmol, 1.5 equiv.) and 2-(tributyl-λ⁵- phosphanylidene)acetonitrile (285 mg, 1.180 mmol, 2 equiv.) were dissolved in toluene (5 mL) and stirred at 100oC. After 15h the reaction mixture was cooled and poured into water (40 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and the solvent removed. The residue was purified by silica gel chromatography (24 g, DCM / MeOH, 0-15%) to obtain a mixture of 383-3 and 383-4 (300 mg, 83.90%). Regioisomers were not isolated and the material was used without further purification. LC-MS m / z 604.35 (M+H+).

[0469] - 1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide and N-(3-(3-(3-methoxyazetidin-1-yl)-2-((1-methylpyrrolidin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide. Compounds 383-3 and 383-4 (300 mg, 0.49 mmol, 1 equiv.) were dissolved in methanol (3 mL) and 4-methylbenzenesulfonic acid monohydrate (22.0 mg, 0.116 mmol, 100 mass%) was added. 250 58226332.1224990 / 23-003-PC / 554457 The reaction mixture was stirred at 60oC for 30 minutes then allowed to cool to rt and sat’d aqueous NaHCO3 solution (0.5 mL) was added and filtered through syringe filter. The filtrate was purified by RP-HPLC (10-100% MeCN / water / FA, product out at 65-70%) to obtain compound 383 (26 mg, 15.12%) and 384 (54 mg, 41.82%).

[0470] Characterization of 383: LC-MS m / z 520.35 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.64 (s, 1H), 8.76 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 4.31 (d, 3H), 4.09 (s, 2H), 3.96 – 3.86 (m, 2H), 3.20 (s, 3H), 2.61 (s, 1H), 2.49 (d, 2H), 2.32 (t, 2H), 2.22 (s, 2H), 2.15 (s, 3H), 1.77 (d, 2H), 1.66 (s, 2H), 1.49 – 1.32 (m, 4H), 0.84 (d, 4H).

[0471] Characterization of 384: LC-MS m / z 520.35 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.77 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.88 (s, 1H), 4.31 (q, 3H), 4.20 – 4.09 (m, 2H), 3.96 – 3.83 (m, 3H), 3.20 (s, 3H), 2.72 – 2.54 (m, 3H), 2.41 – 2.29 (m, 2H), 2.23 (d, 3H), 1.82 (d, 1H), 1.66 (t, 2H), 1.46 (dq, 5H), 1.37 (s, 2H), 0.90 (s, 5H).

[0472] Compounds 379-384 in Table 5 were synthesized according to the above Examples.Compounds 385-511 in Table 5 were synthesized using variously-substituted 1H-pyrazol-4- amines and 4-azaspiro[2.5]octane or 4-azaspiro[2.5]octane-5,5-d2 according to the general procedures of Scheme 44 and Scheme 45. 251 58226332.1224990 / 23-003-PC / 554457 Table 5 Compound LC-MS Structure1H NMR No. m / z252 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, (t,253 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z ), ), , 9 , ), , , m, 50 –254 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z (t, 9 ), ), 9 ),255 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z – , r t, t, s,256 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s,257 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z t, ), ),258 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z – t s, ), ), – – – –259 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, – – ) , ), ), )260 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, 7 m, ,261 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z ), ), , ), s,262 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z (t, 5 (t, , 7 ), - 6263 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z – - ), ), d, s,264 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, ), – – ),265 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z , , ), , –266 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z ), ), ), m, ), m,267 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z ), ), ), (t, ),268 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, ), – – 1 s, s, ,269 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 7 ), t, , 8 – – , ), d, 4 , , – 31 , 2270 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 2 ), – – ). s, d, , ), 2 4 – 6 3 ), ), , .271 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1 – ), , ), – ), s,272 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, s, ), , . ), , . (t, 3 1 7 9273 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z – d, ). 9 ). s, s,274 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 0 ), 3 , , , , , – ), ), ), ). s, – – – ),275 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z – – m, s, 3 s,276 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 2 – , , 2 m, 4 s, , , , , 6 ), 9 – – – – 9277 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1H NMR (400 MHz Methanol-d4) δ 884 – – – – 1 – 2 8 8 1 0 , m,278 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 2 – , , 9 05 ), – – , – 9 4 9 – t,279 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1H NMR (400 MHz DMSO-d ) δ 1283 2 ),- - c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 512). 280 58226332.1224990 / 23-003-PC / 554457

[0473] Step 1: 1-of 5-hydroxy-1H-pyridin-2-one (15 g, 135 mmol, 1 eq.) and KOH (30.30 g, 540 mmol, 4 eq.) in DMAc (150 mL) was stirred at 20 °C for 30 min, then BnBr (40.1 mL, 337 mmol, 2.5 eq.) was added dropwise at 5 °C and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 200 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide a residue. The residue was diluted with water (150 mL), filtered, washed with petroleum ether (100 mL) and dried under reduced pressure to give 1-benzyl-5-benzyloxy- pyridin-2-one (26.1 g, 66%) as a pink solid. The filtrate was concentrated in vacuo and purified by silica gel chromatography (ISCO®; 40 g SepaFlash®Silica Flash Column, 0 to 45% ethyl acetate in petroleum ether, gradient 80 mL / min) to give compound 512-2 (11.9 g, 24%, 80% purity) as brown liquid. LC-MS m / z 292.1 (M+H+).

[0474] Step 2: 1-benzyl-5-benzyloxy-pyridin-2-one (11.9 g, 32.7 mmol, 1 eq.), Pd / C (10%, 1.2 g, 1.13 mmol) in MeOH (200 mL) was degassed and purged with H2 for 3 times and stirred at 20 °C for 12 hours under H2 (15 psi) atmosphere. The resulting mixture was filtered through a pad of Celite®and washed with MeOH (3 x 100 mL). The combined filtrates were concentrated in vacuo and purified by silica gel chromatography (ISCO®; 80 g SepaFlash®Silica Flash Column, 0 to 45% ethyl acetate in petroleum ether, gradient 50 mL / min) to give compound 512-3 (2.3 g, 26%, 75% purity) as brown liquid. LC-MS m / z 204.0 (M+H+). 58226332.1224990 / 23-003-PC / 554457

[0475] Step 3: 1-Benzyl-6-oxo-1,4,5,6-tetrahydropyridin-3-yltrifluoromethanesulfonate. To a stirred solution of 1-benzylpiperidine-2,5-dione (2.30 g, 8.49 mmol, 1 eq.) and THF (25 mL) under nitrogen at −65 °C was added LiHMDS (1.0 M in THF, 10.2 mL, 1.2 eq.) for 1 h. N-phenylbis(trifluoromethanesulfonimide) (3.64 g, 10.2 mmol, 1.2 eq.) in THF (30 mL) was added dropwise at −65 °C and the resulting mixture was stirred at −65 °C for 2 h under N2. The reaction mixture was allowed to warm to 20 °C and stirred for 12 h under N2. The reaction mixture was quenched with saturated aqueous NH4Cl (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were washed by brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, 0 to 15% ethyl acetate in petroleum ether, gradient 40 mL / min) to give 512-4 compound (2.0 g, 70%) as blueliquid. LC-MS m / z 235.9 (M+H+).

[0476] Step 4: 1-4-yl)-3,4-dihydropyridin-2(1H)-one. A mixture of (1-benzyl-2-oxo-3,4-dihydropyridin-5-yl) trifluoromethanesulfonate (2.25 g, 6.71 mmol, 1 eq.), 1-tetrahydropyran-2-yl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.79 g, 10.0 mmol, 1.5 eq.), Pd(dppf)Cl2(495 mg, 676 μmol, 0.1 eq.), K2CO3 (1.85 g, 13.4 mmol, 2 eq.) in 1,4-dioxane (30 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, 0 to 40% ethyl acetate / petroleum ether, gradient 50 mL / min) to givecompound 512-5 (2.1 g, 6.2 mmol, 93%) as yellow oil. LC-MS m / z 338.1 (M+H+).282 58226332.1224990 / 23-003-PC / 554457

[0477] Step 5: 1-4-yl)piperidin-2-one. A mixture of 1-benzyl-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,4-dihydropyridin-2-one (2.1 g, 6.2 mmol, 1 eq.), Pd / C (10%, 500 mg, 0.47 mmol) in MeOH (20 mL) was degassed and purged with H2for 3 times, and then the mixture was stirred at 25 °C for 12 h under H2(45 psi) atmosphere. The reaction mixture was filtered and concentrated to give compound 512-6 (1.85 g, 5.45 mmol, 87%) as brown oil. LC-MS m / z 362.1 (M+Na+).

[0478] Step 6:4-yl)-4-azaspiro[2.5]octane. A solution of Ti(OiPr)4 (2.26 g, 7.95 mmol, 2.35 mL, 1.5 eq.) in THF (20 mL) was added EtMgBr (3 M, 5.30 mL, 3 eq.) under N2 atmosphere at −60 °C and the mixture was stirred for 10 min. Then a solution of 1-benzyl-5-(1-tetrahydropyran-2-ylpyrazol-4- yl)piperidin-2-one (1.8 g, 5.30 mmol, 1 eq.) in THF (20 mL) was added dropwise at −60 °C. The reaction mixture was warmed to room temperature and stirred for 12 hours under N2 atmosphere. The reaction mixture was quenched by water (3 mL), treated with Na2SO4, filtered and washed with EtOAc (10 mL). The combined filtrates were concentrated in vacuo and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, 0 to 5% methanol in dichloromethane, gradient 35 mL / min) to provide compound 512-7 (580 mg,31%) as yellow oil. LC-MS m / z 352.1 (M+H+).58226332.1224990 / 23-003-PC / 554457

[0479] Step 7: 6-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane. A mixture of 4-benzyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)-4- azaspiro[2.5]octane (700 mg, 1.99 mmol, 1 eq.), Pd / C (10%, 200 mg, 0.188 mmol) in MeOH (20 mL) was degassed and purged with H2for 3 times, and then the mixture was stirred at 40 °C for 12 h under H2 (20 psi) atmosphere. The mixture was filtered through a pad of Celite®and washed with methanol (3 x 100 mL). The combined filtrates were concentrated in vacuo and purified by PrepHPLC (0.1% HCl condition) to give compound 512-7 (480 mg, 92%) asyellow oil. LC-MS m / z 262.1 (M+H+).

[0480] Step 8: 6-of 6-(1-tetrahydropyran-2-ylpyrazol-4-yl)-4-azaspiro[2.5]octane (440 mg, 1.68 mmol, 1 eq.) and HCl (2 M in MeOH, 5.0 mL) was stirred at 15 °C for 2 h. The reaction mixture was concentrated in vacuo and purified by PrepHPLC (column: Welch Xtimate C18150*25 mm*5 µm; mobile phase: water (NH4OH + NH4HCO3) / MeCN; gradient: 3% to 36% MeCN over 8 min) to give thetitle compound (58.9 mg, 20%) as a white solid. LC-MS m / z 178.1 (M+H+).--c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 512). Compound 52 (4.0 mg, 16%) was synthesized using compound 24-5 and 512-9 following the same procedure as example 20.1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 12.62 (s, 1H), 10.80 (s, 1H), 9.28 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.51 (s, 2H), 5.64 (d, 2H), 284 58226332.1224990 / 23-003-PC / 554457 4.27 (s, 1H), 2.83 (s, 1H), 2.63 (s, 1H), 2.16 (s, 1H), 2.05 – 1.99 (m, 1H), 1.87 – 1.75 (m, 1H), 1.45 (s, 1H), 1.37 (s, 1H), 1.20 (m, 1H), 0.75 (s, 2H). LC-MS m / z 486.1 (M+H+).

[0482] Compound 512 was prepared according to the above Example. Compounds 515-635in Table 6 were prepared by coupling variously substituted using 1H-pyrazol-4-amines with commercially available amines, e.g., with N,N′-disuccinimidyl carbonate as described in Example 20. Table 6 LC-MS Compound No. Structure1H NMR m / z s, 8 ), s, 1 8 δ 1 – m, m,285 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ 16 ). d, , , δ , 1 . δ 90286 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ , δ , ), – , , δ , s, ). s, 6287 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z s, 5 ), s, 5 ), s, 6 , s, 9 ), m, 7 ),288 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 s, 3 – s, 7 m, s, 4 6 ),289 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z – m, 6 9 s, s, 5 s, , . s, , , 7 3290 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 m, , , , s, 14 , s, , 4 –291 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 3 – , 5 4 5 – t, s, 7 , s, 7 , , 6 s, m,292 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z s, m, s, 2 (t, s, 2 (t, s, 8 ), m, s, –293 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO d ) δ s, 1 – 5 s, 4 ), s, 2 , s, 9 ), s, 5294 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z s, 6 7 5 ), s, 3 ), s, 4 ), s, 4 ), s, 4 ,295 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO-d6) δ s, 4 , m, 1 ), s, 3 9 ), s, 4 3 , s, s, 2 ),296 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR 4 MH DM s, 4 – s, 6 , 2 ), s, 5 - s, 7 ,297 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z s, 1 – s, 7 , s, 4 s, 4 – s, 9298 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ s, 5 , 8 . s, 5 , 8 . s, 9 – m, s, 9 – m,299 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz DMSO-d6) δ s, 9 – m, , s, 9 – m, m, δ 9 s, 4 s, 1 0 s, 5 2300 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 s, 2 – m, s, 1 – m, s, 9 – m, s, 9 – m, 2 ot nt301 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 s, 1 36 . ) s, 3 , s, , , 8 – δ 2 ), 1302 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ 1 s, 5 δ 3 ), , 33 δ 8 – , δ 1 δ 9303 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ 4 ), δ m, s, , 8 – m, δ 4 δ ,304 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z δ m, δ , δ δ δ –305 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z s, 0 m, r s, 3 , s, 0 m, r s, 0 m, r δ , 6 , 3306 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz Methanol-d4) δ 4 , 3 ), m, s, 0 m, r s, 3 , , 5 ), m,307 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1H NMR (400 MHz CDCl3) δ , 8 ), m, , 8 ), m, δ δ , 4 – s, 4 m,308 58226332.1224990 / 23-003-PC / 554457 LC-MS Compound No. Structure1H NMR m / z 1 s, 4 m,Scheme 47- - 6-yl)-1H-pyrazol-4-yl)-2-cyano-2-(piperidin-4-yl)acetamide (Compound 634). 58226332.1224990 / 23-003-PC / 554457

[0483] Step 1: tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl) piperidine-1-carboxylate.To asolution of ethyl 2-cyano-2-(1-{[(2-methylprop-2-yl) oxy] carbonyl} hexahydropyridin-4- ylidene) acetate (200 mg, 0.68 mmol) in MeOH (3 mL) was added Pd on carbon 20 percent (50 mg, 10 mass %). The reaction mixture was stirred under H2at 40oC for 2 hours. The reaction mixture was filtered through Celite®, and the solvent removed to obtain 634-1 (100 mg, 49.7%).

[0484] Step 2: 2-(1-(tert-butoxycarbonyl) piperidin-4-yl)-2-cyanoacetic acid. To asolution of ethyl 2-cyano-2-(1-{[(2-methylprop-2-yl) oxy] carbonyl} hexahydropyridin-4-yl) acetate (634-1, 100 mg, 0.34 mmol, 1 equiv) in MeOH (0.6 mL) and water (0.2 mL) was added LiOH (3.0 eq). The reaction mixture was stirred at 20oC for 18 hours. The reaction mixture was adjusted pH to 3 with diluted HCl aqueous solution, and filtered to obtain 634-2 (90 mg, 99.4%).

[0485] - -pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)-1- cyano-2-oxoethyl)piperidine-1-carboxylate. To a solution of 2-cyano-2-(1-{[(2-methylprop-2- yl)oxy]carbonyl}hexahydropyridin-4-yl)acetic acid (634-2, 50 mg, 0.19 mmol, 1.0 equiv) in DMF (1 mL) were added 3-[3-(azetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6- yl]-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-4-amine (1.0 eq), HATU (1.0 equiv) and DIPEA (2.0 eq). The reaction mixture was stirred at rt for 18 hours. The reaction mixture was 310 58226332.1224990 / 23-003-PC / 554457 concentrated and subjected to FCC (Hexanes:EtOAc, 100:0 to 0:100) to give 634-3 (30 mg, 24.0%).

[0486] pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)amino)-1-cyano-2-oxoethyl)piperidine-1- carboxylate. To a solution of tert-butyl 4-(2-((3-(3-(azetidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)-1-cyano-2- oxoethyl)piperidine-1-carboxylate (643-3, 30 mg, 1.0 eq) in MeOH (0.6 mL) was added TsOH (2.0 eq). The reaction mixture was stirred at 50oC for 15 minutes. The reaction mixture was subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to obtain 634-4 (20 mg, 76.2%).

[0487] Step 5: N-(3-(3-(azetidin-1-yl)-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-2-cyano-2-(piperidin-4-yl) acetamide. To N-(3-(3-(azetidin- 1-yl)-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridin-6-yl)-1H-pyrazol-4-yl)-2-cyano-2- (piperidin-4-yl) acetamide (634-4, 20 mg, 0.034 mmol, 1 eq) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 0.5 hours. The reaction mixture was concentrated and was subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to obtain compound 634 (10 mg, 45.6%).1H NMR (400 MHz, Methanol-d4) δ 8.91 (d, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 4.99 (q, 2H), 4.58 (s, 1H), 4.26 (t, 4H), 3.44 (t, 2H), 3.16 – 2.96 (m, 2H), 2.64 – 2.46 (m, 3H), 2.05 (dd, 2H), 1.87 – 1.70 (m, 2H). LC-MS m / z 488 (M+H+). Scheme 48 311 58226332.1224990 / 23-003-PC / 554457- - pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)propanamide (Compound 635).

[0488] Step 1: 4, 6- - [4, 3-c] pyridine. 4, 6-dichloro-1H-pyrazolo [4, 3-c] pyridine (1.1 g, 5.85 mmol, 1.0 equiv) was dissolved in DMF (22 mL).2, 2, 2-trifluoroethyl trifluoromethanesulfonate (1.5 equiv) and K2CO3(2.0 equiv) were added, and the reaction mixture was stirred at rt for 16 hours. The reaction mixture was poured 312 58226332.1224990 / 23-003-PC / 554457 into water (60 mL) and extracted with ethyl acetate (60 mL) twice. The organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated. The residue was subjected to FCC (Hexanes:EtOAc, 100:0 to 80:20) to give 635-1 (820 mg, 51.9%).

[0489] Step 2: tert-butyl 4-(6-chloro-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c]pyridine -4-yl) piperazine-1-carboxylate. To a solution of 4, 6-dichloro-1-(2, 2, 2- trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridine (635-1, 200 mg, 0.74 mmol, 1 eq) in DMF (5 mL) were added 2-methylpropan-2-yl piperazine-1-carboxylate (1.2 eq) and DIPEA (1.5 eq). The reaction mixture was stirred at 50oC for 16 hours. The reaction mixture was stirred at 80oC for 2 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl aetate (20 mL) twice. The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was subjected to FCC (Hexanes: EtOAc, 100:0 to 80:20) to give 635-2 (150 mg, 48.2%).

[0490] Step 3: tert-butyl 4-(6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridin-4-yl) piperazine-1-carboxylate. To a solution of tert-butyl 4-(6-chloro-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridine -4-yl) piperazine-1-carboxylate (635-2, 140 mg, 0.33 mmol, 1.0 eq) in DMF (1 mL) were added 4- nitro-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl) pyrazole (2.0 eq), Pd(OAc)2 (0.2 eq), Catacxiumn A 313 58226332.1224990 / 23-003-PC / 554457 (0.15 eq), 2,2-dimethylpropanoic acid (0.3 eq) and K2CO3(3.0 eq). The reaction mixture was stirred at 110oC for 4 hours. The reaction mixture was concentrated and subjected to FCC (Hexanes:EtOAc, 100:0 to 0:100) to give 635-3 (130 mg, 67.2%).

[0491] Step 4: tert-butyl 4-(6-(4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2, 2, 2- trifluoroethyl)-1H-pyrazolo [4,3-c]pyridin-4-yl)piperazine-1-carboxylate (635-3, 130 mg, 0.22 mmol, 1 eq) in MeOH (3 mL) were added Zn (10.0 eq), NH4Cl (10.0 eq) in water (1 mL). The reaction mixture was stirred at r.t for 1 hour then filtered and concentrated. The residue was subjected to FCC ((DCM: MeOH, 100:0 to 90:10) to give 635-4 (110 mg, 89.2%).

[0492] Step 5: tert-butyl 4-(6-(4-(2-cyclobutylpropanamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridin-4-yl)piperazine- 1-carboxylate. To a solution of tert-butyl 4-(6-(4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)piperazine-1-carboxylate 314 58226332.1224990 / 23-003-PC / 554457 (635-4, 90 mg, 0.163 mmol, 1 eq) in DMF (3 mL) were added 2-cyclobutylpropanoic acid (1.2 eq), HATU (1.2 eq) and DIPEA (2.0 eq). The reaction mixture was stirred at 50oC for 3 hours, allowed to cool and was subjected to FCC ((Hexanes:EtOAc, 100:0 to 0:100) to give 635-5 (108 mg, 100%).

[0493] Step 6: 2-cyclobutyl-N-(3-(4-(piperazin-1-yl)-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridin-6-yl)-1H-pyrazol-4-yl)propanamide. To a solution of tert-butyl 4- (6-(4-(2-cyclobutylpropanamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2, 2, 2- trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)piperazine-1-carboxylate (635-5, 100 mg, 0.15 mmol, 1.0 eq) in MeOH (5 mL) was added TsOH (2.0 eq). The reaction mixture was stirred at 50oC for 15 minutes then concentrated. The residue was dissolved in HCl-dioxane (1 mL). The reaction mixture was stirred at r.t for 1 hour then purified by prep-HPLC to obtain Compound 635 (30 mg, 41.7%).1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.26 (s, 1H), 7.60 (s, 1H), 5.17 (q, 2H), 3.99 – 3.83 (m, 4H), 3.20 – 3.08 (m, 4H), 2.57 (dd, 1H), 2.48 – 2.35 (m, 1H), 2.17 (dd, 1H), 2.02 (d, 1H), 1.92 (d, 1H), 1.84 – 1.69 (m, 3H), 1.15 (d, 3H). ESI-LCMS: 477 (M+H+)

[0494] Compounds 636-732 in Table 7 were synthesized using variously substituted 1H-pyrazol-4-amines and carboxylic acids according to the general procedure of Scheme 47 and Scheme 48. 315 58226332.1224990 / 23-003-PC / 554457 Table 7 Compound LC-MS Structure1H NMR No. m / z ), , ), , ), t, q,316 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 2 t, s, d, 6 s, 6 - r, 2 s, ,317 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 5 d, , 7 ), , d, m, ), , 6 s, , 6 s, 33 d,318 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 5 s, , . d, , – m, s, d, , , d, d, d,319 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1H NMR (400 MHz DMSO-d ) δ 1322 ), d, d, – – – s, e 42 , 15 , , p, ), ,320 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1H NMR 400 MH DMSO d δ 1297 d, 4 s, d, 62 ), s, d, d, 5 e 5 8 9321 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 4.28 (d 0.4H) 4.08 (t 0.6H) 2.80 – 2.67 H)s, – – ), – m, 7 d, 2 5 , – s,322 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1 ), d, – , d, d, ), d, t, s, e ), 4 3 6 8323 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1H NMR (400 MHz DMSO-d6) δ 13.06 t, – – , , e 1 ), 2 , 7 5 ), –324 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1H NMR (400 MHz DMSO-d6) δ 12.95 t, d, , d, d, t, H) d,325 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1 s, – d, d, d, d, 39 4 d, 8 d, s, 4326 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 5 s, , , ), – , , .327 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z s, 8 d, 0 s, d, 3 – ), 08 s,328 58226332.1224990 / 23-003-PC / 554457 Compound LC-MS Structure1H NMR No. m / z 1 9 s, , , 2 s, , 3 s, 2 , 9 (t,329 58226332.1224990 / 23-003-PC / 554457 Scheme 49- 1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (Compound 732).

[0495] Into a 10mL sealed tube were added tert-butyl 7-(difluoromethyl)-7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate (100 mg, 0.361 mmol, 1 equiv), dioxane (3.6 mL) and DMAP (4.41 mg, 0.036 mmol, 0.1 equiv) at room temperature. To the reaction mixture was added pyridine (171.14 mg, 2.166 mmol, 6 equiv) and SOCl2(257.39 mg, 2.166 mmol, 6 equiv) dropwise at 0 °C. The resulting reaction mixture was stirred for 14h at 60°C. The reaction mixture was quenched with sat. NaHCO3 (aq.) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (Petroleum ether / Ethyl acetate 10:1) to afford tert-butyl 7-(difluoromethyl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate (50 mg, 53.47%). 330 58226332.1224990 / 23-003-PC / 554457

[0496] Into a 25mL round-bottom flask were added tert-butyl 7-(difluoromethyl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate (50 mg, 0.193 mmol, 1 equiv), MeOH (1 mL) and Pd / C (50 mg) at room temperature. The resulting mixture was stirred for 14h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was used in the next step directly without further purification.

[0497] Into a 25 mL round-bottom flask were added tert-butyl 7-(difluoromethyl)-4-azaspiro[2.5]octane-4-carboxylate (29 mg, 0.111 mmol, 1 equiv) and 4 M HCl (g) in MeOH (0.3 mL) at room temperature. The resulting mixture was stirred for 4 h at room temperature then concentrated under reduced pressure. The residue was used in the next step directly without further purification.224990 / 23-003-PC / 554457

[0498] Into a 80mL vial were added 3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-amine (27 mg, 0.079 mmol, 1.00 equiv), DMF (0.5 mL)and CDI (32.15 mg, 0.198 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the mixture was added 7-(difluoromethyl)-4-azaspiro[2.5]octane (25.57 mg, 0.158 mmol, 2 equiv) in DMF (0.5 mL) at room temperature. The resulting mixture was stirred for additional 3 h at room temperature then DIPEA (20.50 mg, 0.158 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 14h at room temperature then diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford 7-(difluoromethyl)-N-(3-[1-(2-methylpropyl)pyrazolo[4,3- c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (35 mg, 73.60%).

[0499] - (2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (35 mg, 0.058 mmol, 1 equiv, 88%) and 4 HCl (gas) in MeOH (0.4 mL) at room temperature. The resulting mixture was stirred for 4 h at room temperature then concentrated under reduced pressure. The reaction mixture pH was adjusted to pH 9 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 332 58226332.1224990 / 23-003-PC / 554457 40% B to 57% B in 8 min; RT1(min): 7.33 to afford 7-(difluoromethyl)-N-(3-[1-(2- methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (14 mg, 53.97%). LC-MS m / z 444 (M+1). NMR:1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.85 (s, 1H), 9.23 (s, 1H), 8.34 (s, 1H), 8.15 (d, 2H), 5.89 (td, 1H), 4.27 (dd, 3H), 2.91 (t, 1H), 2.48 – 2.13 (m, 2H), 1.91 (t, 1H), 1.64 (d, 1H), 1.46 (s, 1H), 1.35 (dt, 1H), 1.31 – 1.19 (m, 2H), 0.88 (d, 6H), 0.78 – 0.70 (m, 2H). Scheme 506- yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (Compound 733). To a stirred solution of 3-[1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1-([2- (trimethylsilyl)ethoxy]methylpyrazol-4-amine (105 mg, 0.255 mmol, 1 equiv) in DCM (2 mL) was added CDI (82.55 mg, 0.510 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the mixture was added DIPEA (98.70 mg, 0.765 mmol, 3 equiv) and 7-(difluoromethyl)-4-azaspiro[2.5]octane hydrochloride (100.62 mg, 0.510 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by silica gel column 333 58226332.1224990 / 23-003-PC / 554457 chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford 7-(difluoromethyl)-N- (3-[1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1-([2- (trimethylsilyl)ethoxy]methylpyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (140 mg, 91.71%).

[0500] [4,3-c]pyridin-6-yl]-1-([2-(trimethylsilyl)ethoxy]methylpyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (130 mg, 0.217 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature. The resulting mixture was stirred for 14h at room temperature then concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Waters®Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 55% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 6.67) to afford 7- (difluoromethyl)-N-(3-[1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4- azaspiro[2.5]octane-4-carboxamide (44.8 mg, 43.36%). LC-MS m / z 470.20 (M+H+). NMR:1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.79 (s, 1H), 9.29 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 5.90 (d, 1H), 5.62 (q, 2H), 4.23 (d, 1H), 2.91 (t, 1H), 2.33 (d, 1H), 1.92 (t, 1H), 1.65 (d, 1H), 1.47 (dt, 1H), 1.36 (dt, 1H), 1.31 – 1.23 (m, 1H), 1.26 – 1.19 (m, 1H), 0.75 (dd, 2H). 334 58226332.1224990 / 23-003-PC / 554457 Scheme 51EXAMPLE 80.7-Amino-N-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl]-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 734).

[0501] A mixture of tert- oxo- carboxylate (1, 100 mg, 444μmol, 1.00 eq.), phenylmethanamine (48.0 mg, 448 μmol, 1.01 eq.) in toluene (2 mL) was heated to 120 °C for 12 hours while removing water via a Dean-Stark trap. TLC (1:1 petroleum ether : ethyl acetate, I2 visualization) showed starting material and a new spot formed. The 335 58226332.1224990 / 23-003-PC / 554457 mixture was concentrated to give the compound tert-butyl (7E)-7-benzylimino-4- azaspiro[2.5]octane-4-carboxylate (2, 130 mg).

[0502] To a4-carboxylate(2, 130 mg, 413 μmol, 1 eq.), DMF (1.2 mmol, 95 μL, 3.0 eq.), KHF2(26 mg, 330 μmol, 0.80 eq.) in MeCN (3 mL) was added TFA (525 μmol, 39.0 μL, 1.27 eq.) dropwise at 0 °C under N2 . The reaction mixture was stirred at 0 °C for 20 minutes under N2. TMSCF3 (88 mg, 618.89 μmol, 1.5 eq.) was added dropwise at 0 °C and the mixture was stirred at 10 °C for 1 hours 40 minutes under N2. The reaction mixture was concentrated to give a residue which was purified by reversed-phase HPLC (0.1% TFA condition) to give the title compound 734-3, tert-butyl 7- (benzylamino)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxylate (3, 32.0 mg, 64.2 μmol, 15.5%) as its TFA salt. LCMS: m / z 385.1 (M+H+).1H NMR: (DMSO-d6) δ: 7.43 (d, 2H), 7.33 (m, 2H), 7.18-7.28 (m, 1H), 3.77-3.86 (m, 2H), 3.69 (br s, 1H), 3.22-3.34 (m, 1H), 2.03 (br d, 1H), 1.86 (br d, 1H), 1.49-1.62 (m, 1H), 1.40 (s, 9H), 1.28-1.36 (m, 1H), 0.94-1.03 (m, 1H), 0.73-0.80 (m, 1H), 0.58-0.70 (m, 2H).

[0503] To tert-butyl 7-(benzylamino)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxylate (3, 32.0 mg, 64.2 μmol, TFA salt) in DCM (3 mL) was added TFA (1 mL) and the reaction mixture was stirred at 15 °C for 4 hours. The reaction mixture was concentrated to give the title compound 734-4, N-benzyl-7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-amine (4, 25.0 mg, 62.8 μmol, 97.8%) as its TFA salt. LCMS:, m / z 285.1 (M+H+). 336 58226332.1224990 / 23-003-PC / 554457

[0504] A2-yl-pyrazol-4-amine (4A, 22.0 mg, 64.6 μmol, 1.03 eq.) in THF (1 mL) was added DSC (16.0 mg, 62.5 μmol, 1.00 eq.). The reaction mixture was stirred at 15 °C for 10 minutes, then TEA was added (188 μmol, 26.0 μL, 3.00 eq.) and N-benzyl-7-(trifluoromethyl)-4-azaspiro[2.5]octan-7- amine (4, 25.0 mg, 62.8 μmol, 1.00 eq., TFA salt) in THF (1 mL). The reaction mixture was stirred at 15 °C for 12 hours then concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, eluent 0 to approximately 30% ethyl acetate / petroleum ether gradient 30 mL / min) to give the title compound 734-5, 7-(benzylamino)-N-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1- tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (5, 25 mg, 61%). LCMS m / z 651.3 (M+H+).

[0505] A6-yl)-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (25 mg, 38 μmol, 1.0 eq) , Pd / C (10 mg, 10% purity) in MeOH (2 mL) was degassed and purged with H2 for 3 times, then the reaction mixture was stirred at 15 °C for 12hr under H2 (15 psi) atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reversed-phase HPLC (0.1% TFA condition) to give the title compound 734-6, 7-amino-N-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)-1-tetrahydropyran-2-yl-pyrazol-4-yl]-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (6, 5.0 mg, 23%). LCMSm / z 561.2 (M+H+).1H NMR: (DMSO-d6) δ: 9.90-10.03 (m, 1H), 9.28-9.37 (m, 1H), 8.40 (s, 1H), 8.05- 337 58226332.1224990 / 23-003-PC / 554457 8.18 (m, 1H), 7.91 (s, 1H), 5.59 (br d, 1H), 4.29 (br d, 2H), 4.06-4.14 (m, 1H), 3.96-4.04 (m, 1H), 3.74-3.85 (m, 1H), 2.27 (m, 1H), 2.15-2.22 (m, 1H), 2.07-2.13 (m, 1H), 1.90-2.03 (m, 2H), 1.80-1.89 (m, 1H), 1.57-1.69 (m, 3H), 1.38-1.46 (m, 1H), 1.20-1.26 (m, 1H), 1.08-1.18 (m, 2H), 0.93-1.07 (m, 2H), 0.90 (br m, 6H). F NMR: (CDCl3-d) δ: −83.087.

[0506] Atetrahydropyran-2-yl-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (6, 5.0 mg, 8.9 μmol, 1.0 eq.) in HCl / MeOH (2 M, 2 mL) was stirred at 15 °C for 4 hours then concentrated. The title compound 734, 7-amino-N-[3-(1-isobutylpyrazolo[4,3-c]pyridin-6-yl)- 1H-pyrazol-4-yl]-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (3.5 mg, 76%) was obtained as its HCl salt. LCMS m / z 477.3 (M+H+).1H NMR: (DMSO-d6) δ: 10.57-10.91 (m, 1H), 9.35-9.73 (m, 2H), 9.28 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 4.30 (br d, 2H), 3.73-3.88 (m, 2H), 2.17-2.29 (m, 2H), 1.79-1.94 (m, 2H), 0.98-1.34 (m, 6H), 0.87 (br d, 6H). F NMR: (CDCl3) δ: −78.876. 338 58226332.1224990 / 23-003-PC / 554457- c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (Compound 735).

[0507] To a stirred solution of methyl 6-oxopiperidine-3-carboxylate (5 g, 31.81 mmol, 1equiv) in DMF (55 mL) was added NaH (1.53 g, 63.6 mmol, 2 equiv) in portions at 0oC. The resulting mixture was stirred for 30 min at 0oC. PMBCl was added to the reaction mixture, (7.47 g, 47.72 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 14h at 60oC then diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0-100% in 40 min) to afford the title compound 735-1, methyl 1-[(4-methoxyphenyl)methyl]-6-oxopiperidine- 3-carboxylate (1.78 g (90% purity) + 2.22 g (51% purity)). 339 58226332.1224990 / 23-003-PC / 5544573-carboxylate (1.1 g, 3.97 mmol, 1 equiv) in THF (11 mL) was added methylmagnesium bromide (6.61 mL, 19.84 mmol, 5 equiv) dropwise at −78oC under nitrogen atmosphere. The resulting mixture was stirred for 14h at room temperature then diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate 100%) to afford 735-2, 5-(2- hydroxypropan-2-yl)-1-[(4-methoxyphenyl)methyl]piperidin-2-one (790 mg, 71.81%).,(8 mL) and tetrakis(propan-2-yloxy)titanium (1133.32 mg, 3.97 mmol, 1.4 equiv) at −78oC. The resulting mixture was stirred for 30 min at −78oC. To the reaction mixture was added 5-(2-hydroxypropan-2-yl)-1-[(4-methoxyphenyl)methyl]piperidin-2-one (790 mg, 2.85 mmol, 1 equiv) and THF (8 mL) at −78oC. The resulting mixture was stirred for 14h at room temperature then diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (Ethyl acetate 100%) to afford the title compound 735-3, 2-(4-[(4- methoxyphenyl)methyl]-4-azaspiro[2.5]octan-6-ylpropan-2-ol (230 mg, 27.90%). 340 58226332.1224990 / 23-003-PC / 554457

[0510] [2.5]octan-6-ylpropan-2-ol (230 mg, 0.80 mmol, 1 equiv), ACN (3 mL), H2O (1 mL) and Ceric ammonium nitrate (CAN) (4372.69 mg, 7.95 mmol, 10 equiv) at room temperature. The reaction mixture was stirred for 14h then diluted with water (100 mL) and the pH adjusted to pH 9 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 5:1) to afford the title compound 735-4, 2-(4-azaspiro[2.5]octan-6-ylpropan-2- ol (55 mg, 40.89%).-1-(oxan-2-yl)pyrazol-4-amine (44.26 mg, 0.13 mmol, 1 equiv), DMF (1 mL) and CDI (41.93 mg,0.26 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature and 2-(4-azaspiro[2.5]octan-6-ylpropan-2-ol (55 mg, 0.33 mmol, 2.5 equiv) was added in portions at room temperature. The resulting mixture was stirred at room temperature for additional 3 h then diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 5:1) to afford the title compound 735-5, 6-(2-hydroxypropan-2-yl)- 341 58226332.1224990 / 23-003-PC / 554457 N-(3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4- azaspiro[2.5]octane-4-carboxamide (30 mg, 17.24%).methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (30 mg, 0.06 mmol, 1 equiv), DCM (0.3 mL) and HCl (gas) in 1,4-dioxane (0.1 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature then diluted with water (50 mL). The pH of the mixture was adjusted to pH 9 with saturated NaHCO3(aq.) then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: mobile phase, water (0.1% FA) and ACN (5% ACN up to 20% in 8 min); Detector, UV 254 nm to generate the title compound, 6-(2-hydroxypropan-2-yl)-N-(3-[1-(2- methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (1.1 mg, 4.14%). LC-MS m / z 452 (M+1). NMR:1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.75 (s, 1H), 9.19 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.36 – 7.30 (m, 1H), 4.31 (d, 2H), 4.20 (s, 1H), 2.67 (t, 1H), 2.30 – 2.20 (m, 1H), 2.01 (t, 1H), 1.83 (d, 1H), 1.64 – 1.46 (m, 1H), 1.38 (d, 3H), 1.23 (s, 3H), 1.08 (d, 5H), 0.87 (d, 6H), 0.65 (t, 2H). 342 58226332.1224990 / 23-003-PC / 554457 Scheme 52pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4,9-diazadispiro[2.2.26.23]decane-4- carboxamide. (Compound 736).

[0513] Step 1: 1-((1-Fluorocyclobutyl)methyl)-3-iodo-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.3-Iodo-6-(4-nitro-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine (1.00 g, 2.27 mmol, 1 equiv.) was dissolved in NMP (5 mL) in a 40 mL vial. Potassium carbonate (440 mg, 3.18 mmol, 1.4 equiv.) and 1-(bromomethyl)-1-fluoro-cyclobutane (500 mg, 2.99 mmol, 1.32 equiv.) were 343 58226332.1224990 / 23-003-PC / 554457 added and the reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was allowed to cool, poured into water (40 mL), and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (40 mL), dried over MgSO4, filtered, and the solvent removed. The residue was suspended in minimal DCM and subjected to flash column chromatography (silica, Hexanes:EtOAc, 100:0 to 50:50) to obtain the 736-1 (785 mg, 66%).

[0514] nitro-1-(tetrahydro- pyran- - - ((1- Fluorocyclobutyl)methyl)-3-iodo-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H- pyrazolo[4,3-c]pyridine (350 mg, 0.665 mmol, 1 equiv.), cesium carbonate (433 mg, 1.33 mmol, 2 equiv.), 3-ethylazetidine (113 mg, 1.33 mmol, 2 equiv.), and Xantphos (38 mg, 0.067 mmol, 0.1 equiv.) were suspended in dioxane (7 mL) in a 40 mL vial and sparged with nitrogen gas. Pd2(dba)3 (30 mg, 0.033 mmol, 0.05 equiv.) was added and the mixture was heated to 100 °C for 14h. The reaction mixture was allowed to cool, poured onto Celite®, and subjected to flash column chromatography (silica, Hexanes:EtOAc, 100:0 to 0:100) to obtain 736-2 (262 mg, 82%).

[0515] Step 3:-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine.3-(3- Ethylazetidin-1-yl)-1-((1-fluorocyclobutyl)methyl)-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine (262 mg, 0.543 mmol, 1 equiv.) was dissolved in 344 58226332.1224990 / 23-003-PC / 554457 ethanol (10 mL) then sparged with nitrogen gas. Pd(OH)2on carbon (20%, 500 mg) was added, the reaction mixture was sparged with hydrogen gas, then stirred at room temperature under a balloon of hydrogen gas for 2.5 hours. The reaction mixture was sparged with nitrogen gas, filtered through Celite®, rinsed with DCM, and the solvent removed to obtain the title compound 736-3 (205 mg, 83%).

[0516] Step 4: 3- -1H-pyrazolo[4,3-c] - 1-yl)-1-((1- fluorocyclobutyl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-amine (205 mg, 0.452 mmol, 1 equiv.) was dissolved in methanol (4 mL). p- TsOH·H2O (43 mg, 0.23 mmol, 0.5 equiv.) was added and the reaction mixture was stirred at 60 °C for 8 hr. The solvent was removed and the mixture was used without further purification in the next step.

[0517] -1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4,9-diazadispiro[2.2.26.23]decane-4- carboxamide. To a solution of 3-(3-(3-ethylazetidin-1-yl)-1-((1-fluorocyclobutyl)methyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine (0.113 mmol, 1 equiv.) in DMF (1 mL) was added DIPEA (0.157 mL, 0.904 mmol, 8 equiv.) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (34.8 mg, 0.136 mmol, 1.2 equiv.). The reaction mixture was briefly sonicated then stirred at room temperature for 15 minutes. 4,9-Diazadispiro[2.2.26.23]decane (31.2 mg, 0.113 mmol, 2 345 58226332.1224990 / 23-003-PC / 554457 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DMF, filtered, and subjected to HPLC (0.1% FA, Water:MeCN, 90:10 to 0:100) to obtain the title compound 736, (20 mg, 33%).524 (M+H+) (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.69 (s, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 4.59 (d, 2H), 4.26 (t, 2H), 3.80 (t, 2H), 3.49 (s, 2H), 2.79 – 2.62 (m, 2H), 2.43 – 2.31 (m, 3H), 2.31 – 2.09 (m, 2H), 1.86 – 1.73 (m, 1H), 1.73 – 1.58 (m, 3H), 1.41 – 0.67 (m, 8H), 0.49 (s, 2H), 0.37 (s, 2H). EXAMPLE 83.7-(Difluoromethyl)-7-(2-hydroxypropan-2-yl)-N-(3-[1-(2- methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (Compound 737)346 58226332.1224990 / 23-003-PC / 554457 Scheme 53

[0518] A solution of 4-tert-butyl 7-methyl 7-(difluoromethyl)-4-azaspiro[2.5]octane-4,7-dicarboxylate (300 mg, 0.939 mmol, 1 equiv) and THF (10 mL) was stirred at 0 °C under nitrogen atmosphere. To the reaction mixture was added CH3MgBr (3M in Et2O) (3.13 mL, 9.390 mmol, 10 equiv) dropwise portions at 0 °C. The resulting mixture was stirred at room temperature for 14h then quenched with saturated NH4Cl (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3x30 mL). The residue was purified by Prep-TLC (petroleum ether / ethyl acetate 4:1) to afford the 737-2, tert-butyl 7-(difluoromethyl)-7-(2-hydroxypropan-2-yl)-4- azaspiro[2.5]octane-4-carboxylate (140 mg, 46.66%). 347 58226332.1224990 / 23-003-PC / 554457

[0519] A solution of tert-butyl 7-(difluoromethyl)-7-(2-hydroxypropan-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (140 mg, 0.438 mmol, 1 equiv) and 4 M HCl (gas) in dioxane (5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was used in the next step without further purification.

[0520] A solution of 3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-amine (50 mg, 0.147 mmol, 1 equiv) and CDI (35.72 mg, 0.220 mmol, 1.5 equiv) in DCM (2 mL) was stirred at room temperature for 1 h. To the reaction mixture were added DIPEA (94.91 mg, 0.735 mmol, 5 equiv) and 2-[7-(difluoromethyl)-4-azaspiro[2.5]octan-7- yl]propan-2-ol hydrochloride (75.12 mg, 0.294 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The residue was purified by Prep- TLC (EA 100%) to afford the title compound 737-4, 7-(difluoromethyl)-7-(2-hydroxypropan-2- yl)-N-(3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4- azaspiro[2.5]octane-4-carboxamide (70 mg, 81.37%). 348 58226332.1224990 / 23-003-PC / 554457methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (50 mg, 0.085 mmol, 1.00 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred for 1 h at rt. The residue was purified by Prep-HPLC with the following conditions: Column: Waters™ XBridge Prep C18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.1%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 36% B to 43% B in 13 min; Wave Length: 254nm / 220nm nm; RT1(min): 12.1 to afford the title compound 737, 7-(difluoromethyl)-7-(2-hydroxypropan-2-yl)-N-(3-[1-(2- methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (12.7 mg, 29.66%, 98.4%purity). LC-MS m / z 502.30 (M+H). NMR:1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.80 (s, 1H), 9.25 (s, 1H), 8.33 (s, 1H), 8.14 (d, 2H), 6.34 (t, 1H), 4.53 (s, 1H), 4.31 (d, 2H), 4.09 (d, 1H), 3.15 (t, 1H), 1.89 (s, 1H), 1.52 (d, 1H), 1.29 (td, 4H), 1.08 (s, 3H), 1.01 (s, 3H), 0.88 (d, 6H), 0.79 (dd, 3H). 349 58226332.1224990 / 23-003-PC / 554457 Scheme 54methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (Compound 738).

[0522] To a stirred solution of 4-tert-butyl 7-methyl 7-(difluoromethyl)-4-azaspiro[2.5]octane-4,7-dicarboxylate (500 mg, 1.566 mmol, 1 equiv) and THF (10 mL) was added LiAlH4 (118.84 mg, 3.132 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h then quenched with water / ice and 15% NaOH (aq) at 0 °C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3x20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 4:1) to afford the title compound 738-1, tert-butyl 7-(difluoromethyl)-7-(hydroxymethyl)-4- azaspiro[2.5]octane-4-carboxylate (320 mg, 70.15%). 350 58226332.1224990 / 23-003-PC / 554457

[0523] A solution of tert-butyl 7-(difluoromethyl)-7-(hydroxymethyl)-4-azaspiro[2.5]octane-4-carboxylate (320 mg, 1.098 mmol, 1 equiv) and 4 M HCl (gas) in 1,4-dioxane (5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was used in the next step without further purification.yl)pyrazol-4-amine (40 mg, 0.117 mmol, 1 equiv) and CDI (15.24 mg, 0.094 mmol, 0.8 equiv) in DCM (1 mL) was stirred at room temperature for 1 h. To the reaction mixture were added DIPEA (80.49 mg, 0.351 mmol, 3 equiv) and [7-(difluoromethyl)-4-azaspiro[2.5]octan-7- yl]methanol hydrochloride (53.50 mg, 0.234 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h and the residue was purified by Prep-TLC (EA 100%) to afford the title compound 738-3, 7-(difluoromethyl)-7-(hydroxymethyl)-N-(3-[1-(2- methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (50 mg, 76.31%). 351 58226332.1224990 / 23-003-PC / 554457

[0525] A solution of 7-(difluoromethyl)-7-(hydroxymethyl)-N-(3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1-(oxan-2-yl)pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (45 mg, 0.081 mmol, 1 equiv) and 4 M HCl(gas) in 1,4-dioxane (1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0....

Claims

224990 / 23-003-PC / 554457 CLAIMS1. A compound of Formula (I):or a pharmaceutically acceptableR1is (C6-C10)aryl or 5- to L is a bond, -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa-C(=O)- CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl; R1is substituted with 0, 1, 2, 3, or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, (C0-C6)alkylene-N(Ra)2,-C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, -O-(C3-C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, - 382 58226332.1224990 / 23-003-PC / 554457 O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R5, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; ring A is substituted with 0, 1, 2, 3, or 4 R4; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, (C0-C6)alkylene-N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, -O-(C3- C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R4, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; and each Ra is independently H, -C(=O)OH, (C1-C8)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, phenyl, or benzhydryl, wherein each cycloalkyl, heterocycloalkyl, phenyl, and benzhydryl portion of any Rais independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3- C6)cycloalkyl, and -O-(C3-C6)cycloalkyl; optionally wherein two Ra, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered; heterocycloalkyl; provided that when R1is thiazolyl and ring A is 3- to 14-membered heterocyclyl, then: ring A is 6- to 14-membered oxygen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group 383 58226332.1224990 / 23-003-PC / 554457 consisting of hydroxy, halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)hydroxyalkyl, or ring A is 3- to 14-membered nitrogen-containing heterocyclyl substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, cyano, -N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C0-C6)alkylene-(C1-C6)alkoxy, and (C1-C6)hydroxyalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whereineach R3is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1- C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3- C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0- C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R5, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, oxo, (C0-C6)alkylene-C(=O)ORa, - SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0- 384 58226332.1224990 / 23-003-PC / 554457 C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R4, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each Ra is independently H, (C1-C8)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, or phenyl, wherein each cycloalkyl, heterocycloalkyl and phenyl portion of any Rais independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C6)cycloalkyl, and -O-(C3- C6)cycloalkyl; optionally wherein two Ra, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, whereinR1is substituted with 0, 1, 2, 3, or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, -N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -C(=O)N(Ra)2, oxo, -C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3- C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C10)cycloalkyl, (C6-C10)aryl, (C0-C6)alkylene-(3- to 14-membered heterocycloalkyl),and 5- to 10-membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; and each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, and -O-(C1-C6)haloalkyl. 385 58226332.1224990 / 23-003-PC / 5544574. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 0, 1, or 2 R3; and each R3is independently selected from the group consisting of cyano, hydroxy, halogen, -N(Ra)2, (C1-C6)alkyl, and (C1-C6)alkoxy.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1is 5- to 10- membered heteroaryl substituted with 0, 1, 2, 3, or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, -N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -C(=O)N(Ra)2, -C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, - SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0- C6)alkylene-(3- to 10-membered heterocycloalkyl), and 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, or 3 R5; and each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, and -O-(C1-C6)haloalkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R1is ;T4, U1, U2, U3, U4, U5, and U6are independently C, CH, N, or NH; subscript n is 0, 1, 2, 3, or 4; and each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, and -O-(C1- C6)haloalkyl. 386 58226332.1224990 / 23-003-PC / 5544577. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1is: , , , ,each R3is independently hydroxy, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, - N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, - C(=O)NH2, -C(=O)NCH3, -C(=O)OH, -C(=O)OMe, -SO2-(C1-C6)alkyl, -SO2-(C3- C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 6-membered heterocycloalkyl), or 5- to 6- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, or 3 R5; and each R5is independently selected from the group consisting of cyano, oxo, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, and -O-(C1- C6)haloalkyl. 387 58226332.1224990 / 23-003-PC / 5544578. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1is ,9. The compound of any one of claims 6-8, or a pharmaceutically acceptable saltthereof, wherein each R3is independently hydroxy, halogen, cyano, (C1-C6)alkyl, (C2- C6)alkenyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, -O-(C1-C6)haloalkyl, - C(=O)NH2, -C(=O)NCH3, -SO2-CH3, -SO2-(3- to 6- membered heterocycloalkyl), (C0- C3)alkylene-(C3-C6)cycloalkyl, or (C0-C3)alkylene-(3- to 6-membered heterocycloalkyl), wherein each cycloalkyl and heterocycloalkyl portion of any R3is independently substituted with 0, 1, or 2 R5; and each R5is independently selected from the group consisting of hydroxy, halogen, oxo, (C1-C6)alkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy.

10. The compound of any one of claims 6-8, or a pharmaceutically acceptable saltthereof, wherein R3is selected from the group consisting of: 388 58226332.1224990 / 23-003-PC / 554457 ; each R5(C1-C6)haloalkyl, - wherein two R5, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; and each subscript k is independently 0, 1, 2, 3, or 4.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable saltthereof, wherein ring A is (C3-C10) carbocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1- C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, (C0-C6)alkylene-(C3- C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, whereinring A is monocyclic (C3-C7)cycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, and phenyl. 389 58226332.1224990 / 23-003-PC / 55445713. The compound of claim 11, or a pharmaceutically acceptable salt thereof, whereinring A is bicyclic (C6-C10)cycloalkyl substituted with 0, 1, or 2 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)hydroxyalkyl.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, whereinring A is phenyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, - C(=O)N(Ra)2, (C3-C6)cycloalkyl, and 4- to 6- membered heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl.

15. The compound of any one of claims 1-10, or a pharmaceutically acceptable saltthereof, wherein ring A is 3- to 14-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, - NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkoxy, 5- to 6- membered heteroaryl, and (C3-C6)cycloalkyl;16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, whereinring A is 4- to 7-membered monocyclic nitrogen- or oxygen-containing heterocycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting 390 58226332.1224990 / 23-003-PC / 554457 of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, (C0- C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, and (C0-C6)alkylene- C(=O)ORa.

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, whereinring A is 5- to 6-membered monocyclic heteroaryl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, -N(Ra)2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C2-C6)alkenyl, - C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, -C(=O)ORa, (C3-C6)cycloalkyl, and (C6-C10)aryl, wherein each cycloalkyl and aryl portion of any R4is independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, and (C1-C6)haloalkyl.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, whereinring A is 6- to 14-membered bicyclic or tricyclic heterocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, - NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, oxo, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)alkoxy, and (C3-C6)cycloalkyl.

19. The compound of claim 15, or a pharmaceutically acceptable salt thereof, whereinring A is 6- to 10-membered bicyclic fused-, spiro-, or bridge-heterocycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4is independently selected from the group consisting of cyano, 391 58226332.1224990 / 23-003-PC / 554457 halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1- C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -C(=O)-(C1-C6)alkyl, -N(Ra)2, -C(=O)N(Ra)2, -(C0- C3)alkylene-C(=O)ORa, (C0-C3)alkylene-(C3-C6)cycloalkyl, -O-(C6-C10)aryl, and (C0- C3)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, and heteroaryl portion of any R4is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy.

20. The compound of any one of claims 1-10, or a pharmaceutically acceptable saltthereof, wherein ring A is selected from the group consisting of 2 X2X3X21 X X1X3m,392 58226332.1224990 / 23-003-PC / 554457each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C2-C6)alkenyl, (C0-C6)alkylene-C(=O)(C1-C6)alkyl, - NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 10- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group 393 58226332.1224990 / 23-003-PC / 554457 consisting of cyano, hydroxy, halogen, oxo, -C(=O)N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkoxy, and (C3-C6)cycloalkyl; and subscript m is independently 0, 1, 2, 3, or 4.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, whereineach cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof, wherein L is -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa- C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein Lis -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, or -NRa-C(=O)-C(Ra)2-.

24. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein Lis -NH-, -NH-C(=O)-, -N(CH3)-C(=O)-, -NH-C(=O)-NH-, -N(CH3)-C(=O)-NH-, -NH-C(=O)- NCH3-, -NH-C(=O)-CH2-, -NH-C(=O)-CH(OCH3)-, -NH-C(=O)-O-, -NH-C(=O)-CH2-O-, - NH-C(=O)-N(cyclopropyl)-CH2-, -NH-C(=O)-N(cyclopropyl)-, -NH-C(=O)NH-CH(phenyl)-, - NH-C(=O)NH-CH(CH2CH2C(CH3)3)-, -NH-C(=O)NH-CH(tetrahydropyranyl)-, or -NH- C(=O)NH-CH2-.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein Lis -NH- or -NH-C(=O)-.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein Lis -NH-.

27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein Lis –NH-C(=O)-. 394 58226332.1224990 / 23-003-PC / 55445728. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof, wherein each Ra independently is H, (C1-C8)alkyl, (C3-C6)cycloalkyl, or phenyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, whereineach Ra independently is H, -Me, cyclopropyl, or phenyl.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, whereineach Ra independently is H or -Me.

31. The compound of claim 1 or 2, which is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein Y1and Y2are independently C, CH, or N; each R3ais independently cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)alkoxy, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, - C(=O)N(Ra)2, -C(=O)ORa, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), (C6-C10)aryl, or 5- to 10- membered heteroaryl; and optionally two R3a, together with the atoms to which they are attached, can form 5- or 6- membered heteroaryl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)ORa, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 6-membered heterocycloalkyl), and 5- to 6- membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, and heteroaryl are independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, 395 58226332.1224990 / 23-003-PC / 554457 halogen, oxo, -N(Ra)2, (C1-C6)alkyl, -O-(C1-C6)haloalkyl, (C0-C6)alkylene-(C1-C6)alkoxy, and (C1-C6)haloalkyl; and subscript n is 0, 1, 2, 3, or 4. 32.The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein ;(C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -C(=O)N(Ra)2, (C0-C3)alkylene-(C3- C6)cycloalkyl, (C0-C3)alkylene-(3- to 8- membered heterocycloalkyl), -SO2-(3- to 6- membered heterocycloalkyl), or 5- to 6- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, oxo, halogen, hydroxy, -N(Ra)2, (C1- C6)alkyl, (C1-C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; and subscript n is 0, 1, 2, 3, or 4.

33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt thereof,wherein ring A is 396 58226332.1224990 / 23-003-PC / 554457is CH, CH2, N, NH, or O; each R4is independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- C6)hydroxyhaloalkyl, -C(=O)-(C1-C6)alkyl, -N(Ra)2, -C(=O)N(Ra)2, -(C0-C3)alkylene- C(=O)ORa, -(C0-C3)alkylene-C(=O)ORa, (C0-C3)alkylene-(C3-C6)cycloalkyl, -O-(C6-C10)aryl, and (C0-C3)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, and heteroaryl portion of any R4is substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; and subscript m is 0, 1, 2, or 3.

34. The compound of any one of claims 31-33, or a pharmaceutically acceptable saltthereof, wherein L is -NH-C(=O)-.

35. The compound of any one of claims 31-34, which is a compound of Formula (III):58226332.1224990 / 23-003-PC / 554457 (III) or a pharmaceutically acceptable salt thereof, wherein each R3is independently cyano, halogen, hydroxy, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, -SO2-(C1-C6)alkyl, - SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)ORa, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(3- to 14-membered heterocycloalkyl), or 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R4ais independently cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyhaloalkyl, -N(Ra)2, -SO2-(C1-C6)alkyl, - C(=O)-(C1-C6)alkyl, -C(=O)N(Ra)2, -NRa-C(=O)(C1-C6)alkyl, -(C0-C6)alkylene-C(=O)ORa, (C0- C6)alkylene-(C3-C6)cycloalkyl, (C0-C6)alkylene-(3- to 10- membered heterocycloalkyl), (C0- C6)alkylene-(C6-C10)aryl, -O-(C6-C10)aryl, or (C0-C6)alkylene-(5- to 10- membered heteroaryl), alternatively, two R4a, together with the piperidine ring to which they are attached, form a fused, spiro, or bridged bicyclic 8- to 12- membered heterocycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, methylene, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- C6)hydroxyhaloalkyl, -N(Ra)2, -SO2-(C1-C6)alkyl, -C(=O)-(C1-C6)alkyl, -C(=O)N(Ra)2, -NRa- C(=O)(C1-C6)alkyl, -(C0-C6)alkylene-C(=O)ORa, (C0-C6)alkylene-(C3-C6)cycloalkyl, (C0- C6)alkylene-(3- to 10- membered heterocycloalkyl), (C0-C6)alkylene-(C6-C10)aryl, -O-(C6- C10)aryl, and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein the cycloalkyl, aryl, and heteroaryl are further substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1- C6)alkoxy; subscript m is 0, 1, 2, 3, or 4; and subscript n is 0, 1, 2, or 3. 398 58226332.1224990 / 23-003-PC / 55445736. The compound of claim 35, or a pharmaceutically acceptable salt thereof, whereinsubscript m is 0, 1, or 2.

37. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein;alkoxy, (C1- C6)hydroxyhaloalkyl, -C(=O)-(C1-C6)alkyl, -N(Ra)2, -C(=O)N(Ra)2, -(C0-C3)alkylene- C(=O)ORa, (C0-C3)alkylene-(C3-C6)cycloalkyl, -O-(C6-C10)aryl, and (C0-C3)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, and heteroaryl portion of any R4ais substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; and subscript m is 0, 1, or 2.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, whereineach R4ais independently selected from the group consisting of -F, -Cl, -OH, -CH3, -CH2CH3, =CH2, -CF3, -CHF2, -CH2CF3, -CH(OH)CF3, -CH2OH, -OCH3, -NH2, -NHCH3, -CH2NH2, C(=O)CH3, -C(=O)NH2, -CH2C(=O)OCH3, .

39. The compound of any one of claims 35-38, or a pharmaceutically acceptable saltthereof, wherein each R3is independently cyano, halogen, hydroxy, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, -SO2-CH3, -SO2-(3- to 6- membered heterocycloalkyl), -C(=O)NH2, -C(=O)NCH3, (C0-C3)alkylene-(C3-C6)cycloalkyl, or (C0-C3)alkylene-(3- to 6-membered heterocycloalkyl), wherein each cycloalkyl and 399 58226332.1224990 / 23-003-PC / 554457 heterocycloalkyl of any R3is independently substituted with 0, 1, or 2 R5; wherein each R5is independently selected from the group consisting of halogen, oxo, hydroxyl, (C1-C6)alkyl, (C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, whereineach R3is independently F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH(CH3)2, - CONH2, -CON(CH3)2, -CONHCH3, -SO2-CH3, , ,41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, whereineach R3is independently F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH(CH3)2, - CONH2, -CON(CH3)2, -CONHCH3, or -SO2-CH3. 400 58226332.1224990 / 23-003-PC / 55445742. The compound of claim 35, or a pharmaceutically acceptable salt thereof, whereineach R3is independently cyano, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C0-C6)alkyl-(C3-C6)cycloalkyl, or (C0-C6)alkyl-(4- to 6- membered heterocycloalkyl), wherein each cycloalkyl and heterocycloalkyl portion of any R3is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of oxo, cyano, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, -O-(C1- C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; , whereinhydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxy; L is -NH-C(=O)-; subscript m is 0, 1, or 2; and subscript n is 0, 1, or 2.

43. A compound selected from any of the compounds in Table 1, or a pharmaceuticallyacceptable salt thereof.

44. A compound selected from any of the compounds in Table 2, or a pharmaceuticallyacceptable salt thereof.

45. A compound selected from any of the compounds in Table 3, or a pharmaceuticallyacceptable salt thereof.

46. A compound selected from any of the compounds in Table 4, or a pharmaceuticallyacceptable salt thereof.

47. A compound selected from any of the compounds in Table 5, or a pharmaceuticallyacceptable salt thereof. 401 58226332.1224990 / 23-003-PC / 55445748. A compound selected from any of the compounds in Table 6, or a pharmaceuticallyacceptable salt thereof.

49. A compound selected from any of the compounds in Table 7, or a pharmaceuticallyacceptable salt thereof.

50. A compound selected from any of the compounds in Table 8, or a pharmaceuticallyacceptable salt thereof.

51. A compound selected from any of the compounds in Table 9, or a pharmaceuticallyacceptable salt thereof.

52. A pharmaceutical composition comprising the compound of any one of claims 1-51,or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

53. A method of treating a disease or disorder mediated at least in part by modulating invivo activity of PLK4 in a subject, the method comprising administering to the subject the compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 52.

54. The method of claim 53, wherein the disease or disorder is cancer.

55. A process for making a compound of Formula (I),or a pharmaceutically acceptablecomprising combining a compound of Formula S-4 and a compound of Formula S-5 to form a compound of Formula (I) 402 58226332.1224990 / 23-003-PC / 554457 wherein:P is H or a group; L1 is H, -COOH, or a leaving group; R1is (C6-C10)aryl or 5- to 14-membered heteroaryl; L is -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa-C(=O)- CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl; R1is substituted with 0, 1, 2, 3, or 4 R3; each R3is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, (C0-C6)alkylene-N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, -O-(C3-C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein 403 58226332.1224990 / 23-003-PC / 554457 two R5, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; ring A is substituted with 0, 1, 2, 3, or 4 R4; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -NRa-(C0-C6)alkylene-(3- to 6- membered heterocycloalkyl), -C(=O)N(Ra)2, -C(=O)-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), -SO2-N(Ra)2, (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6- C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of cyano, hydroxy, halogen, oxo, (C0-C6)alkylene-N(Ra)2, - C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, -O-(C3- C6)cycloalkyl, -O-(C1-C3)alkylene-(C1-C3)alkoxy, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R4, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; and each Rais independently H, -C(=O)OH, (C1-C8)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, phenyl, or benzhydryl, wherein each cycloalkyl, heterocycloalkyl, phenyl, and benzhydryl portion of any Ra is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3- C6)cycloalkyl, and -O-(C3-C6)cycloalkyl; optionally wherein two Ra, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl.

56. The process of claim 55, wherein:P is H or a protecting group; L1is H, -COOH, or a leaving group; 404 58226332.1224990 / 23-003-PC / 554457 R1is (C6-C10)aryl or 5- to 14-membered heteroaryl; L is -NRa-, -NRa-C(=O)-, -NRa-C(=O)-NRa-, -NRa-C(=O)-C(Ra)2-, -NRa-C(=O)- CH(OCH3)-, -NRa-C(=O)-O-, -NRa-C(=O)-C(Ra)2-O-, or -NRa-C(=O)NRa-C(Ra)2-; ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl, R1is substituted with 0, 1, 2, 3, or 4 R3; each R3is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0-C6)alkylene-(C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, -O-(C6- C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene-C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1- C6)alkyl, -C(=O)N(Ra)2, (C0-C6)alkylene-C(=O)ORa, -SO2-(C1-C6)alkyl, -SO2-(C3- C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0-C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0- C6)alkylene-(5- to 10- membered heteroaryl), wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R3is independently substituted with 0, 1, 2, 3, or 4 R5; optionally wherein two R3, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each R5is independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R5, together with the atom(s) to which they are attached, may form (C3- C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; ring A is substituted with 0, 1, 2, 3, or 4 R4; each R4is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C0-C6)alkylene-N(Ra)2, (C0- C6)alkylene-(C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyhaloalkyl, (C1-C6)hydroxyalkyl, - O-(C1-C6)haloalkyl, -O-(C6-C10)aryl, -O-(5-10 membered heteroaryl), (C0-C6)alkylene- C(=O)(C1-C6)alkyl, -NRa-C(=O)(C1-C6)alkyl, -C(=O)N(Ra)2, oxo, (C0-C6)alkylene-C(=O)ORa, - SO2-(C1-C6)alkyl, -SO2-(C3-C6)cycloalkyl, -SO2-(3- to 6- membered heterocycloalkyl), (C0- C6)alkylene-(C3-C10)cycloalkyl, (C0-C6)alkylene-(C6-C10)aryl, (C0-C6)alkylene-(3 to 14- membered heterocycloalkyl), and (C0-C6)alkylene-(5- to 10- membered heteroaryl), wherein 405 58226332.1224990 / 23-003-PC / 554457 each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4is independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of cyano, hydroxy, halogen, oxo, -N(Ra)2, -C(=O)N(Ra)2, (C1-C6)alkyl, (C0-C6)alkylene-(C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl; optionally wherein two R4, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl; each Rais independently H, (C1-C8)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, 3- to 8- membered heterocycloalkyl, or phenyl, wherein each cycloalkyl, heterocycloalkyl and phenyl portion of any Ra is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of hydroxy, halogen, cyano, (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C6)cycloalkyl, and -O-(C3- C6)cycloalkyl; optionally wherein two Ra, together with the atom(s) to which they are attached, may form (C3-C6)cycloalkyl or 3- to 8- membered heterocycloalkyl.

57. The process of claim 55 or 56, further comprising:(a) coupling a compound of Formula S-1 with a compound of Formula S-2 to form a compound of Formula S-3 (b) reducing Formula S-4:, wherein Lv is a leaving group.406 58226332.1

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