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WO2025111251A1 - Compounds that inhibit polo-like kinase 4 - Google Patents

Compounds that inhibit polo-like kinase 4 Download PDF

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Publication number
WO2025111251A1
WO2025111251A1 PCT/US2024/056493 US2024056493W WO2025111251A1 WO 2025111251 A1 WO2025111251 A1 WO 2025111251A1 US 2024056493 W US2024056493 W US 2024056493W WO 2025111251 A1 WO2025111251 A1 WO 2025111251A1
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Prior art keywords
alkylene
alkyl
cycloalkyl
haloalkyl
compound
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French (fr)
Inventor
Sanjay BHATTARAI
Benjamin R. BOSWELL
Trevor CHANG
David J. Cole
Heather Finlay
Paul Gillespie
Ryan L. Gonciarz
Joon Won Jeong
Nigam M. Mishra
Danny Ng
Huy Nguyen
Andrew RAUB
Justin SALVANT
John Sanders
Brian Sherer
Andre ST. AMANT
Wei Xu
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Exelixis Inc
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Exelixis Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the polo-like kinase (PLK) family of serine/threonine kinases comprises at least four known 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.
  • R 1 is (C6-C10)aryl or 5- to 14-membered heteroaryl;
  • R 1 is (C6-C10)aryl or 5- to 14-membered heteroaryl
  • ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl, wherein R 1 and 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, (C 1 -C 6 )alkyl, (C 2 ).
  • Another aspect of the present disclosure provides a method of treating or preventing conditions 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.
  • Another aspect of the present disclosure provides a medical use of compounds according 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.
  • Another aspect of the present disclosure provides a use of compounds according to Formula (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.
  • Another aspect provides pharmaceutical compositions comprising a compound of the disclosure and an excipient and/or pharmaceutically acceptable carrier. Also provided is the use 4 58226332.1 224990/23-003-PC/554457 of such compositions for treating or preventing conditions or diseases associated with enzymatic activity of PLK4.
  • Another aspect provides processes for making compounds of the disclosure. [0013]
  • the nine hydrogens are depicted in the right-hand structure.
  • a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, –CH 2 CH 2 –. 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.
  • a group “R” is as for example in the formula: then, unless otherwise defined, a reside 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.
  • the term “Cn-m” or “Cn-Cm” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbon atoms. Examples include C 1-4 , C 1 -C 4 , C 1-6 , C1-C6, and the like.
  • Alkyl refers to a branched or straight hydrocarbon chain having 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, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl.
  • Cn-m alkyl refers to an alkyl group having n to m carbon atoms. In some embodiments, alkyl refers to (C 1 -C 6 )alkyl.
  • Alkylene refers to an optionally substituted bivalent saturated aliphatic radical having 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.
  • Cn-m alkylene refers to an alkylene group having n to m carbon atoms.
  • 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.
  • Alkenyl refers to a straight or branched chain hydrocarbon having 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 and containing at least one carbon-carbon double bond.
  • the Ci alkenyl is double bonded to a carbon (i.e., methylene).
  • the chain includes 1 to 10, about 2 to 10, about 2 to 8, or about 2 to 6 carbon atoms.
  • 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.
  • ethenyl i.e., vinyl
  • propenyl i.e., butenyl
  • crotyl pentenyl
  • hexenyl hexenyl
  • heptenyl hexenyl
  • octenyl nonenyl
  • decenyl decenyl
  • cyclopentenyl
  • Alkoxy refers to a moiety of the formula –OR’, wherein R’ is an (C1-C6)alkyl moiety as defined herein.
  • C n-m alkoxy or (C n -C m ) 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.
  • Aryl refers to a monovalent six- to fourteen-membered, mono-, bi, or tri-carbocyclic ring (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.
  • 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.
  • Carbocyclyl refers to a saturated, partially unsaturated, or aromatic ring having 3 to 14 carbon atoms.
  • the carbocyclyl can be a 3 to 7 membered monocycle, 6 to 12 membered 6 58226332.1 224990/23-003-PC/554457 bicycle or polycycle.
  • the bicycle or polycycle can be a bridged-ring, fused-ring, or spiro-ring system.
  • Cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, spirocyclic, or polycyclic), including cyclized alkyl and alkenyl groups.
  • Cn-m cycloalkyl or “(C n -C m ) 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 C 3-14 cycloalkyl 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.
  • cycloalkyl includes a single saturated carbocyclic ring of three to eight ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • a cycloalkyl group can be unsubstituted or optionally substituted.
  • a substituted cycloalkyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en- 1-yl).
  • Cyano and “nitrile” refer to a group of formula –C ⁇ N, which also may be written as –CN or CN.
  • Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.
  • Haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • Cn-m haloalkyl or (Cn-Cm) haloalkyl refers to a Cn- m alkyl 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.
  • the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • the halogen atoms include fluoro atoms.
  • the haloalkyl group is a fluoroalkyl group.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like. 7 58226332.1 224990/23-003-PC/554457 [0030] “Heteroatom” refers to an atom other than carbon and hydrogen. Examples of a heteroatom include boron, phosphorus, sulfur, oxygen, and nitrogen.
  • Heterocyclyl refers to a saturated, partially unsaturated, or aromatic ring or ring system, 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.
  • 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.
  • the heterocyclyl group is an aromatic monocyclic or bicyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • heterocyclyl groups include pyridinyl, naphthyridinyl, pyridazopyrazinyl, pyridopyrazinyl, quinolinyl, quinoxalinyl, and the like.
  • 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.
  • 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).
  • 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.
  • each heteroatom is independently oxygen, sulfur, or nitrogen.
  • a bicyclic ring structure includes the fused, spiro, or bridged moiety.
  • 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, tetrahydr
  • “Hydroxyl” and “hydroxy” refer to an –OH moiety.
  • “Hydroxyalkyl” refers to an alkyl group, as defined herein, substituted with at least one hydroxy group, e.g., 1, 2, 3, or 4, hydroxy groups.
  • the term “C n-m hydroxyalkyl” or (C n -C m ) 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.
  • Haldroxyhaloalkyl refers to a haloalkyl group, as defined herein, substituted with at least 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.
  • Oxo refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, a sulfoxide or sulfone group when attached to sulfur, or an N-oxide group when attached to nitrogen.
  • Subject for the purposes of the present disclosure includes humans and any other animals, 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.
  • “Therapeutically effective amount” is an amount of a compound as described herein that, 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.
  • “Cancer” refers to cellular-proliferative disease states, including carcinomas, sarcomas, leukemias, and lymphomas.
  • “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts.” “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids as well as organic acids. “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases and organic bases. 9 58226332.1 224990/23-003-PC/554457 [0042] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • Compounds as described herein can also include all isotopes of atoms occurring in synthetic 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.
  • Protecting group refers to a chemical moiety that is suitable for preventing undesired reactions 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).
  • acyl groups such as formyl, acetyl and
  • leaving group refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • 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.
  • the leaving group is a halogen.
  • any one of the process steps or sequences disclosed and/or claimed herein can be performed under an inert gas atmosphere, more particularly under argon or nitrogen.
  • the methods of the present disclosure may be carried out as semi-continuous or continuous processes.
  • the nomenclature used in this Application is based on naming conventions adopted 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.
  • ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl;
  • R 1 is substituted with 0, 1, 2, 3, or
  • ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl, wherein R 1 and ring A are each independently substituted with 0, 1, 2, 3,
  • R1 is phenyl substituted with 0, 1, or 2 R3; and each R3 is independently selected from the group consisting of cyano, hydroxy, halogen, -N(Ra)2, (C1- C 6 )alkyl, and (C 1 -C 6 )alkoxy.
  • R1 is 14 58226332.1 224990/23-003-PC/554457 subscript n is 0, 1, 2, 3, or 4; and each R 5 is 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.
  • R3 is selected from the group consisting of: ; each R 5 (C1- C 6 )haloalkyl, -O-(C 1 -C 6 )haloalkyl, and (C 0 -C 6 )alkylene-(C 1 -C 6 )alkoxy; optionally wherein two 16 58226332.1 224990/23-003-PC/554457 R 5 , 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.
  • ring A is monocyclic (C3-C7)cycloalkyl substituted with 0, 1, 2, or 3 R 4 ; and each R 4 is independently selected from the group consisting of hydroxy, halogen, cyano, methylene, oxo, (C 1 -C 6 )alkyl, (C 0 -C 6 )alkylene-N(R a ) 2 , (C 0 -C 6 )alkylene-(C 1 -C 6 )alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -O-(C1-C6)haloalkyl, and phenyl.
  • ring A is bicyclic (C6-C10)cycloalkyl substituted with 0, 1, or 2 R 4 ; and each R 4 is independently selected from the group consisting of hydroxy, halogen, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )hydroxyalkyl.
  • ring A is selected from the group consisting of X 2 X 2 X 2 1 X 1 X 3 X 1 X 3 X 1 m , 224990/23-003-PC/554457 X 2 and X 3 are independently CH, CH2, NH, N, or O; each R 4 is 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
  • each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R 4 is 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- C 6 )alkoxy.
  • each cycloalkyl, heterocycloalkyl, and heteroaryl of any R 3 is independently substituted with 0, 1, or 2 substituents each independently selected from the group consisting of cyano, oxo, halogen, hydroxy, -N(R a ) 2 , (C 1 - C6)alkyl, (C1-C6)haloalkyl, -O-(C1-C6)haloalkyl,
  • 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.
  • each R3 is independently cyano, halogen, (C1-C6)alkyl, (C1- C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, (C 0 -C 6 )alkyl-(C 3 -C 6 )cycloalkyl, or (C 0 -C 6 )alkyl-(4- to 6- membered heterocycloalkyl), wherein each cycloalkyl and heterocycloalkyl portion of any R 3 is 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- C 6 )haloalkyl, and (C 0 -C 6 )alkylene-(C 1 -C 6 )alkoxy; , L is -NH-C(
  • At least one R3 is selected from the group consisting of: , (C 1 - C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy, -O-(C1-C3)alkylene- (C1-C3)alkoxy, or two R 5 , together with the atom(s) to which they are attached, form a 3- to 8- membered heterocycloalkyl or (C 3 -C 6 )cycloalkyl; and each subscript k is independently 0, 1, 2, 3, or 4.
  • Another aspect of the present disclosure provides compounds selected from any of the Compounds in Table 1, or a pharmaceutically acceptable salt thereof. 28 58226332.1 No. Structure No. Structure No.
  • Structure 29 58226332.1 224990/23-003-PC/554457 No. Structure No. Structure 30 58226332.1 224990/23-003-PC/554457 No. Structure No. Structure 31 58226332.1 224990/23-003-PC/554457 No. Structure No. Structure 224990/23-003-PC/554457 No. Structure No. Structure 224990/23-003-PC/554457 No. Structure No. Structure 224990/23-003-PC/554457 No. Structure No. Structure [0095] In some embodiments, one or more Compounds in Table 2 and pharmaceutically acceptable salts thereof are provided. [0096] In some embodiments, one or more Compounds in Table 3 and pharmaceutically acceptable salts thereof are provided.
  • one or more Compounds in Table 4 and pharmaceutically acceptable salts thereof are provided.
  • one or more Compounds in Table 5 and pharmaceutically acceptable salts thereof are provided.
  • one or more Compounds in Table 6 and pharmaceutically acceptable salts thereof are provided.
  • 34 58226332.1 224990/23-003-PC/554457 In some embodiments, one or more Compounds in Table 7 and pharmaceutically acceptable salts thereof are provided.
  • one or more Compounds in Table 8 and pharmaceutically acceptable salts thereof are provided.
  • one or more Compounds in Table 9 and pharmaceutically acceptable salts thereof are provided.
  • compositions comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Compounds of the present disclosure inhibit PLK4 and are thus useful in the treatment or 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.
  • 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.
  • a related aspect provides for the use of any of the compounds disclosed herein, or a pharmaceutically 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.
  • Administration of the compounds provided herein, or their pharmaceutically acceptable 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.
  • 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.
  • the compositions will typically include a conventional pharmaceutical carrier or excipient 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 58226332.1 224990/23-003-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 physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, 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.
  • compositions for rectal administration include, for example, suppositories that can be prepared 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.
  • Dosage forms for topical administration include ointments, powders, sprays, and inhalants.
  • 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.
  • the pharmaceutically acceptable 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.
  • 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 58226332.1 224990/23-003-PC/554457 Remington The Science and Practice of Pharmacy, 23rd Ed., (Academic Press 2020).
  • 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.
  • the compounds described herein, or their pharmaceutically acceptable salts are generally 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.
  • the 72 58226332.1 224990/23-003-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.
  • the compounds disclosed and claimed herein have asymmetric carbon atoms or quaternized 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.
  • 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.
  • One aspect of the present disclosure provides a process for making a compound of Formula (I), or a pharmaceutically acceptable comprises 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; L 1 is H, -COOH, or a leaving group; and R 1 , L and ring A are as defined herein.
  • Step 1 can be carried out in the presence of a suitable base, catalyst, and solvent.
  • the 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 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)- CH 2 Cl 2 adduct.
  • 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.
  • the compound of formula S-3 can be converted to the compound of formula S-5 by reduction, such as hydrogenation reaction with a catalyst including 75 58226332.1 224990/23-003-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.
  • L1 is H
  • the compound of formula S-4 and the compound 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.
  • step 3 when L1 is -COOH, the coupling between the compound of formula S-4 and the 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).
  • DCC dicyclohexylcarbodiimide
  • EDC l-(3-dirnethylarninopropyl)-3-ethylcarbodiirnide
  • BOP benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • TBTU O-
  • 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.
  • THP THP
  • SEM SEM
  • an inorganic acid an organic acid or an inorganic acid.
  • the following examples are provided for the purpose of further illustration and are not intended to limit the scope of the claimed invention.
  • Scheme 1 4- yl)-8-(trifluoromethyl)-5-azaspiro[3.5]nonane-5-carboxamide (Compound 1).
  • Step 1 tert-Butyl 8-(trifluoromethyl)-8-((trimethylsilyl)oxy)-5- azaspiro[3.5]nonane-5-carboxylate.
  • 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 58226332.1 224990/23-003-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.
  • Step 2 8-(Trifluoromethyl)-5-azaspiro[3.5]nonan-8-ol 2,2,2-trifluoroacetate.
  • 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.
  • Step 3 6-Chloro-1-isobutyl-1H-pyrazolo[4,3-c]pyridine.
  • 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.
  • NMP N- methylpyrrolidone
  • EtOAc 1-bromo-2-methyl- propane
  • Step 4 6-(1-Benzyl-4-nitro-1H-pyrazol-3-yl)-1-isobutyl-1H-pyrazolo[4,3- c]pyridine.
  • Step 5 3-(1-Isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine.
  • 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, 1 equiv.) was dissolved in DMF (1 mL) and DIPEA (8 equiv.).
  • Step 2 6-Methyl-4-azaspiro[2.5]octan-6-ol 2,2,2-trifluoroacetate.
  • tert-Butyl 6- (2-1, 0.888 mmol theo., 1 equiv.) was dissolved in a mixture of TFA (2 mL) in DCM (2 mL) and incubated for 30 min. The solvent was removed.
  • 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%).
  • reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4 x 200 mL). The mixture was filtered and concentrated under 82 58226332.1 224990/23-003-PC/554457 reduced pressure to give the title compound (40.3 g, 110 mmol, 99%) as a yellow oil.
  • Step 3 Enantiopure 7-(trifluoromethyl)-4-azaspiro[2.5]octan-7-ol.
  • 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.
  • Step 1 1-(6-Chloro-1H- 1-yl)-2-methylpropan-2-ol.
  • 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.
  • 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.
  • 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.
  • Step 4 1-(6-(4-Amino-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2- methylpropan-2-ol.
  • 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). 58226332.1 224990/23-003-PC/554457 [0167] Compound 4 was synthesized in the same fashion as Compound 1 to afford the title compound (4.2 mg, 14%).
  • Step 1 tert-Butyl 7- [2.5]octane-4-carboxylate.
  • tert-Butyl mmol, 1 equiv.) MeCN (1 mL
  • DIPEA 4.8 equiv.
  • 2,2,2-trifluoroethyl trifluoromethanesulfonate 1.8 equiv.
  • the mixture was diluted with a saturated solution of sodium bicarbonate (20 mL) and extracted with EtOAc (20 87 58226332.1 224990/23-003-PC/554457 mL).
  • Step 2 7-(2,2,2-Trifluoroethyl)-4,7-diazaspiro[2.5]octane bis(2,2,2- trifluoroacetate).
  • tert-Butyl 7- 4-carboxylate (5-1, 474 mg, 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.
  • 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. title compound (49 mg, 53%).
  • Racemic 7- 6-yl)-1H-pyrazol-4- yl)-7- - mg, 0.735 mmol) was subjected to chiral SFC (Mobile phase: 75:25, CO 2 /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%).
  • 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).
  • 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 58226332.1 224990/23-003-PC/554457 [0190] mg, 0.31 mmol, , - 2-yl- pyrazol-4-amine (prepared in a similar fashion to 4-3, 100 mg, 282 ⁇ mol, 1 equiv.) in n-BuOH (2 mL) was added TsOH (5.0 mg, 29 ⁇ mol, 0.1 equiv.).
  • Step 1 tert-Butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)- carboxylate.
  • NaIO 4 (1190 mg, 5.58 mmol, 3 equiv.
  • RuCl 3 126 mg, 0.56 mmol, 0.3 equiv.
  • MeCN 5 mL
  • 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).
  • 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.
  • Step 2 1,1-Dicyclopropyl-3-(3-(1-isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H- pyrazol-4-yl)urea. (Compound 14).
  • Step 2 6-Chloro-N4-isobutylpyridine-3,4-diamine. 102 58226332.1 224990/23-003-PC/554457
  • a solution (15-1, 10.0 g, 43.5 mmol, 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 °C.
  • 6-Chloro-1-isobutyl-1H-[1,2,3]triazolo[4,5-c]pyridine [0214] A solution of 6- (15-2, 1.0 g, 5.0 mmol, 1 equiv.) and NaNO 2 (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).
  • 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.
  • 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. NH 4 Cl (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.
  • LiAlH 4 (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).
  • 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 58226332.1 224990/23-003-PC/554457 [0231] Compound 17 was as Compound 1 beginning with (bromomethyl)cyclobutane and to (27.7 mg, 36%).
  • 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 8. mg, 0.015 mmol
  • n-BuOH 1.5 mL
  • Step 2 4, 7-Diazaspiro[2.5]octan-7-yl-(2-methylimidazo[1,2-a]pyridin-3- yl)methanone.
  • a mixture of 3-carbonyl)-4,7- diazaspiro[2.5]octane-4-carboxylate (763 mg, 2.06 mmol, 1 equiv.), HCl in MeOH (2 M, 10 mL).
  • Step 3 3-(4, 7-Diazaspiro [2.5] octan-7-ylmethyl)-2-methyl-imidazo [1, 2-a] pyridine.
  • [1,2-a]pyridin-3- yl)methanone 300 mg, 1.11 mmol, 1 equiv.
  • THF 10 mL
  • LAH 2.5 M, 0.444 mL, 1 equiv.
  • 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). to afford the title compound (9.5 mg, 45%).
  • 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).
  • Step 2 4-Benzyl-6,6-difluoro-4-azaspiro[2.5]octane.
  • EtMgBr 3 M, 14.4 mL, 42.6 mmol, 4 equiv.
  • THF 20 mL
  • Ti(Oi-Pr) 4 6.3 mL, 21.4 mmol, 2 equiv.
  • Step 3 6,6-Difluoro-4-azaspiro[2.5]octane [0265] To a solution of (450 mg, 1.90 mmol, 1 equiv.), 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).
  • 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 to obtain the title compound (8.0 mg, 17%).
  • 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).
  • Compound 26 was synthesized following the same procedure as Compound 20 to obtain the title compound (12.5 mg, 37%).
  • Step 1 1-(6-Chloro-1-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidin-2-one.
  • 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.
  • 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.
  • 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.
  • 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).
  • Step 4 6-(1-Benzyl-4-nitro-pyrazol-3-yl)-1-isobutyl-3-(3-methoxyazetidin-1- yl)pyrazolo[4,3-c]pyridine.
  • 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 N 2 for 5 mins.
  • the reaction was heated to 120 °C for 1 hour, followed by heating to 130 °C for 3 hours.
  • the mixture was poured into water (75 mL) and extracted with EtOAc (3 ⁇ 100 mL).
  • Step 5 3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1H- pyrazol-4-amine.
  • 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 N 2 was added Pd(OH)2/C (20 wt.
  • 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).
  • Step 2 3-[1-Isobutyl-3-(3-methoxyazetidin-1-yl)pyrazolo[4,3-c]pyridin-6-yl]-1- tetrahydropyran-2-yl-pyrazol-4-amine.
  • 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.
  • 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).
  • 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 58226332.1 224990/23-003-PC/554457 compound (20.3 mg, 0.042 mmol, 65%).
  • 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 was procedure as Compound 31 to give the title compound (20.9 mg, 58%).
  • Step 2 6-Chloro-3-(3-methoxyazetidin-1-yl)-1-(2,2,2-trifluoroethyl)pyrazolo[4,3- c]pyridine.
  • 6-chloro-3-iodo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine 900 mg, 2.49 mmol, 1.0 equiv.
  • 3-methoxyazetidine hydrochloride (308 mg, 2.49 mmol, 1.0 equiv.)
  • Xantphos 144 mg, 0.25 mmol, 0.10 equiv.
  • Pd 2 (dba) 3 60 mg, 0.064 mmol, 0.026 equiv.
  • Cs 2 CO 3 (1.62 g,
  • 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.
  • 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 CH 2 Cl 2 (approximately 30 mL), EtOAc (approxmately 10 mL) and the filtrate concentrated to a crude oil.
  • 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).
  • 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 ⁇ L, 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%).
  • 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 was procedure as Compound 30 to give the title compound (19.8 mg, 56%).
  • 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.
  • Intermediate 38-6 was synthesized following the same procedure as Compound 31 to give the title compound (209 mg, 69%).
  • 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
  • the reaction was gradually warmed to rt and stirred for 3 hours. Upon completion, the reaction was reverse quenched in an ice-cold satd. NaHCO 3 solution 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 (MgSO 4 ), filtered and concentrated in vacuo to a crude residue.
  • 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).
  • Step 1 6-Chloro-1-( 1H-pyrazolo[4,3-c]pyridine.
  • DMAc 3-fluorooxetan- g, 1.83 equiv.
  • NaOH 260.4 mg, 6.51 mmol, 2 equiv.
  • the mixture was stirred at 100 °C for 12hr.
  • the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (3 x 30 mL).
  • 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.
  • 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.
  • 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
  • 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.
  • 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).
  • Step 1 6-Bromo-1- [4,3-c]pyridine.
  • Step 3 3-(1-(Cyclopropylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-4-amine.
  • Step 4 3-(1-(Cyclopropylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4- amine.
  • 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.
  • 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).
  • Step 4 3-(1-Isobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine.
  • 2-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.
  • Step 2 1-Isobutyl-6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H- pyrrolo[3,2-c]pyridine [0361] 4.792 mmol, 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 K 2 CO 3 (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.).
  • Step 3 3-(1-Isobutyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-4-amine
  • (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 B 2 (OH) 4 (575 mg, 6.414 mmol, 3 equiv.) and 4-(pyridin-4-yl) pyridine (16.70 uL, 0.011 mmol, 0.005 equiv.).
  • Step 4 3-(1-Isobutyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazol-4-amine
  • 2-yl) pyrazol-4-amine 440 mg, 1.296 mmol, 1 equiv.
  • HCl(gas)in 1,4-dioxane 8 mL
  • the mixture was stirred overnight at rt.
  • the precipitated solids were collected by filtration and 151 58226332.1 224990/23-003-PC/554457 washed with MeOH (3 x 3 mL).
  • 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, 0.1 mmol, 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • Compound 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 was as Compound 1 using chiral SFC (Column Chiralpak ® IC, 4.6 mm x 150 mm, 5 ⁇ m, flow 2.5 mL/min, back pressure 100 bar, gradient 70:30 CO 2 /methanol) where peak 1 afforded the title compound (23.7 mg, 21%).
  • Compound 54 was as Compound 1.
  • Chiral ® SFC Cold Chiralpak IC, 2.5 mL/min, back pressure 100 bar, gradient 70:30 CO 2 /methanol) where peak 2 afforded the title compound (12.5 mg, 11%).
  • Compound 56 was procedure as Compound 1 using 6-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%).
  • Step 3 Tert-butyl 7-phenoxy-4-azaspiro[2.5]octane-4-carboxylate.
  • 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 using amine 24-5. The residue was concentrated, dissolved in DMF, and subjected to preparatory HPLC (H 2 O:MeCN + 0.1% formic acid, 5:95 to 100:0) to give the title compound (5.8 mg, 12%).
  • 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.
  • 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.
  • 3-(trifluoromethyl)azetidin-3-ol hydrochloride 50.4 mg, 0.284 mmol, 1.5 equiv.
  • 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.
  • 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).
  • Step 1 (6- [0412] To a 25.2 mmol, 1 equiv.) in anhydrous THF (60 mL) was added sodium hydride (1.20 g, 30.0 mmol, 1.2 equiv, 60% oil dispersion) at 0 o C. 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 MgSO 4 , filtered, and concentrated to an oil.
  • 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.
  • a c]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 120 o C 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.
  • Step 3 6-(4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H- pyrazolo[4,3-c]pyridine.
  • Step 4 3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)-1H-pyrazolo[4,3- c]pyridine.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 N 2 in 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).
  • 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 58226332.1 224990/23-003-PC/554457 mL).
  • 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.
  • 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 + ).
  • 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.
  • 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.
  • 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 ⁇ m, flow 2.5 mL/min, back pressure 100 bar, gradient 55:45 CO 2 /methanol) where peak 1 afforded Compound 253 (13.5 mg, 11%).
  • 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.
  • 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).
  • 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).
  • 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.
  • EtMgBr 3 M, 5.30 mL, 3 eq.
  • 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.
  • 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 Na 2 SO 4 , 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.
  • Step 7 6-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4- azaspiro[2.5]octane.
  • 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.
  • Step 2 2-(1-(tert-butoxycarbonyl) piperidin-4-yl)-2-cyanoacetic acid.
  • ethyl 2-cyano-2-(1- ⁇ [(2-methylprop-2-yl) oxy] carbonyl ⁇ hexahydropyridin-4-yl) acetate 634-1, 100 mg, 0.34 mmol, 1 equiv
  • MeOH MeOH
  • water 0.2 mL
  • reaction mixture was stirred at rt for 18 hours.
  • the reaction mixture was 310 58226332.1 224990/23-003-PC/554457 concentrated and subjected to FCC (Hexanes:EtOAc, 100:0 to 0:100) to give 634-3 (30 mg, 24.0%).
  • FCC Hexanes:EtOAc, 100:0 to 0:100
  • 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.
  • Step 2 tert-butyl 4-(6-chloro-1-(2, 2, 2-trifluoroethyl)-1H-pyrazolo [4, 3-c] pyridine -4-yl) piperazine-1-carboxylate.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 58226332.1 224990/23-003-PC/554457 ethanol (10 mL) then sparged with nitrogen gas.
  • 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 ⁇ H 2 O (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.
  • 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 (0.1% NH3.H2O+10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.
  • column, C18 silica gel mobile phase, MeCN in Water (0.1% NH3.H2O+10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.
  • 1,1-difluoro-2-iodo-ethane (904 mg, 4.709 mmol, 2 equiv.) was added to tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (739-1, 500 mg, 2.355 mmol, 1 equiv.), dicesium carbonate (615 mg, 4.709 mmol, 2 equiv.) and N,N-dimethylformamide (3 mL).
  • the reaction mixture was stirred for 14h at room temperature then water (10 mL) was added and the reaction mixture and extracted with ethyl acetate (2 x 15 mL).
  • Step 2 7- chloride.
  • tert-butyl 7-(2,2-difluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 739-2, 300 mg, 1.143 mmol, 1 equiv. was dissolved in dichloromethane (1 mL) and cooled to 0 o C.
  • Step 3 3-(3-cyclopropoxyazetidin-1-yl)-1-((1-fluorocyclopropyl)methyl)-6-(4- nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.1-[(1- fluorocyclopropyl)methyl]-3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3- c]pyridine (739-4, 200 mg, 0.390 mmol, 1 equiv.), 3-(cyclopropoxy)azetidine;2,2,2- trifluoroacetic acid (272 mg, 0.778 mmol, 2 equiv., 65 mass%), dicesium carbonate (385 mg, 1.181mmol,
  • Step 5 N-(3-(3-(3-cyclopropoxyazetidin-1-yl)-1-((1-fluorocyclopropyl)methyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-(2,2- difluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxamide.
  • reaction mixture was allowed to cool to rt and satd aq. NaHCO 3 solution (0.5 mL) was added and filtered through syringe filter.
  • the filtrate was purified by RP-HPLC (10-100% ACN/water/FA, product out at 65-70%) and the fractions containing 739 lyophilized, (25 mg, 28.59%).

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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 four known 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 PLK4 inhibitors. [0005] The present disclosure provides a compound according to Formula (I): or a pharmaceutically acceptable salt
Figure imgf000002_0001
[0006] In some embodiments, R1 is (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 58226332.1 224990/23-003-PC/554457 ring A is (C3-C10)carbocyclyl or 3- to 14-membered heterocyclyl; R1 is substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is 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 R5 is 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 R4 is 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 R4 is 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 58226332.1 224990/23-003-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 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 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; 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 R1 is 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, R1 is (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 R1 and 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 58226332.1 224990/23-003-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 R1 is 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 preventing conditions 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 compounds according 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 to Formula (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 the disclosure and an excipient and/or pharmaceutically acceptable carrier. Also provided is the use 4 58226332.1 224990/23-003-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 unless the context clearly dictates otherwise. [0015] When a variable is defined generically, with a number of possible substituents, each individual radical can be defined with or without the bond. For example, if R1 can 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” is
Figure imgf000006_0001
as for example in the formula: then, unless otherwise defined, a
Figure imgf000006_0002
reside 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 n and m are integers and indicate the number of carbon atoms. Examples include C1-4, C1-C4, C1-6, C1-C6, and the like. 5 58226332.1 224990/23-003-PC/554457 [0019] “Alkyl” refers to a branched or straight hydrocarbon chain having 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, 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 radical having 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 10 carbon 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 moiety as defined herein. The term “Cn-m alkoxy” 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-carbocyclic ring (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 to 14 carbon atoms. The carbocyclyl can be a 3 to 7 membered monocycle, 6 to 12 membered 6 58226332.1 224990/23-003-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 C3-14 cycloalkyl 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 optionally substituted, 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 has been replaced by a halogen atom. The term “Cn-m haloalkyl” or (Cn-Cm) haloalkyl refers to a Cn- m alkyl 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 58226332.1 224990/23-003-PC/554457 [0030] “Heteroatom” refers to an atom other than carbon and hydrogen. Examples of a heteroatom include boron, phosphorus, sulfur, oxygen, and nitrogen. [0031] “Heterocyclyl” refers to a saturated, partially unsaturated, or aromatic ring or ring system, 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 58226332.1 224990/23-003-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 one hydroxy group, e.g., 1, 2, 3, or 4, hydroxy groups. The term “Cn-m hydroxyalkyl” 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 at least 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 group when 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 other animals, 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 herein that, 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 addition salts” and “pharmaceutically acceptable base addition salts.” “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids as well as organic acids. “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases and organic bases. 9 58226332.1 224990/23-003-PC/554457 [0042] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, 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 in synthetic 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 undesired reactions 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 in heterolytic 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 be performed 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 conventions adopted 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 58226332.1 224990/23-003-PC/554457 Compounds of the Disclosure [0048] One aspect of the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable R1 is (C6-C10)aryl or 5- to
Figure imgf000012_0001
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; R1 is substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is 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 R5 is 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 R4 is 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 58226332.1 224990/23-003-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 R4 is 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 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 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; provided that when R1 is 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 58226332.1 224990/23-003-PC/554457 and pharmaceutically acceptable salts R1 is (C6-C10)aryl or 5- to 14-
Figure imgf000014_0001
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 R1 and 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 Ra independently 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 R1 is thiazolyl and ring A is 3- to 14-membered heterocyclyl, then: 13 58226332.1 224990/23-003-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 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 R3 is independently substituted with 0, 1, 2, 3, or 4 R5; and each R5 is 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 is independently 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 R3 is 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 R3 is independently substituted with 0, 1, 2, or 3 R5; and each R5 is 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 is 14 58226332.1 224990/23-003-PC/554457
Figure imgf000016_0001
subscript n is 0, 1, 2, 3, or 4; and each R5 is 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: , , , ,
Figure imgf000016_0002
each R3 is 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 58226332.1 224990/23-003-PC/554457 each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3 is independently substituted with 0, 1, 2, or 3 R5; and each R5 is 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 ,
Figure imgf000017_0001
[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 R3 is independently substituted with 0, 1, or 2 R5; and each R5 is 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
Figure imgf000017_0002
(C1- C6)haloalkyl, -O-(C1-C6)haloalkyl, and (C0-C6)alkylene-(C1-C6)alkoxy; optionally wherein two 16 58226332.1 224990/23-003-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 4 R4; and each R4 is 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 R4 is 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 R4 is 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 2 R4; and each R4 is 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 R4 is 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 R4 is 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 R4 is 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 58226332.1 224990/23-003-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 R4 is 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 R4 is 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 substituted with 0, 1, 2, or 3 R4; and each R4 is 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 R4 is 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 heterocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4 is 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 R4 is 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 R4 is independently selected from the 18 58226332.1 224990/23-003-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 R4 is 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 of X2 X 2 X2 1 X 1 X 3 X1 X3 X1 m ,
Figure imgf000020_0001
224990/23-003-PC/554457
Figure imgf000021_0001
X2 and X3 are independently CH, CH2, NH, N, or O; each R4 is 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 R4 is 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 portion of any R4 is 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 58226332.1 224990/23-003-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 pharmaceutically
Figure imgf000022_0001
Y1 and Y2 are independently C, CH, or N; each R3a is 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 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, 21 58226332.1 224990/23-003-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.
Figure imgf000023_0001
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 R3 is 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 58226332.1 224990/23-003-PC/554457 [0080] In some embodiments, ring A is ;
Figure imgf000024_0001
or each R4 is 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 R4 is 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 pharmaceutically
Figure imgf000024_0002
each R3 is 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 58226332.1 224990/23-003-PC/554457 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3 is 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 R4a 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, -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.
Figure imgf000025_0001
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 58226332.1 224990/23-003-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 R4a is 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 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,
Figure imgf000026_0001
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 R3 is independently substituted with 0, 1, or 2 R5; wherein each R5 is 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, ,
Figure imgf000026_0002
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 R3 is 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; ,
Figure imgf000027_0001
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 ,
Figure imgf000027_0002
X2 is CH, CH2, NH, N, or O; and each R4 is 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 58226332.1 224990/23-003-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 R4 is 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-
Figure imgf000028_0001
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 pharmaceutically
Figure imgf000028_0002
each R3b is 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 58226332.1 224990/23-003-PC/554457 membered heterocycloalkyl), or 5- to 10- membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl portion of any R3b is 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 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, -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 the Compounds in Table 1, or a pharmaceutically acceptable salt thereof. 28 58226332.1 No. Structure No. Structure
Figure imgf000030_0001
29 58226332.1 224990/23-003-PC/554457 No. Structure No. Structure
Figure imgf000031_0001
30 58226332.1 224990/23-003-PC/554457 No. Structure No. Structure
Figure imgf000032_0001
31 58226332.1 224990/23-003-PC/554457 No. Structure No. Structure
Figure imgf000033_0001
224990/23-003-PC/554457 No. Structure No. Structure
Figure imgf000034_0001
224990/23-003-PC/554457 No. Structure No. Structure
Figure imgf000035_0001
[0095] In some embodiments, one or more Compounds in Table 2 and pharmaceutically acceptable salts thereof are provided. [0096] In some embodiments, one or more Compounds in Table 3 and pharmaceutically acceptable salts thereof are provided. [0097] In some embodiments, one or more Compounds in Table 4 and pharmaceutically acceptable salts thereof are provided. [0098] In some embodiments, one or more Compounds in Table 5 and pharmaceutically acceptable salts thereof are provided. [0099] In some embodiments, one or more Compounds in Table 6 and pharmaceutically acceptable salts thereof are provided. 34 58226332.1 224990/23-003-PC/554457 [0100] In some embodiments, one or more Compounds in Table 7 and pharmaceutically acceptable salts thereof are provided. [0101] In some embodiments, one or more Compounds in Table 8 and pharmaceutically acceptable salts thereof are provided. [0102] In some embodiments, one or more Compounds in Table 9 and pharmaceutically acceptable salts thereof are provided. 35 58226332.1 7 , ) , ) , ) H, 5 4 1 d , ( H, s 1 1 s ( H, , s 7 1 s ,s ( , s 6 ( 4 5 ( 2 . ( 5 . 2 ( 8 . 0 3. 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 l
Figure imgf000037_0001
er ut cu r t S 1. 23 36 . 2 o 9 2 8 N 5 0 6 1 6 5 7 , ) H, , ) 7 H ) 5 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000038_0001
z/ +) +) +) m H H H S + + + M- M ( M ( M ( C 77 46 9 L 4 4 73 er ut cu r t S 1. 23 36 . 2 o 2 2 8 N 6 3 6 4 6 5 7 , s , ) , ) , ) HH H 6 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000039_0001
N , ) 6, ) N1 5 N1 93 1 1 . 3 1 1 4 . 84 . 1 1 4 86 , 1 HH H H H. . 1 d ( z/ +) +) +) m H H H S + + + M- M ( M 0 ( M 0 ( C 8 2 4 L 4 4 34 er ut cu r t S 1. 23 36 . 2 o 5 6 7 2 8 N 6 6 6 5 7 , ) H, 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/
Figure imgf000041_0001
m H H H S + + + M- M ( M ( M ( C 19 2 4 L 4 94 24 er ut cu r t S 1. 23 36 . 2 o 1 2 2 8 N 7 7 3 7 5 7 , ) 3 , 6 ) H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M- C
Figure imgf000042_0001
L 94 64 94 er ut cu r t S 1. 23 36 . 2 o 4 5 6 2 8 N 7 7 7 5 7 7, 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M-
Figure imgf000043_0001
C 8 2 9 L 74 24 84 O N H H N N r H S e N ut cu N rt S N N C3 C H 3 H 1. 23 36 . 2 o 7 8 2 8 N 7 7 9 7 5 7 , ) , s , ) H ( H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ m
Figure imgf000044_0001
+ S M + + M- ( M ( M ( C 3 . 5 2 L 59 15 6 3 4 er ut cu r t S 1. 23 36 . 2 o 0 1 2 8 N 8 8 2 8 5 7 , ) 8 , ) , ) H 0 H s H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000045_0001
z/ +) +) ) + m H H H S + + + M- M ( M ( M ( C 05 30 8 L 4 5 54 er ut cu r t S 1. 23 36 . 2 o 3 2 8 N 8 4 8 5 8 5 7 , ) , , ) H H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000046_0001
z/ +) +) +) m H H H S + + + M- M ( M M 2 ( ( C L 9 2 4 9 2 4 94 er ut cu r t S 1. 23 36 . 2 o 6 2 8 N 8 7 8 8 8 5 7 , ) , ) , ) H H H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M-
Figure imgf000047_0001
C 8 4 5 L 74 64 54 er ut cu r t S 1. 23 36 . 2 o 9 0 2 8 N 8 9 1 9 5 7 , ) , ) , , ) H H m H, ) 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S
Figure imgf000048_0001
M M M- ( ( M 8 ( C . 8 8 . 5 L 7 8 4 7 3 4 4 er ut cu r t S 1. 23 36 . 2 o 2 3 2 8 N 9 9 4 9 5 7 , ) H 5 ) 0) 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ m
Figure imgf000049_0001
+ + S + 2 . 6H M- M ( M 5+ 3 ( 9 3 C 6 2 M ( L 4 5 er ut cu r t S 1. 23 36 . 2 o 5 6 2 8 N 9 9 7 9 5 7 , ) 5 4 H , 8 3 5 ) . ) 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S
Figure imgf000050_0001
M- M ( M ( M ( C 97 0 0 L 4 14 14 er ut cu r t S 1. 23 36 . 2 o 8 9 0 2 8 N 9 9 0 1 5 , , 7 m m , s 5 ) 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M- C L
Figure imgf000051_0001
er ut cu r t S 1. 23 36 . 2 o 1 2 3 4 2 8 N 0 1 0 1 0 1 0 1 5 7 8 6 6 2 8 8 , ) 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M- C L
Figure imgf000052_0001
er ut cu r t S 1. 23 36 . 2 o 5 6 7 8 2 8 N 0 1 0 1 0 1 0 1 5 7 , ) , H s , ) 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M- C L
Figure imgf000053_0001
er ut cu r t S 1. 23 36 . 2 o 9 0 1 2 2 8 N 0 1 1 1 1 1 1 1 5 3 2 , 7 d 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000054_0001
D5, 4 ,z 9 . m D 61 ( , z . , t H 7, ) 6 H 6, ( 2 ) ) 7 MH. 001 2 H H - 1 M1 5 . 1 4, s 4, 0 ( 3 . d 0, 4d , ) ( 4 ( 3 ( ( H R1 . 2, ) 8 . R2 51 , M 8 N , ) H1 0, M. ) 7d ,) ( 3 6 5 1 HH, 1 d ( H N 6 1 HH 26 . 1 z/ +) +) m H H S + + M- M ( M 1 ( C 7 L 25 74 er ut cu r t S 1. 23 36 . 2 o 3 4 2 8 N 1 1 1 1 5 7 , s 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/
Figure imgf000056_0001
m H H H S + + + M- M ( M M 7 ( ( C L 1 7 5 7 5 4 04 er ut cu r t S 1. 23 36 . 2 o 7 2 N 1 8 9 8 1 1 1 1 1 5 7 , ) , ) , ) . H H H l 5 a 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000057_0001
/ +) ) z +) + m H H H + + S + M- M M ( ( M ( C 5 8 . 8 . L 0 70 5 4 5 05 er ut cu r t S 1. 23 36 . 2 o 0 1 2 2 8 N 2 1 2 1 2 1 5 7 , ) , Hd ( , ) H 9 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ m
Figure imgf000058_0001
S + + + M- M ( M ( M ( C 80 67 8 L 5 5 74 er ut cu r t S 1. 23 36 . 2 o 3 2 N 2 4 5 8 1 2 1 2 1 5 7 3 , 2 ) , H q 5 ( 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/
Figure imgf000060_0001
+ + + m H H H S + + + M- M ( M ( M ( C 4 8 9 L 45 15 44 er ut cu r t S 1. 23 36 . 2 o 0 1 2 2 8 N 3 1 3 1 3 1 5 , ) , ) , H H ) ) RM N H z /
Figure imgf000061_0001
+ + + m H H H S + + + M- M ( M C 9 ( M 7 ( 9 L 44 15 45 e r u t c u r t S 1. 23 36 . 2o 3 4 6 2 N 3 1 3 8 1 3 1 5 , m 4, m, RM N H z / m
Figure imgf000062_0001
S + + + M- M ( M ( M (C 5 3 7 L 35 65 95 e r u t c u r t S 1. 23 36 . 2o 7 8 9 2 8 N 3 1 3 1 3 1 5 7 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000063_0001
z/ +) +) 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 er u N t cu r t S N N C N 3 H C3 H N2 H 1 . 23 36 . 2 o 1 4 6 2 8 N 4 1 4 1 4 1 5 7 1 , 9 ) , ) H 1 H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ m
Figure imgf000064_0001
+ 5+ 5+ S M 5H 5H M- ( 5+ 5+ C 26 M ( 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 N N H N N N N er H H H N N N ut cu N N N rt S 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 8 2 N 4 9 8 1 4 1 4 1 5 7 , ) H 5 ) 4 . ) 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000065_0001
z/ +) ) m ) + H + H S + 1 + M- M ( 8H 5+ M C 3 ( 6 M ( 5 L 5 75 er ut cu r t S 1. 23 36 . 2 o 0 1 3 2 8 N 5 1 5 1 5 1 5 7 . ) , , ) , s ( H ( 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000066_0001
/ ) +) z + +) m H H H + + S + M- M ( M M ( C 8 ( 7 7 . L 15 7 3 5 06 er ut cu r t S 1. 23 36 . 2 o 4 5 6 2 8 N 5 1 5 1 5 1 5 , ) 5 , ) , 7 H 5 H m 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H
Figure imgf000067_0001
+) +) z/ +) m H + H H + + S M M- ( M M ( C 8 . ( 7 3 2 . L 7 2 9 5 6 15 er ut cu r t S 1. 23 36 . 2 o 7 8 9 2 8 N 5 1 5 1 5 1 5 7 , ) H 1 , ) , Hs , ( ) , ) H H 1 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2 R M N 1H z/ S M- C L
Figure imgf000068_0001
O N H N N H er N ut N cu r t S N N C3 C H 3 H 1. 23 36 . 2 o 0 1 2 2 N 6 1 6 3 8 1 6 1 6 1 5 7 , ) H 5 4 4 5 5 / CP-3 0 0-3 2 / 0 9 9 4 2 2
Figure imgf000069_0001
.0 , 1 ) , ) H R , ) H 1 2 M H, s , s N 1 ( ( , 8 1 s 9 H ( 2 . 4 . 7 51 8 . , ) , ) 21 HH δ 1 1, ) , t 6 ( d ( d- 2 74 O. S 51 . , 2 M) , ) DH , 1 H z , 1 , Hs ( 2 m ( M 1 . 0 0 82 . 04, ) 2 – ) ( H H R 1 0 , 3 . 1 Ms ( N0 2 , s ,) ( 8 9 6 1 H2 . 8H 17 . 0 z/ +) m H S + M- M ( C 0 L 64 er ut cu r t S 1. 23 36 . 2 o 4 2 8 N 6 1 5 224990/23-003-PC/554457 Pharmaceutical Composition and Medical Treatment or Uses [0103] Another aspect provides a pharmaceutical composition comprising any of the compounds 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 treatment or 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 a pharmaceutically 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 pharmaceutically acceptable 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 or excipient 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 58226332.1 224990/23-003-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 physiologically acceptable 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 acceptable emulsions, 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 be prepared 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, and inhalants. 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 pharmaceutically acceptable 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 58226332.1 224990/23-003-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, are generally 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 -
Figure imgf000072_0001
71 58226332.1 224990/23-003-PC/554457 Abbreviation Meaning eq or equiv Equivalent de General Sy
Figure imgf000073_0001
nthetic Methods [0116] Compounds of this invention can be made by the synthetic procedures described below. 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 58226332.1 224990/23-003-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 or quaternized 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 of single 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 General Synthetic Scheme 1 shown below. 73 58226332.1 224990/23-003-PC/554457 General Synthetic Scheme 1 A L1 P P P H
Figure imgf000075_0001
to 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 of Formula (I), or a pharmaceutically acceptable
Figure imgf000075_0002
comprises combining a compound of Formula S-4 and a compound of Formula S-5 to form a compound of Formula (I) wherein:
Figure imgf000075_0003
P is H or a protecting group; L1 is 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 58226332.1 224990/23-003-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. The 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 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 the compound of formula S-5 by reduction, such as hydrogenation reaction with a catalyst including 75 58226332.1 224990/23-003-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 the compound 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 and the 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-4 and 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 be involved. 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 not intended to limit the scope of the claimed invention. 76 58226332.1 224990/23-003-PC/554457 Synthetic Examples Scheme 1
Figure imgf000078_0001
4- 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.
Figure imgf000078_0002
[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 58226332.1 224990/23-003-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-
Figure imgf000079_0001
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-
Figure imgf000079_0002
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 58226332.1 224990/23-003-PC/554457 [0139] 6- , 1-
Figure imgf000080_0001
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-
Figure imgf000080_0002
(1-4, 0.278 mmol, 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.
Figure imgf000080_0003
224990/23-003-PC/554457 [0143] 3-(1-Isobutylpyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-amine (1-5, 0.18 mmol, 1 equiv.) 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 2
Figure imgf000081_0001
pyrazol-4- yl)-6-methyl-4-azaspiro[2.5]octane-4-carboxamide (Compound 2). [0144] Step 1: tert-Butyl 6-
Figure imgf000081_0002
octane-4-carboxylate. 80 58226332.1 224990/23-003-PC/554457 [0145] tert-Butyl 6- mg, 0.888 mmol, 1 equiv.)
Figure imgf000082_0001
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-
Figure imgf000082_0002
(2-1, 0.888 mmol theo., 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).
Figure imgf000082_0003
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 58226332.1 224990/23-003-PC/554457 Scheme 3
Figure imgf000083_0001
1H- pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 3). [0150] Step 1: tert-Butyl
Figure imgf000083_0002
oxy)-4- azaspiro[2.5]octane-4-carboxylate.
Figure imgf000083_0003
[0151] To a solution of tert-butyl 7-oxo-4-azaspiro [2.5] octane-4-carboxylate (25 g, 110 mmol, 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 58226332.1 224990/23-003-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 of
Figure imgf000084_0001
4- 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-
Figure imgf000084_0002
g, 76.8 mmol) was further 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, Evaporator Temp: 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 58226332.1 224990/23-003-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).
Figure imgf000085_0001
pyrazol-4-yl)-7-oxa-4-azaspiro[2.5]octane-4-carboxamide Compound 4. 84 58226332.1 224990/23-003-PC/554457 [0158] Step 1: 1-(6-Chloro-1H- 1-yl)-2-methylpropan-2-ol.
Figure imgf000086_0001
Figure imgf000086_0002
[0159] 6- g, was dissolved in NMP (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-
Figure imgf000086_0003
2.22 mmol, 1 equiv.), 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 58226332.1 224990/23-003-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-
Figure imgf000087_0001
[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]
Figure imgf000087_0002
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). 58226332.1
Figure imgf000087_0003
224990/23-003-PC/554457 [0167] Compound 4 was synthesized in the same fashion as Compound 1 to afford the title compound (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 EXAMPLE
Figure imgf000088_0001
4-yl)-7-(2,2,2- trifluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 5). [0168] Step 1: tert-Butyl 7-
Figure imgf000088_0002
[2.5]octane-4-carboxylate. [0169] tert-Butyl
Figure imgf000088_0003
mmol, 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 58226332.1 224990/23-003-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-
Figure imgf000089_0001
4-carboxylate (5-1, 474 mg, 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.
Figure imgf000089_0002
title compound (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 58226332.1 224990/23-003-PC/554457 Scheme 6 6-yl)-
Figure imgf000090_0001
1H-pyrazol-4-yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 6). [0174] Step 1. 7-hydroxy-N-
Figure imgf000090_0002
c]pyridin-6-yl)-1H-pyrazol-4- yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide.
Figure imgf000090_0003
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 58226332.1 224990/23-003-PC/554457 [0177] Racemic 7- 6-yl)-1H-pyrazol-4-
Figure imgf000091_0001
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 7
Figure imgf000091_0002
cubane- 1-carboxamide (Compound 7). [0178] Cubane-1-carboxylic acid (0.319 mmol, 1.5 equiv.) was dissolved in DMF (1 mL) and DIPEA (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 58226332.1 224990/23-003-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 with
Figure imgf000092_0001
neopentyl 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 was
Figure imgf000092_0002
as 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 58226332.1 224990/23-003-PC/554457 Scheme 8
Figure imgf000093_0001
4-yl)-7- (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 10). [0181] Step 1: 2-Chloro-4-
Figure imgf000093_0002
58226332.1
Figure imgf000093_0003
224990/23-003-PC/554457 [0182] 2,4-Dichloro-5-methyl-pyridine (2.01 g, 12.4 mmol, 1 equiv.), potassium hydroxide (2 equiv.), 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 was
Figure imgf000094_0001
as Compound 1 to obtain the title compound (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 9
Figure imgf000094_0002
pyrazol-4-yl)amino)nicotinamide (Compound 11). 93 58226332.1 224990/23-003-PC/554457 [0185] Step 1: Methyl 6-
Figure imgf000095_0001
[0186] A g, 3.99 mmol, 1
Figure imgf000095_0002
equiv.), 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
Figure imgf000095_0003
(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 58226332.1 224990/23-003-PC/554457 [0190] mg, 0.31
Figure imgf000096_0001
mmol, , - 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 10
Figure imgf000096_0002
2,7- naphthyridin-1(2H)-one (Compound 12). 58226332.1
Figure imgf000096_0003
224990/23-003-PC/554457 [0191] Step 1: tert-Butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)- carboxylate. [0192] To a 10
Figure imgf000097_0001
1H-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 a
Figure imgf000097_0002
2,7- 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 58226332.1 224990/23-003-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 11
Figure imgf000098_0001
c]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.
Figure imgf000098_0002
[0196] To a solution of 6-chloro-2-methyl-1H-pyrrolo[3,2-c] pyridine (1.8 g, 11 mmol, 1 equiv.) 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 58226332.1 224990/23-003-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
Figure imgf000099_0001
[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 58226332.1 224990/23-003-PC/554457 [0200] To a 6-yl] -4-
Figure imgf000100_0001
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]
Figure imgf000100_0002
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 58226332.1 224990/23-003-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]
Figure imgf000101_0001
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 12
Figure imgf000101_0002
pyrazol-4-yl)urea (Compound 14). 58226332.1
Figure imgf000101_0003
224990/23-003-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-
Figure imgf000102_0001
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).
Figure imgf000102_0002
[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 58226332.1 224990/23-003-PC/554457 Scheme 13
Figure imgf000103_0001
6-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 of
Figure imgf000103_0002
equiv.), 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 58226332.1 224990/23-003-PC/554457 [0212] A solution (15-1, 10.0 g, 43.5
Figure imgf000104_0001
mmol, 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-
Figure imgf000104_0002
(15-2, 1.0 g, 5.0 mmol, 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 58226332.1 224990/23-003-PC/554457 [0216] (15-3,
Figure imgf000105_0001
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 a
Figure imgf000105_0002
pyridin-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 58226332.1 224990/23-003-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-
Figure imgf000106_0001
(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] A
Figure imgf000106_0002
c] 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 58226332.1 224990/23-003-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).
Figure imgf000107_0001
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 58226332.1 224990/23-003-PC/554457 Scheme 14 4-
Figure imgf000108_0001
yl)spiro[cyclopropane-1,3'-indoline]-1'-carboxamide (Compound 16). [0225] Step 1: 7'-Fluorospiro
Figure imgf000108_0002
-2'-one. [0226] A solution of
Figure imgf000108_0003
equiv.) in THF (15 mL) was cooled 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 58226332.1 224990/23-003-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, 2.87
Figure imgf000109_0001
mmol, 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).
Figure imgf000109_0002
title compound (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 58226332.1 224990/23-003-PC/554457 [0231] Compound 17 was as Compound 1 beginning with
Figure imgf000110_0001
(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
Figure imgf000110_0002
- 7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 18). 109 58226332.1 224990/23-003-PC/554457 [0232] Step 1. 6-Chloro-3-(2- [1,2-a]pyrazine.
Figure imgf000111_0001
[0233] 3-
Figure imgf000111_0002
, MeCN (10 mL), 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]
Figure imgf000111_0003
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)2 110 58226332.1 224990/23-003-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-
Figure imgf000112_0001
1-(oxan-2- yl)pyrazole (18-2, 150 mg, 0.41 mmol, 1 equiv.), MeOH (3 mL) and Pd(OH)2 on 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).
Figure imgf000112_0002
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 58226332.1 224990/23-003-PC/554457 Scheme 16 -5-
Figure imgf000113_0001
. [0240] Step 1: 6-[[3-(1-
Figure imgf000113_0002
6-yl)-1H-pyrazol-4-yl]amino]-5- methyl-pyridine-3-carbonitrile.
Figure imgf000113_0003
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). 58226332.1
Figure imgf000113_0004
224990/23-003-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 EXAMPLE
Figure imgf000114_0001
pyrazol-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 58226332.1 224990/23-003-PC/554457 Scheme 18
Figure imgf000115_0001
(2- methylimidazo[1,2-a]pyridin-3-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 21). [0245] Step 1: tert-Butyl
Figure imgf000115_0002
3-carbonyl)-4,7- diazaspiro[2.5]octane-4-carboxylate. [0246] To a solution of
Figure imgf000115_0003
acid (400 mg, 2.27 mmol, 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 58226332.1 224990/23-003-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 of
Figure imgf000116_0001
3-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
Figure imgf000116_0002
[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. MgSO4 was 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 58226332.1 224990/23-003-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).
Figure imgf000117_0001
to afford 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 EXAMPLE
Figure imgf000117_0002
4- yl]indane-1-carboxamide (Compound 22). O F [0253]
Figure imgf000117_0003
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 58226332.1 224990/23-003-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 20
Figure imgf000118_0001
4- yl]-2H-pyrazolo[4,3-b]pyridin-5-amine (Compound 23). [0254] Step 1: 6-Chloro-5-
Figure imgf000118_0002
3-amine. 58226332.1
Figure imgf000118_0003
224990/23-003-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 a
Figure imgf000119_0001
amine (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 58226332.1 224990/23-003-PC/554457 [0259]
Figure imgf000120_0001
- (1-5, 14 mg, 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
Figure imgf000120_0002
-1H- pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 24). 119 58226332.1 224990/23-003-PC/554457 [0260] Step 1: 1-Benzyl-
Figure imgf000121_0001
Figure imgf000121_0002
[0261] To a stirred one g, 14.8 mmol, 1 equiv.) in THF (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.
Figure imgf000121_0003
[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 N2 atmosphere 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 58226332.1 224990/23-003-PC/554457 [0264] Step 3: 6,6-Difluoro-4-azaspiro[2.5]octane [0265] To a solution of (450 mg, 1.90 mmol, 1
Figure imgf000122_0001
equiv.), 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).
Figure imgf000122_0002
20 to obtain 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). 58226332.1
Figure imgf000122_0003
224990/23-003-PC/554457 [0268] Compound 25 was synthesized following the same procedure as Compound 20 to obtain 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
Figure imgf000123_0001
- - methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane-4-carboxamide (Compound 26).
Figure imgf000123_0002
[0269] Step 1: tert-Butyl 7-[(3-methylimidazol-4-yl)methyl]-4,7-diazaspiro[2.5]octane-4- carboxylate. 122 58226332.1 224990/23-003-PC/554457 [0270] A mixture of
Figure imgf000124_0001
(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.
Figure imgf000124_0002
[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).
Figure imgf000124_0003
[0274] Compound 26 was synthesized following the same procedure as Compound 20 to obtain the title compound (12.5 mg, 37%).1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 123 58226332.1 224990/23-003-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 was
Figure imgf000125_0001
as Compound 20 to obtain 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).
Figure imgf000125_0002
[0276] Compound 28 was synthesized following the same procedure as Compound 22 to obtain 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), 8.43
Figure imgf000125_0003
1H), 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 58226332.1 224990/23-003-PC/554457 Scheme 23
Figure imgf000126_0001
(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, 2.76 mmol, 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 58226332.1 224990/23-003-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 58226332.1 224990/23-003-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, 0.059 mmol, 45%). 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, minor tautomer), 12.84 (s, 1H), 10.81 (s, 1H), 10.60
Figure imgf000128_0001
minor 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 58226332.1 224990/23-003-PC/554457 Scheme 23
Figure imgf000129_0001
methylpropyl)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, 1.0 equiv.) 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 58226332.1 224990/23-003-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, 2.8 mmol, 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 N2 for 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 N2 in 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 N2 for 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 58226332.1 224990/23-003-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 N2 was added Pd(OH)2/C (20 wt. %)( 935 mg, 3.10 mmol, 1.64 equiv.) and the mixture degassed with N2 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 58226332.1 224990/23-003-PC/554457 Scheme 24
Figure imgf000132_0001
c]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 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, 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 58226332.1 224990/23-003-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 58226332.1 224990/23-003-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 was
Figure imgf000134_0001
procedure as Compound 31 to give 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 was
Figure imgf000134_0002
procedure as Compound 31 with the 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 58226332.1 224990/23-003-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 25
Figure imgf000135_0001
trifluoroethyl)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, 1.0 equiv.) 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 (900 mg, 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 58226332.1 224990/23-003-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 mixture degassed with N2 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, 135 58226332.1 224990/23-003-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 was
Figure imgf000137_0001
procedure as Compound 34 to afford 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 58226332.1 224990/23-003-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 was
Figure imgf000138_0001
procedure as Compound 34 to afford 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 was
Figure imgf000138_0002
procedure as Compound 30 to give 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 58226332.1 224990/23-003-PC/554457 Scheme 26
Figure imgf000139_0001
methylpropyl)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 to give 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. NaHCO3 solution 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 58226332.1 224990/23-003-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 (3 mL) under N2, was added 4-methylbenzenesulfonic acid hydrate (7.0 mg, 0.04 mmol, 0.50 equiv.) 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 the reaction stirred at 65 °C for 4 hours. The mixture was cooled, passed through a 45 μm filter and purified 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 27
Figure imgf000140_0001
pyrazol-4-yl]-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 39). 139 58226332.1 224990/23-003-PC/554457 [0328] Step 1: 6-Chloro-1-( 1H-pyrazolo[4,3-c]pyridine.
Figure imgf000141_0001
[0329] To a 1 equiv.) and
Figure imgf000141_0002
(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]
Figure imgf000141_0003
(39-1, 400 mg, 1.66 mmol, 1 equiv.), 4-nitro-1-tetrahydropyran-2-yl-pyrazole (326.4 mg, 1.66 mmol, 1 140 58226332.1 224990/23-003-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 N2 for 3 times, and then the mixture was stirred at 120 °C for 12h under N2 atmosphere. 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]
Figure imgf000142_0001
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 H2 for 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 58226332.1 224990/23-003-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.
Figure imgf000143_0001
-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]
Figure imgf000143_0002
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 58226332.1 224990/23-003-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
Figure imgf000144_0001
- - . [0338] Step 1: 6-Bromo-1- [4,3-c]pyridine.
Figure imgf000144_0002
Figure imgf000144_0003
[0339] To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (1.2 g, 6.06 mmol, 1 equiv.) in DMAc (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 58226332.1 224990/23-003-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, 2.90
Figure imgf000145_0001
mmol, 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 N2 atmosphere. 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. 58226332.1
Figure imgf000145_0002
224990/23-003-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]
Figure imgf000146_0001
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).
Figure imgf000146_0002
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-
Figure imgf000147_0001
yl)carbamoyl)-4-azaspiro[2.5]octan-7-yl)acetate (Compound 41). [0348] Step 1: 6-Bromo-1-
Figure imgf000147_0002
pyridine. 58226332.1
Figure imgf000147_0003
224990/23-003-PC/554457 [0349] To a solution of 6-bromo-1H-pyrazolo [4, 3-c] pyridine (7 g, 35.35 mmol, 1 equiv.) in CH3CN (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, 1
Figure imgf000148_0001
equiv.), 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 N2 atmosphere. 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 58226332.1 224990/23-003-PC/554457 [0353] To yl) pyrazolo [4, 3-c]
Figure imgf000149_0001
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 a
Figure imgf000149_0002
2-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 58226332.1 224990/23-003-PC/554457 [0357] 4, 26 mg, 0.1 mmol,
Figure imgf000150_0001
, 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 30
Figure imgf000150_0002
4- yl)-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 42). 149 58226332.1 224990/23-003-PC/554457 mmol, 1 equiv.) in
Figure imgf000151_0001
was 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]
Figure imgf000151_0002
4.792 mmol, 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 58226332.1 224990/23-003-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
Figure imgf000152_0001
[0363]
Figure imgf000152_0002
(2-methylpropyl) pyrrolo[3,2-c]
Figure imgf000152_0003
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]
Figure imgf000152_0004
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 58226332.1 224990/23-003-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, 0.1
Figure imgf000153_0001
mmol, 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 31
Figure imgf000153_0002
224990/23-003-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-
Figure imgf000154_0001
H N Morpholinosulfur trifluoride N DCM, -35OC to rt, 24 h TFA, DCM, H2O, r.t. (2 h)
Figure imgf000154_0002
[0369] Tert-butyl 6-
Figure imgf000154_0003
[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 58226332.1 224990/23-003-PC/554457 [0371] To 3-(1- 1H-pyrazol-4-amine (24-5, 29 mg, 0.1
Figure imgf000155_0001
, 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 32
Figure imgf000155_0002
pyrazol-4-yl]-4-azaspiro[2.5]octane-4-carboxamide (Compound 44). [0372] Step 1: Tert-butyl (4-
Figure imgf000155_0003
[4,3-c]pyridin-6-yl)-1H-pyrazol- 4-yl)carbamoyl)-4-azaspiro[2.5]octan-7-yl)carbamate. 154 58226332.1 224990/23-003-PC/554457 [0373] 5, 26 mg, 0.1 mmol,
Figure imgf000156_0001
, 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-
Figure imgf000156_0002
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 58226332.1 224990/23-003-PC/554457 Scheme 33 pyrazol-
Figure imgf000157_0001
4-yl)indoline-1-carboxamide (Compound 45). [0376] To 3-(1-isobutyl-1H- pyrazol-4-amine (1-5, 26 mg,
Figure imgf000157_0002
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.
Figure imgf000157_0003
4-yl)-7- methylene-4-azaspiro[2.5]octane-4-carboxamide (Compound 46). 156 58226332.1 224990/23-003-PC/554457 [0377] To 3-(1-isobutyl-1H- -1H-pyrazol-4-amine (1-5, 26 mg, 0.1 mmol, 1 equiv.), DCM (0.5
Figure imgf000158_0001
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-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 35
Figure imgf000158_0002
1H-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 58226332.1 224990/23-003-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 36
Figure imgf000159_0001
4- yl)-6-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 48).
Figure imgf000159_0002
[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 58226332.1 224990/23-003-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
Figure imgf000160_0001
, 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). CF3 N NH [0382] Compound 49 was
Figure imgf000160_0002
procedure as Compound 1. Chiral SFC (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 58226332.1 224990/23-003-PC/554457 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 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 was
Figure imgf000161_0001
procedure as Compound 1. Chiral SFC (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 was
Figure imgf000161_0002
procedure as Compound 1. Chiral SFC (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 58226332.1 224990/23-003-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). CF3 N NH [0385] Compound 52 was
Figure imgf000162_0001
procedure as Compound 1. Chiral SFC (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 was
Figure imgf000162_0002
as 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 58226332.1 224990/23-003-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 ®
Figure imgf000163_0001
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 was
Figure imgf000163_0002
procedure as Compound 1 using 7,7-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 58226332.1 224990/23-003-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 using
Figure imgf000164_0001
6-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 37
Figure imgf000164_0002
6-yl)- 1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 57). 163 58226332.1 224990/23-003-PC/554457 [0390] Step 1: Tert-butyl 7- 4-carboxylate.
Figure imgf000165_0001
[0391] To a solution of tert-
Figure imgf000165_0002
4-carboxylate (800.0 mg, 3.55 mmol, 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.
Figure imgf000165_0003
[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 58226332.1 224990/23-003-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 added potassium phenoxide (1.60 g,
Figure imgf000166_0001
. 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.
Figure imgf000166_0002
[0397] To a solution of 57-4 mg, in DCM (3 mL) was added TFA (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 58226332.1 224990/23-003-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 using
Figure imgf000167_0001
amine 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 was
Figure imgf000167_0002
procedure as Compound 1 using amine 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 similar processes as in Examples 1-58. Analytical data for the compounds is included in Table 2. 166 58226332.1 224990/23-003-PC/554457 Scheme 38 H N F3C N NBn NBn HCl OH
Figure imgf000168_0001
(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-
Figure imgf000168_0002
pyrazolo[4,3-c]pyridin-3-yl)-3-(trifluoromethyl)azetidin-3-ol. [0403]
Figure imgf000168_0003
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 58226332.1 224990/23-003-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)-
Figure imgf000169_0001
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)2 on 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] The
Figure imgf000169_0002
described in Scheme 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 58226332.1 224990/23-003-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
Figure imgf000170_0001
- 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). F3C N NH
Figure imgf000170_0002
[0408] The compound was synthesized following the same procedure as Compound 165 using 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 58226332.1 224990/23-003-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).
Figure imgf000171_0001
[0409] The compound was synthesized following the same procedure as Compound 166 using (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).
Figure imgf000171_0002
[0410] The compound was same procedure as Compound 166 using 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 58226332.1 224990/23-003-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 40
Figure imgf000172_0001
224990/23-003-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-
Figure imgf000173_0001
[0412] To a
Figure imgf000173_0002
25.2 mmol, 1 equiv.) in anhydrous THF (60 mL) was added sodium hydride (1.20 g, 30.0 mmol, 1.2 equiv, 60% oil dispersion) at 0 oC. 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 58226332.1 224990/23-003-PC/554457 [0414] A
Figure imgf000174_0001
c]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.
Figure imgf000174_0002
[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 58226332.1 224990/23-003-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 250
Figure imgf000175_0001
2-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 90 oC 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.
Figure imgf000175_0002
[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 58226332.1 224990/23-003-PC/554457 mixture was heated at 80 oC 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.
Figure imgf000176_0001
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 58226332.1 224990/23-003-PC/554457
Figure imgf000177_0001
6-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.
Figure imgf000177_0002
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 58226332.1 224990/23-003-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
Figure imgf000178_0001
- - - (trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide. (Compound 171) 177 58226332.1 224990/23-003-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 N2 in 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 58226332.1 224990/23-003-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 58226332.1 224990/23-003-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 58226332.1 224990/23-003-PC/554457 Table 3 Compound Structure LC-MS m/z 1H NMR No.
Figure imgf000182_0001
181 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , , 3 , , , ,
Figure imgf000183_0001
182 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , , (s, 2 , 7 d, 78 , ,
Figure imgf000184_0001
183 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , s, 7 , , 39 (s, , , 7 , , 7 (s, , 0
Figure imgf000185_0001
184 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz DMSO-d6) δ , 1 , ), ), s, , , , , , 94 m, 10 – , , 96 m, 30 – , ), , 30
Figure imgf000186_0001
185 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz DMSO-d6) δ , , , 1 d, , , 49 – , 1 65 ), 5 , , 6 , 9 ), 1
Figure imgf000187_0001
186 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 8 , , 4 33 , 1 , 8 , 0 , 4
Figure imgf000188_0001
187 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , 2 , 3 , , , , , , δ 3 72
Figure imgf000189_0001
188 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , 6 , , , d, 31 - , 9 , q, ,
Figure imgf000190_0001
189 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , 95 s, 53 δ 4 – δ 8 , , , 4
Figure imgf000191_0001
190 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , , 65 ), 7 δ 0 , δ 6 δ ,
Figure imgf000192_0001
191 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z H δ – , , d, 31 – δ 44 , 59 δ 7 ,
Figure imgf000193_0001
192 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ 38 , δ 8 d, 10 – δ 44 s, 85 δ 43 ,
Figure imgf000194_0001
193 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ 38 m, 64 – δ 9 - , 0 m, 23 , 5 30
Figure imgf000195_0001
194 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 , , 09 – , 9 , 5 3 , 1 7
Figure imgf000196_0001
195 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz DMSO-d6) δ , ), , (s, 11 , 8 , , , 5 8
Figure imgf000197_0001
196 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , d, , 3 , , , 3 , , 58 (s, , 4 6 , , 1 1 (t, ),
Figure imgf000198_0001
197 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z , 2 45 , 7 9 , ), 2 , , 1 , 7 . , 0 07
Figure imgf000199_0001
198 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz DMSO-d6) δ , 7 11 , 14 –
Figure imgf000200_0001
199 58226332.1 224990/23-003-PC/554457 Scheme 42
Figure imgf000201_0001
Example 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).
Figure imgf000201_0002
[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 58226332.1 224990/23-003-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 flash silica gel chromatography (0-80% Hex:EtOAc) to give the title compound (721.4 mg, 71.3%) as a pale yellow oil. LC-MS m/z 525 (M+H+).
Figure imgf000202_0001
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+).
Figure imgf000202_0002
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 title compound (160.4 mg, 94.7%) was taken forward without further purification. LC-MS m/z 457 (M+H+).
Figure imgf000203_0001
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 purified via 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 58226332.1 224990/23-003-PC/554457
Figure imgf000204_0001
[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.) was dissolved 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+).
Figure imgf000204_0002
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 58226332.1 224990/23-003-PC/554457
Figure imgf000205_0001
[0444] Further purification via reverse-phase chromatography (EZ Thermo Fisher Hypersil GOLD™ 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 253 using 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
Figure imgf000205_0002
(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 58226332.1 224990/23-003-PC/554457 [0446] 2H-
Figure imgf000206_0001
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 100 oC. 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]
Figure imgf000206_0002
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 58226332.1 224990/23-003-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 100 oC. 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]
Figure imgf000207_0001
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 Na2SO4 and 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 58226332.1 224990/23-003-PC/554457
Figure imgf000208_0001
(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 58226332.1 224990/23-003-PC/554457
Figure imgf000209_0001
(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 NaHCO3 solution (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 with saturated 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. Compounds 256-378 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 58226332.1 224990/23-003-PC/554457 Table 4 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph
Figure imgf000210_0001
209 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000211_0001
210 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000212_0001
211 58226332.1 224990/23-003-PC/554457 Compound LC-MS Chiral Structure 1H NMR No. m/z Chromatograph 2H) 1.36 (d 5H) 1.23 m m
Figure imgf000213_0001
212 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000214_0001
213 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000215_0001
214 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000216_0001
215 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000217_0001
216 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1.71 (s 2H) 1.40 (s
Figure imgf000218_0001
217 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 3H) 1.31 – 1.27 (m
Figure imgf000219_0001
218 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000220_0001
219 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz m, 0 Rt m, 0 Rt
Figure imgf000221_0001
220 58226332.1 224990/23-003-PC/554457 Compound LC-MS Chiral Structure 1H NMR No. m/z Chromatograph 1H NMR (400 MHz 6 m, 0 k
Figure imgf000222_0001
221 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 6 m, 0 k
Figure imgf000223_0001
222 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000224_0001
223 58226332.1 224990/23-003-PC/554457 Compound LC-MS Chiral Structure 1H NMR No. m/z Chromatograph 1H NMR (400 MHz 6 m, 5 2, m 5, ar n
Figure imgf000225_0001
224 58226332.1 224990/23-003-PC/554457 Compound LC-MS Chiral Structure 1H NMR No. m/z Chromatograph 1H NMR (400 MHz m 5, ar n
Figure imgf000226_0001
225 58226332.1 224990/23-003-PC/554457 Compound LC-MS Chiral Structure 1H NMR No. m/z Chromatograph 1H NMR (400 MHz e: : e: : m 5, ar n k
Figure imgf000227_0001
226 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz m 5, ar n m, 0
Figure imgf000228_0001
227 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz m, 0
Figure imgf000229_0001
228 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph H 1H NMR (400 MHz
Figure imgf000230_0001
229 58226332.1 224990/23-003-PC/554457 Compound LC-MS Chiral Structure 1H NMR No. m/z Chromatograph 1H NMR (400 MHz m 5, ar n m 5, ar n
Figure imgf000231_0001
230 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000232_0001
231 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000233_0001
232 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000234_0001
233 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 4H) 0.56 (dd 2H)
Figure imgf000235_0001
234 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000236_0001
235 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000237_0001
236 58226332.1 224990/23-003-PC/554457 Compound LC-MS 1 Chiral Structure H NMR No. m/z Chromatograph 1H NMR (400 MHz
Figure imgf000238_0001
237 58226332.1 224990/23-003-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-
Figure imgf000239_0001
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 1 using 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+).
Figure imgf000239_0002
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 58226332.1 224990/23-003-PC/554457 [0455]
Figure imgf000240_0001
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+).
Figure imgf000240_0002
[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 58226332.1 224990/23-003-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+).
Figure imgf000241_0001
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 title compound (12 mg, 61%) after lyophilization. LC-MS m/z 567.3 (M+H+). 240 58226332.1 224990/23-003-PC/554457
Figure imgf000242_0001
yl)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 title compound (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 58226332.1 224990/23-003-PC/554457 Scheme 44
Figure imgf000243_0001
pyrrolo[3,2-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 381).
Figure imgf000243_0002
[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 58226332.1 224990/23-003-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%).
Figure imgf000244_0001
-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 58226332.1 224990/23-003-PC/554457 [0461]
Figure imgf000245_0001
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%).
Figure imgf000245_0002
-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 58226332.1 224990/23-003-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.
Figure imgf000246_0001
(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 58226332.1 224990/23-003-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).
Figure imgf000247_0001
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]+
Figure imgf000247_0002
(2- fluoro-2-methyl-propyl)pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]-N-methyl-carbamate. A 246 58226332.1 224990/23-003-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]+
Figure imgf000248_0001
- 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 58226332.1 224990/23-003-PC/554457 [0467] 3-yl]-1-(2- fluoro-2-
Figure imgf000249_0001
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 58226332.1 224990/23-003-PC/554457
Figure imgf000250_0001
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 and 384).
Figure imgf000250_0002
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 58226332.1 224990/23-003-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 100 oC. 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]
Figure imgf000251_0001
- 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 58226332.1 224990/23-003-PC/554457 The reaction mixture was stirred at 60 oC 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 58226332.1 224990/23-003-PC/554457 Table 5 Compound LC-MS Structure 1H NMR No. m/z
Figure imgf000253_0001
252 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, (t,
Figure imgf000254_0001
253 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z ), ), , 9 , ), , , m, 50 –
Figure imgf000255_0001
254 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z (t, 9 ), ), 9 ),
Figure imgf000256_0001
255 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z – , r t, t, s,
Figure imgf000257_0001
256 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s,
Figure imgf000258_0001
257 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z t, ), ),
Figure imgf000259_0001
258 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z – t s, ), ), – – – –
Figure imgf000260_0001
259 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, – – ) , ), ), )
Figure imgf000261_0001
260 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, 7 m, ,
Figure imgf000262_0001
261 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z ), ), , ), s,
Figure imgf000263_0001
262 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z (t, 5 (t, , 7 ), - 6
Figure imgf000264_0001
263 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z – - ), ), d, s,
Figure imgf000265_0001
264 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, ), – – ),
Figure imgf000266_0001
265 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z , , ), , –
Figure imgf000267_0001
266 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z ), ), ), m, ), m,
Figure imgf000268_0001
267 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z ), ), ), (t, ),
Figure imgf000269_0001
268 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, ), – – 1 s, s, ,
Figure imgf000270_0001
269 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 7 ), t, , 8 – – , ), d, 4 , , – 31 , 2
Figure imgf000271_0001
270 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 2 ), – – ). s, d, , ), 2 4 – 6 3 ), ), , .
Figure imgf000272_0001
271 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1 – ), , ), – ), s,
Figure imgf000273_0001
272 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, s, ), , . ), , . (t, 3 1 7 9
Figure imgf000274_0001
273 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z – d, ). 9 ). s, s,
Figure imgf000275_0001
274 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 0 ), 3 , , , , , – ), ), ), ). s, – – – ),
Figure imgf000276_0001
275 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z – – m, s, 3 s,
Figure imgf000277_0001
276 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 2 – , , 2 m, 4 s, , , , , 6 ), 9 – – – – 9
Figure imgf000278_0001
277 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1H NMR (400 MHz Methanol-d4) δ 884 – – – – 1 – 2 8 8 1 0 , m,
Figure imgf000279_0001
278 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 2 – , , 9 05 ), – – , – 9 4 9 – t,
Figure imgf000280_0001
279 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1H NMR (400 MHz DMSO-d ) δ 1283 2 ),
Figure imgf000281_0002
Figure imgf000281_0001
- - c]pyridin-6-yl)-1H-pyrazol-4-yl)-4-azaspiro[2.5]octane-4-carboxamide (Compound 512). 280 58226332.1 224990/23-003-PC/554457 [0473] Step 1: 1-
Figure imgf000282_0001
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-
Figure imgf000282_0002
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+). 58226332.1
Figure imgf000282_0003
224990/23-003-PC/554457 [0475] Step 3: 1-Benzyl-6-oxo-1,4,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate. 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 blue liquid. LC-MS m/z 235.9 (M+H+). [0476] Step 4: 1-
Figure imgf000283_0001
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 N2 atmosphere. 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 give compound 512-5 (2.1 g, 6.2 mmol, 93%) as yellow oil. LC-MS m/z 338.1 (M+H+). 282 58226332.1 224990/23-003-PC/554457 [0477] Step 5: 1-
Figure imgf000284_0001
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 H2 for 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:
Figure imgf000284_0002
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+). 58226332.1
Figure imgf000284_0003
224990/23-003-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 H2 for 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%) as yellow oil. LC-MS m/z 262.1 (M+H+). [0480] Step 8: 6-
Figure imgf000285_0001
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 the title compound (58.9 mg, 20%) as a white solid. LC-MS m/z 178.1 (M+H+).
Figure imgf000285_0002
- - 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 58226332.1 224990/23-003-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 515-635 in 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. Structure 1H NMR m/z s, 8 ), s, 1 8 δ 1 – m, m,
Figure imgf000286_0001
285 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ 16 ). d, , , δ , 1 . δ 90
Figure imgf000287_0001
286 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ , δ , ), – , , δ , s, ). s, 6
Figure imgf000288_0001
287 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z s, 5 ), s, 5 ), s, 6 , s, 9 ), m, 7 ),
Figure imgf000289_0001
288 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 s, 3 – s, 7 m, s, 4 6 ),
Figure imgf000290_0001
289 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z – m, 6 9 s, s, 5 s, , . s, , , 7 3
Figure imgf000291_0001
290 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 m, , , , s, 14 , s, , 4 –
Figure imgf000292_0001
291 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 3 – , 5 4 5 – t, s, 7 , s, 7 , , 6 s, m,
Figure imgf000293_0001
292 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z s, m, s, 2 (t, s, 2 (t, s, 8 ), m, s, –
Figure imgf000294_0001
293 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz DMSO d ) δ s, 1 – 5 s, 4 ), s, 2 , s, 9 ), s, 5
Figure imgf000295_0001
294 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z s, 6 7 5 ), s, 3 ), s, 4 ), s, 4 ), s, 4 ,
Figure imgf000296_0001
295 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz DMSO-d6) δ s, 4 , m, 1 ), s, 3 9 ), s, 4 3 , s, s, 2 ),
Figure imgf000297_0001
296 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR 4 MH DM s, 4 – s, 6 , 2 ), s, 5 - s, 7 ,
Figure imgf000298_0001
297 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z s, 1 – s, 7 , s, 4 s, 4 – s, 9
Figure imgf000299_0001
298 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ s, 5 , 8 . s, 5 , 8 . s, 9 – m, s, 9 – m,
Figure imgf000300_0001
299 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H 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 2
Figure imgf000301_0001
300 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 s, 2 – m, s, 1 – m, s, 9 – m, s, 9 – m, 2 ot nt
Figure imgf000302_0001
301 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 s, 1 36 . ) s, 3 , s, , , 8 – δ 2 ), 1
Figure imgf000303_0001
302 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ 1 s, 5 δ 3 ), , 33 δ 8 – , δ 1 δ 9
Figure imgf000304_0001
303 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ 4 ), δ m, s, , 8 – m, δ 4 δ ,
Figure imgf000305_0001
304 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z δ m, δ , δ δ δ –
Figure imgf000306_0001
305 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z s, 0 m, r s, 3 , s, 0 m, r s, 0 m, r δ , 6 , 3
Figure imgf000307_0001
306 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz Methanol-d4) δ 4 , 3 ), m, s, 0 m, r s, 3 , , 5 ), m,
Figure imgf000308_0001
307 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1H NMR (400 MHz CDCl3) δ , 8 ), m, , 8 ), m, δ δ , 4 – s, 4 m,
Figure imgf000309_0001
308 58226332.1 224990/23-003-PC/554457 LC-MS Compound No. Structure 1H NMR m/z 1 s, 4 m,
Figure imgf000310_0003
Scheme 47
Figure imgf000310_0001
- - 6-yl)-1H-pyrazol-4-yl)-2-cyano-2-(piperidin-4-yl)acetamide (Compound 634). 58226332.1
Figure imgf000310_0002
224990/23-003-PC/554457 [0483] Step 1: tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl) piperidine-1-carboxylate.To a solution 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 H2 at 40 oC for 2 hours. The reaction mixture was filtered through Celite®, and the solvent removed to obtain 634-1 (100 mg, 49.7%).
Figure imgf000311_0001
[0484] Step 2: 2-(1-(tert-butoxycarbonyl) piperidin-4-yl)-2-cyanoacetic acid. To a solution 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 20 oC 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%).
Figure imgf000311_0002
[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 58226332.1 224990/23-003-PC/554457 concentrated and subjected to FCC (Hexanes:EtOAc, 100:0 to 0:100) to give 634-3 (30 mg, 24.0%). [0486]
Figure imgf000312_0001
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 50 oC 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%).
Figure imgf000312_0002
[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 58226332.1 224990/23-003-PC/554457
Figure imgf000313_0001
Figure imgf000313_0003
- - pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)propanamide (Compound 635).
Figure imgf000313_0002
[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 58226332.1 224990/23-003-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%).
Figure imgf000314_0001
[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 80 oC 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%).
Figure imgf000314_0002
[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 58226332.1 224990/23-003-PC/554457 (0.15 eq), 2,2-dimethylpropanoic acid (0.3 eq) and K2CO3 (3.0 eq). The reaction mixture was stirred at 110 oC 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%).
Figure imgf000315_0001
[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%).
Figure imgf000315_0002
[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 58226332.1 224990/23-003-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 50 oC 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%).
Figure imgf000316_0001
[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 50 oC 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 58226332.1 224990/23-003-PC/554457 Table 7 Compound LC-MS Structure 1H NMR No. m/z ), , ), , ), t, q,
Figure imgf000317_0001
316 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 2 t, s, d, 6 s, 6 - r, 2 s, ,
Figure imgf000318_0001
317 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 5 d, , 7 ), , d, m, ), , 6 s, , 6 s, 33 d,
Figure imgf000319_0001
318 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 5 s, , . d, , – m, s, d, , , d, d, d,
Figure imgf000320_0001
319 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1H NMR (400 MHz DMSO-d ) δ 1322 ), d, d, – – – s, e 42 , 15 , , p, ), ,
Figure imgf000321_0001
320 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1H NMR 400 MH DMSO d δ 1297 d, 4 s, d, 62 ), s, d, d, 5 e 5 8 9
Figure imgf000322_0001
321 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H 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,
Figure imgf000323_0001
322 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1 ), d, – , d, d, ), d, t, s, e ), 4 3 6 8
Figure imgf000324_0001
323 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1H NMR (400 MHz DMSO-d6) δ 13.06 t, – – , , e 1 ), 2 , 7 5 ), –
Figure imgf000325_0001
324 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1H NMR (400 MHz DMSO-d6) δ 12.95 t, d, , d, d, t, H) d,
Figure imgf000326_0001
325 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1 s, – d, d, d, d, 39 4 d, 8 d, s, 4
Figure imgf000327_0001
326 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 5 s, , , ), – , , .
Figure imgf000328_0001
327 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z s, 8 d, 0 s, d, 3 – ), 08 s,
Figure imgf000329_0001
328 58226332.1 224990/23-003-PC/554457 Compound LC-MS Structure 1H NMR No. m/z 1 9 s, , , 2 s, , 3 s, 2 , 9 (t,
Figure imgf000330_0001
329 58226332.1 224990/23-003-PC/554457 Scheme 49
Figure imgf000331_0001
- 1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (Compound 732).
Figure imgf000331_0002
[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 58226332.1 224990/23-003-PC/554457
Figure imgf000332_0001
[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.
Figure imgf000332_0002
[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.
Figure imgf000332_0003
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]
Figure imgf000333_0001
- (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 58226332.1 224990/23-003-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 50
Figure imgf000334_0001
6- 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 58226332.1 224990/23-003-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]
Figure imgf000335_0001
[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 58226332.1 224990/23-003-PC/554457 Scheme 51
Figure imgf000336_0001
EXAMPLE 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).
Figure imgf000336_0002
[0501] A mixture of tert- oxo- carboxylate (1, 100 mg, 444 μmol, 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 58226332.1 224990/23-003-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 a
Figure imgf000337_0001
4-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).
Figure imgf000337_0002
[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 58226332.1 224990/23-003-PC/554457 [0504] A
Figure imgf000338_0001
2-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] A
Figure imgf000338_0002
6-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 58226332.1 224990/23-003-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] A
Figure imgf000339_0001
tetrahydropyran-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 58226332.1 224990/23-003-PC/554457
Figure imgf000340_0001
- c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4-carboxamide (Compound 735).
Figure imgf000340_0002
[0507] To a stirred solution of methyl 6-oxopiperidine-3-carboxylate (5 g, 31.81 mmol, 1 equiv) in DMF (55 mL) was added NaH (1.53 g, 63.6 mmol, 2 equiv) in portions at 0 oC. The resulting mixture was stirred for 30 min at 0 oC. 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 58226332.1 224990/23-003-PC/554457
Figure imgf000341_0001
3- 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 −78 oC 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%).
Figure imgf000341_0002
, (8 mL) and tetrakis(propan-2-yloxy)titanium (1133.32 mg, 3.97 mmol, 1.4 equiv) at −78 oC. The resulting mixture was stirred for 30 min at −78 oC. 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 −78 oC. 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 58226332.1 224990/23-003-PC/554457 [0510]
Figure imgf000342_0001
[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%).
Figure imgf000342_0002
-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 58226332.1 224990/23-003-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%).
Figure imgf000343_0001
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 58226332.1 224990/23-003-PC/554457 Scheme 52
Figure imgf000344_0001
pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-4,9-diazadispiro[2.2.26.23]decane-4- carboxamide. (Compound 736).
Figure imgf000344_0002
[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 58226332.1 224990/23-003-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-
Figure imgf000345_0001
(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:
Figure imgf000345_0002
-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 58226332.1 224990/23-003-PC/554457 ethanol (10 mL) then sparged with nitrogen gas. Pd(OH)2 on 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-
Figure imgf000346_0001
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]
Figure imgf000346_0002
-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 58226332.1 224990/23-003-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)
Figure imgf000347_0001
346 58226332.1 224990/23-003-PC/554457 Scheme 53
Figure imgf000348_0001
[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 58226332.1 224990/23-003-PC/554457
Figure imgf000349_0001
[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.
Figure imgf000349_0002
[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 58226332.1 224990/23-003-PC/554457
Figure imgf000350_0001
methylpropyl)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 58226332.1 224990/23-003-PC/554457 Scheme 54
Figure imgf000351_0001
methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4-azaspiro[2.5]octane-4- carboxamide (Compound 738).
Figure imgf000351_0002
[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 58226332.1 224990/23-003-PC/554457
Figure imgf000352_0001
[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.
Figure imgf000352_0002
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 58226332.1 224990/23-003-PC/554457
Figure imgf000353_0001
[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 (0.1% NH3.H2O+10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in compound 738, 7-(difluoromethyl)-7- (hydroxymethyl)-N-(3-[1-(2-methylpropyl)pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl-4- azaspiro[2.5]octane-4-carboxamide (6.2 mg, 98.4% purity). LC-MS m/z 474.30 (M+1).1H NMR: (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.85 (s, 1H), 9.22 (s, 1H), 8.33 (d, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 6.12 – 5.65 (m, 1H), 5.01 (t, 1H), 4.31 (d, 2H), 3.94 (s, 1H), 3.68 (s, 2H), 2.38 – 2.15 (m, 1H), 1.94 (s, 1H), 1.46 (m, 3H), 1.23 (m, 3H), 0.88 (m, 8H). 352 58226332.1 224990/23-003-PC/554457 Scheme 55 F Br O O H .HCl F F
Figure imgf000354_0001
pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(2,2-difluoroethyl)-4,7- diazaspiro[2.5]octane-4-carboxamide (Compound 739). 58226332.1
Figure imgf000354_0002
224990/23-003-PC/554457 [0526] Step 1: tert-butyl 7-(2,2-difluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate. In a 40 ml scintillation vial, 1,1-difluoro-2-iodo-ethane (904 mg, 4.709 mmol, 2 equiv.) was added to tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (739-1, 500 mg, 2.355 mmol, 1 equiv.), dicesium carbonate (615 mg, 4.709 mmol, 2 equiv.) and N,N-dimethylformamide (3 mL). The reaction mixture was stirred for 14h at room temperature then water (10 mL) was added and the reaction mixture and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with water (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (739-2, 300 mg, 46%) which was used in the next step without further purification. LC-MS m/z 277.2 (M+H+). [0527] Step 2: 7-
Figure imgf000355_0001
chloride. In a 40 mL scintillation vial, tert-butyl 7-(2,2-difluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (739-2, 300 mg, 1.143 mmol, 1 equiv.) was dissolved in dichloromethane (1 mL) and cooled to 0oC. Hydrogen chloride (2 mL, 8 mmol, 4 mol/L) was added slowly and reaction mixture was allowed to warm to rt and stirred for 2h then the reaction mixture was concentrated under high vacuum to yield the title compound (739-3, 180 mg, 38.47 %) was obtained which was used for the next step without further purification. LC-MS m/z 177.3 (M+H+). 58226332.1
Figure imgf000355_0002
224990/23-003-PC/554457 [0528] Step 3: 3-(3-cyclopropoxyazetidin-1-yl)-1-((1-fluorocyclopropyl)methyl)-6-(4- nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridine.1-[(1- fluorocyclopropyl)methyl]-3-iodo-6-(4-nitro-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3- c]pyridine (739-4, 200 mg, 0.390 mmol, 1 equiv.), 3-(cyclopropoxy)azetidine;2,2,2- trifluoroacetic acid (272 mg, 0.778 mmol, 2 equiv., 65 mass%), dicesium carbonate (385 mg, 1.181mmol, 3 equiv.), and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl- phosphane (23 mg, 0.0397 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (18 mg, 0.019 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 100 oC for 14h then allowed to cool to room temperature. Water (15 mL) was added to the reaction mixture and then extracted with ethyl acetate (2 x 15 mL). The combined organic portions were washed with brine (10 mL), dried over anhy. sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (12G Redisep® column) using Hexanes/ethyl acetate (30- 100%) as eluent to obtain the title compound (739-5, 200 mg, 92.66%). LC-MS m/z 498.2 (M+H+). [0529]
Figure imgf000356_0001
methyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine. A solution of 3-[3-(cyclopropoxy)azetidin-1-yl]-1-[(1-fluorocyclopropyl)methyl]-6-(4-nitro-1- tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[4,3-c]pyridine (739-5, 200 mg, 0.401mmol, 1 equiv.), and zinc (262 mg, 10 equiv.) in methanol (4 mL) and satd ammonium hydrochloride (1 mL) in water was stirred for 1h at room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (5 mL). The filtrate was concentrated under reduced pressure and then diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over 355 58226332.1 224990/23-003-PC/554457 anhydrous Na2SO4 and concentrated under reduced pressure to obtain the title compound (739- 6, 150 mg, 75.81%). LC-MS m/z 468.2 (M+H+). [0530] Step 5: N-(3-(3-(3-cyclopropoxyazetidin-1-yl)-1-((1-fluorocyclopropyl)methyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7-(2,2- difluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxamide. To a solution of 3-[3-[3- (cyclopropoxy)azetidin-1-yl]-1-[(1-fluorocyclopropyl)methyl]pyrazolo[4,3-c]pyridin-6-yl]-1- tetrahydropyran-2-yl-pyrazol-4-amine (739-6, 75 mg, 0.160 mmol, 1 equiv.) in anhydrous N,N- dimethylformamide (1 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (45 mg, 0.175 mmol, 1.1 equiv.) and N-ethyl-N-isopropyl-propan-2-amine (0.06 mL, 0.3 mmol, 2 equiv.). The resulting orange solution was sonicated for 1 min and allowed to stir at rt for 15 mins. To this reaction mixture was added a pre-mixed solution of 7-(2,2-difluoroethyl)-4,7- diazaspiro[2.5]octane;hydrochloride (739-2, 60 mg, 0.282 mmol, 1.8 equiv.), N-ethyl-N- isopropyl-propan-2-amine (0.12 mL, 0.69 mmol, 4 equiv.) and anhydrous N,N- dimethylformamide (1 mL) and the resulting mixture stirred for 14h. The reaction mixture was cooled in ice bath, 10 mL water was added and then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (15 mL), dried over anhy. sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (739-7, 100 mg, 93.74%) and used directly for next step. LC-MS m/z 670.2 (M+H+).
Figure imgf000357_0001
- 1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-4-yl)-7-(2,2-difluoroethyl)-4,7- diazaspiro[2.5]octane-4-carboxamide. A mixture of N-[3-[3-[3-(cyclopropoxy)azetidin-1-yl]- 1-[(1-fluorocyclopropyl)methyl]pyrazolo[4,3-c]pyridin-6-yl]-1-tetrahydropyran-2-yl-pyrazol-4- 356 58226332.1 224990/23-003-PC/554457 yl]-7-(2,2-difluoroethyl)-4,7-diazaspiro[2.5]octane-4-carboxamide (739-7, 100 mg, 0.149 mmol, 1 equiv.) and 4-methylbenzenesulfonic acid monohydrate (22.0 mg, 0.116 mmol, 0.8 equiv.) in methanol (3 mL), was stirred at 60oC for 4h. The reaction mixture was allowed to cool to rt and satd aq. NaHCO3 solution (0.5 mL) was added and filtered through syringe filter. The filtrate was purified by RP-HPLC (10-100% ACN/water/FA, product out at 65-70%) and the fractions containing 739 lyophilized, (25 mg, 28.59%). LC-MS m/z 586.2 (M+H+); 1H NMR (400 MHz, DMSO-d6): δ 12.77 (s, 1H), 10.66 (s, 1H), 8.79 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 6.05 (tt, 1H), 4.63 (d, 2H), 4.53 (tt, 1H), 4.38 – 4.30 (m, 2H), 3.96 (dd, 2H), 3.33 (dq, 3H), 3.27 (s, 1H), 2.63 (td, 3H), 1.12 – 0.78 (m, 9H), 0.56 – 0.28 (m, 4H). [0532] Compounds 732-739 in Table 8 were synthesized according to the Examples above. Compounds 740-791 in Table 8 were synthesized according to the general procedure of Schemes 49-55 using variously-substituted 1H-pyrazol-4-amines and piperidine, piperidnol, piperazine, or pyrrolidine. Table 8 Compound Struct 1 No. ure LC-MS m/z H NMR
Figure imgf000358_0001
357 58226332.1 224990/23-003-PC/554457 Compound Str 1 No. ucture LC-MS m/z H NMR
Figure imgf000359_0001
358 58226332.1 224990/23-003-PC/554457 Compound Structure 1 No. LC-MS m/z H NMR s, , s, 3 s, s, s,
Figure imgf000360_0001
359 58226332.1 224990/23-003-PC/554457 Compound Structur 1 No. e LC-MS m/z H NMR s, s, , s, ), s,
Figure imgf000361_0001
360 58226332.1 224990/23-003-PC/554457 Compound Structure LC 1 No. -MS m/z H NMR s, 2 s, 2 s, s, s, s, 2 ,
Figure imgf000362_0001
361 58226332.1 224990/23-003-PC/554457 Compound Structure L 1 No. C-MS m/z H NMR H N 1H NMR 400 MH DMSOd δ 1279 (s, s, p s, s, 22 ), , , s, , s,
Figure imgf000363_0001
362 58226332.1 224990/23-003-PC/554457 Compound Structur 1 No. e LC-MS m/z H NMR , , s, 5 3 s, ),
Figure imgf000364_0001
363 58226332.1 224990/23-003-PC/554457 Compound Structure L 1 No. C-MS m/z H NMR s, s, 0 s, , s, , 32 ,
Figure imgf000365_0001
364 58226332.1 224990/23-003-PC/554457 Compound Structure LC-M 1 No. S m/z H NMR 24 s, 6 2 s, 4 3 s, ), s, ), s, ,
Figure imgf000366_0001
365 58226332.1 224990/23-003-PC/554457 Compound Structure LC 1 No. -MS m/z H NMR 1H NMR (400 MHz DMSO-d6) δ 12.82 (s,
Figure imgf000367_0001
pyrazol-4-amines. Table 9 Compound Structure LC 1 No. -MS m/z H NMR s, s, 6 , m, s, s, 79 s,
Figure imgf000367_0002
366 58226332.1 224990/23-003-PC/554457 Compound Structure LC-M 1 No. S m/z H NMR s, s, s, 0 d, s, s, s, ), s, 10
Figure imgf000368_0001
367 58226332.1 224990/23-003-PC/554457 Compound Structure LC- 1 No. MS m/z H NMR s, 5 s, s, 8 d, s, 59 , s, 5
Figure imgf000369_0001
368 58226332.1 224990/23-003-PC/554457 Compound Structur 1 No. e LC-MS m/z H NMR s, ), 6 , H) , ,
Figure imgf000370_0001
369 58226332.1 224990/23-003-PC/554457 Compound Structure LC-MS m 1 No. /z H NMR br ,
Figure imgf000371_0001
[0537] Compounds synthesized as described above were tested using an ADP-Glo® Kinase Assay (Promega, V9102). In brief, compounds were dispensed to an empty 384-well plate via an automated liquid handler at a volume of 15 nL/well. A reaction mixture containing 2.1 ng of PLK4, 200 ng MBP Protein substrate and 15 ^M ATP in a final volume of 5 ^L/well was assembled. After a 240-minute incubation at 25 oC, the reaction was terminated by the addition of 5 uL of ADP-Glo®. After a 40-minute incubation, 10 ^L of Kinase Detection Reagent was added and allowed to incubate for 30 minutes. Plate luminescence was then recorded using a PHERAstar® microplate reader. Reported values are normalized to wells. The IC50 values against PLK4 ADP-Glo® KmATP Low Enzyme are shown in Table 10. Table 10 PLK4 ADP-Glo® PLK4 ADP-Glo® K ATP Low K ATP Low
Figure imgf000371_0002
370 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000372_0001
371 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000373_0001
372 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000374_0001
373 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000375_0001
374 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000376_0001
375 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000377_0001
376 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000378_0001
377 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000379_0001
378 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000380_0001
379 58226332.1 224990/23-003-PC/554457 PLK4 ADP-Glo® PLK4 ADP-Glo® Cmpd. No. KmATP Low Cmpd. No. KmATP Low
Figure imgf000381_0001
Other Embodiments [0538] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. 380 58226332.1 224990/23-003-PC/554457 [0539] The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. 381 58226332.1

Claims

224990/23-003-PC/554457 CLAIMS 1. A compound of Formula (I): or a pharmaceutically acceptable
Figure imgf000383_0001
R1 is (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; R1 is substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is 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 R5 is 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 58226332.1 224990/23-003-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 R4 is 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 R4 is 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 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; provided that when R1 is 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 58226332.1 224990/23-003-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, wherein each R3 is 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 R3 is 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 R5 is 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 R4 is 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 58226332.1 224990/23-003-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 R4 is 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 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. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is independently substituted with 0, 1, 2, 3, or 4 R5; and each R5 is 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 58226332.1 224990/23-003-PC/554457 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with 0, 1, or 2 R3; and each R3 is 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 R1 is 5- to 10- membered heteroaryl substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is independently substituted with 0, 1, 2, or 3 R5; and each R5 is 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 R1 is ;
Figure imgf000387_0001
T4, U1, U2, U3, U4, U5, and U6 are independently C, CH, N, or NH; subscript n is 0, 1, 2, 3, or 4; and each R5 is 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 58226332.1 224990/23-003-PC/554457 7. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is: , , , ,
Figure imgf000388_0001
each R3 is 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 R3 is independently substituted with 0, 1, 2, or 3 R5; and each R5 is 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 58226332.1 224990/23-003-PC/554457 8. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is ,
Figure imgf000389_0001
9. The compound of any one of claims 6-8, or a pharmaceutically acceptable salt thereof, wherein 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 R3 is independently substituted with 0, 1, or 2 R5; and each R5 is 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 salt thereof, wherein R3 is selected from the group consisting of: 388 58226332.1 224990/23-003-PC/554457 ; each R5 (C1-
Figure imgf000390_0001
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 salt thereof, wherein ring A is (C3-C10) carbocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4 is 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 R4 is 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, wherein ring A is monocyclic (C3-C7)cycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4 is 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 58226332.1 224990/23-003-PC/554457 13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein ring A is bicyclic (C6-C10)cycloalkyl substituted with 0, 1, or 2 R4; and each R4 is 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, wherein ring A is phenyl substituted with 0, 1, 2, or 3 R4; and each R4 is 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 R4 is 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 salt thereof, wherein ring A is 3- to 14-membered heterocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4 is 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 R4 is 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, wherein ring A is 4- to 7-membered monocyclic nitrogen- or oxygen-containing heterocycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4 is independently selected from the group consisting 390 58226332.1 224990/23-003-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, wherein ring A is 5- to 6-membered monocyclic heteroaryl substituted with 0, 1, 2, or 3 R4; and each R4 is 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 R4 is 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, wherein ring A is 6- to 14-membered bicyclic or tricyclic heterocyclyl substituted with 0, 1, 2, 3, or 4 R4; and each R4 is 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 R4 is 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, wherein ring A is 6- to 10-membered bicyclic fused-, spiro-, or bridge-heterocycloalkyl substituted with 0, 1, 2, or 3 R4; and each R4 is independently selected from the group consisting of cyano, 391 58226332.1 224990/23-003-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 R4 is 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 salt thereof, wherein ring A is selected from the group consisting of 2 X2 X 3 X2 1 X X1 X3 m ,
Figure imgf000393_0001
392 58226332.1 224990/23-003-PC/554457
Figure imgf000394_0001
each R4 is 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 R4 is independently substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group 393 58226332.1 224990/23-003-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, wherein each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4 is 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 acceptable salt 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 L is -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 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-. 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L is -NH- or -NH-C(=O)-. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein L is -NH-. 27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein L is –NH-C(=O)-. 394 58226332.1 224990/23-003-PC/554457 28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt 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, wherein each Ra independently is H, -Me, cyclopropyl, or phenyl. 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein each Ra independently is H or -Me. 31. The compound of claim 1 or 2, which is a compound of Formula (II):
Figure imgf000396_0001
or a pharmaceutically acceptable salt thereof, wherein Y1 and Y2 are independently C, CH, or N; each R3a is 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 58226332.1 224990/23-003-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 ;
Figure imgf000397_0001
(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 R3 is 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 58226332.1 224990/23-003-PC/554457
Figure imgf000398_0001
is CH, CH2, N, NH, or O; each R4 is 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 R4 is 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 salt thereof, wherein L is -NH-C(=O)-. 35. The compound of any one of claims 31-34, which is a compound of Formula (III): 58226332.1
Figure imgf000398_0002
224990/23-003-PC/554457 (III) or a pharmaceutically acceptable salt thereof, wherein each R3 is 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 R3 is 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 R4a 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, -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 58226332.1 224990/23-003-PC/554457 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein subscript m is 0, 1, or 2. 37. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein ;
Figure imgf000400_0001
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 R4a is 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, wherein each R4a is 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, .
Figure imgf000400_0002
39. The compound of any one of claims 35-38, or a pharmaceutically acceptable salt thereof, wherein each R3 is 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 58226332.1 224990/23-003-PC/554457 heterocycloalkyl of any R3 is independently substituted with 0, 1, or 2 R5; wherein each R5 is 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, wherein each R3 is independently F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH(CH3)2, - CONH2, -CON(CH3)2, -CONHCH3, -SO2-CH3, , ,
Figure imgf000401_0001
41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH2CH(CH3)2, - CONH2, -CON(CH3)2, -CONHCH3, or -SO2-CH3. 400 58226332.1 224990/23-003-PC/554457 42. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein 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 R3 is 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; , wherein
Figure imgf000402_0001
hydroxy, (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 pharmaceutically acceptable salt thereof. 44. A compound selected from any of the compounds in Table 2, or a pharmaceutically acceptable salt thereof. 45. A compound selected from any of the compounds in Table 3, or a pharmaceutically acceptable salt thereof. 46. A compound selected from any of the compounds in Table 4, or a pharmaceutically acceptable salt thereof. 47. A compound selected from any of the compounds in Table 5, or a pharmaceutically acceptable salt thereof. 401 58226332.1 224990/23-003-PC/554457 48. A compound selected from any of the compounds in Table 6, or a pharmaceutically acceptable salt thereof. 49. A compound selected from any of the compounds in Table 7, or a pharmaceutically acceptable salt thereof. 50. A compound selected from any of the compounds in Table 8, or a pharmaceutically acceptable salt thereof. 51. A compound selected from any of the compounds in Table 9, or a pharmaceutically acceptable 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 in vivo 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 acceptable
Figure imgf000403_0001
comprising combining a compound of Formula S-4 and a compound of Formula S-5 to form a compound of Formula (I) 402 58226332.1 224990/23-003-PC/554457 wherein:
Figure imgf000404_0001
P is H or a group; L1 is H, -COOH, or a leaving group; R1 is (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; R1 is substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is 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 R5 is 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 58226332.1 224990/23-003-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 R4 is 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 R4 is 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 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; L1 is H, -COOH, or a leaving group; 404 58226332.1 224990/23-003-PC/554457 R1 is (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, R1 is substituted with 0, 1, 2, 3, or 4 R3; each R3 is 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 R3 is 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 R5 is 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 R4 is 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 58226332.1 224990/23-003-PC/554457 each cycloalkyl, aryl, heterocycloalkyl, and heteroaryl portion of any R4 is 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 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:
Figure imgf000407_0001
, wherein Lv is a leaving group.
Figure imgf000407_0002
406 58226332.1
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