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WO2024148247A2 - Azaindazoles as jak2 inhibitors - Google Patents

Azaindazoles as jak2 inhibitors Download PDF

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Publication number
WO2024148247A2
WO2024148247A2 PCT/US2024/010456 US2024010456W WO2024148247A2 WO 2024148247 A2 WO2024148247 A2 WO 2024148247A2 US 2024010456 W US2024010456 W US 2024010456W WO 2024148247 A2 WO2024148247 A2 WO 2024148247A2
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compound
nitrogen
sulfur
oxygen
independently selected
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WO2024148247A3 (en
Inventor
Craig E. Masse
Jiayi Xu
Kevin Robert DEMARCO
Phani GHANAKOTA
Jeremy R. Greenwood
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Ajax Therapeutics Inc
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Ajax Therapeutics 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
    • 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

  • JAKs can interact with certain cytokine receptors and can couple cytokine binding to cytoplasmic signaling cascades, including the signal transducers and activators of transcription (STAT) pathway.
  • JAK proteins also contain a pseudokinase domain (JH2).
  • JH1 and JH2 contain an ATP binding site, but catalytic activity is believed to come predominantly from JH1, as JH2 lacks essential residues for phosphorylation catalysis.
  • JH2 mediates critical regulatory functions in JAKs and is believed to primarily serve to inhibit basal JAK2 activity.
  • provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2.
  • the present disclosure provides a compound of Formula I’: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , L 2 , m, n, R 1 , R a , R b , X, and Y are as defined herein.
  • the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, m, n, R 1 , R a , R b , X, and Y are as defined herein.
  • Aliphatic refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 ).
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C 6-14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • the term “aryl” may be used interchangeably with the term “aryl ring”.
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2- a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)– one, and benzoisoxazolyl.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings.
  • Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3- dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • Substituted applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least refers to at least ).
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ ,
  • the present disclosure provides a compound of Formula I’-A: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 2 , m, n, R, R 1 , R a , and R b are as defined above for Formula I’ or Formula I and described in classes and subclasses herein, both singly and in combination, and x is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of Formula I-B-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R 1 , R a , and R b are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I-C: or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R 1 , R a , R b , X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I-C-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R 1 , R a , and R b are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy 1 , n, p, R 1 , R a , R b , R c , X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of Formula II-C: or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R 1 , R a , R b , R c , X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of Formula II-C: or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R 1 , R a , R b , R c , X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of Formula II-D: or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R 1 , R a , R b , R c , X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of Formula III-A: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy 1 , Cy 2 , n, q, R 1 , R a , R b , R c , and R d are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of Formula III-B- 1: or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy 1 , Cy 2 , n, q, R 1 , R a , R b , R c , and R d are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.
  • Ring A is absent such that in any Formulae described herein the place of Ring A is replaced with a hydrogen to satisfy valence and R a is absent.
  • L 1 is a bond and Ring A is absent such that in any Formulae described herein the entire side chain represented by is replaced by a hydrogen to satisfy valence.
  • the present disclosure provides a compound of or a pharmaceutically acceptable salt thereof, wherein Ring B, L 2 , n, R 1 , R b , X, and Y are as defined in classes and subclasses herein both singly and in combination.
  • L 2 is a bond.
  • L 3 is optionally substituted C 1 -C 6 aliphatic and one or more methylene groups are optionally and independently replaced with -C(O)N(R)- or -N(R)C(O)- and R is as described herein.
  • L 3 is , wherein z is 0, 1, 2, 3, 4, or 5.
  • L 3 is wherein z is 0, 1, 2, 3, 4, or 5 and * is a point of attachment to Ring A.
  • Y is CR y . In some embodiments, Y is CH. In some embodiments, Y is N. [0074] In some embodiments of any Formulae described herein, X is CR x and Y is CR y . In some embodiments, both X and Y are CH. [0075] In some embodiments of any Formulae described herein, R x is hydrogen, halogen, - CN, or optionally substituted C 1-6 alkyl. In some embodiments, R x is hydrogen. In some embodiments, R x is halogen (e.g., fluoro or chloro). In some embodiments, R x is –CN.
  • R x is optionally substituted C 1-6 aliphatic. In some embodiments, R x is optionally substituted C 1-6 alkyl.
  • R y is hydrogen, halogen, - CN, or optionally substituted C 1-6 alkyl. In some embodiments, R y is hydrogen. In some embodiments, R y is halogen (e.g., fluoro or chloro). In some embodiments, R y is –CN. In some embodiments, R y is optionally substituted C 1-6 aliphatic. In some embodiments, R y is optionally substituted C 1-6 alkyl.
  • Ring A is an optionally substituted group selected from phenyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is an optionally substituted group selected from 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered bicyclic cycloaliphatic, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a piperidine ring. [0084] In some embodiments, Ring A is optionally substituted 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Cy 1 is phenyl substituted with p R c groups.
  • Cy 1 is 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p R c groups.
  • Cy 1 is 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p R c groups.
  • Cy 1 is 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p R c groups.
  • Cy 1 substituted with p R c groups is selected from: . [0108] In some embodiments, Cy 1 substituted with p R c groups is selected from: . [0109] In some embodiments, Cy 1 substituted with p R c groups is selected from: [0110] In some embodiments, Cy 1 substituted with p R c groups is selected from: .
  • the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2.
  • provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as JAK2 inhibitors that bind the pseudokinase (JH2) domain of JAK2. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.
  • JAK e.g., JAK2
  • JAK2 has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40) and acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (The Lancet. doi: 10.1016/80140-6736(20)30628-0).
  • a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
  • additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors.
  • CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res.2016, 5(Suppl.4), S616-S628).
  • JAK-STAT3 pathway Jaffer, T., Ma, D. Transl. Cancer Res.2016, 5(Suppl.4), S616-S628).
  • EXAMPLES EXAMPLES [0150] As described in the Examples below, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • EA ethyl acetate
  • DMF ⁇ , ⁇ -dimethylformamide
  • Dess-Martin periodinane 1,1-dihydro-1,1,1-triacetoxy-l,2-benzoiodooxol-3(1H)-one
  • DCM Dichloromethane
  • THF Tetrahydrofuran
  • LAH Lithium aluminium hydride
  • DME 1,2-Dimethoxyethane
  • TEA Triethylamine
  • EIPEA Ethyldiisopropylamine
  • DEAD Diethylazodicarboxylate
  • DIAD Diisopropyl azodicarboxylate
  • HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • EDCI N-(3-dimethylamino
  • Example I-3 (R)-N-(1-methyl-3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide [0159] Synthesis of compound 3.1. To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4- c]pyridine (0.2 g, 0.617 mmol, 1 equiv) in DMF (4 mL) was added sodium hydride (0.054 g, 1.234 mmol, 2 equiv) at 0 oC and stirred at room temperature of 15 min.
  • Compound 3.2 was prepared from compound 3.1 and 2.2, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 349.2 [M+H] + . [0161] Synthesis of I-3. Compound I-3 was prepared from compound 3.2, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane).
  • Example I-6 N-(3-(3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0170] Synthesis of compound 6.1. To a solution of 4-bromo-1H-pyrazole (5.0 g, 34.013 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60 % in mineral oil, 3.4 g, 85.034 mmol, 2.5 equiv) in portions at 0 °C and stirred for 30 min.
  • N, N-dimethylethylenediamine (0.253 g, 2.87 mmol, 0.3 equiv) and copper iodide (0.366 g, 1.91 mmol, 0.2 equiv) were added, and degassed for 5 min.
  • the reaction mixture was stirred at 120 oC for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sufhate, filtered, and concentrated under reduced pressure.
  • Example I-10 N-(3-(2-methoxy-3-(1-((1S,2S)-2-methoxycyclopentyl)-1H-pyrazol-4-yl)phenyl)- 1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(2-methoxy-3-(1- ((1R,2R)-2-methoxycyclopentyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)cyclopropanecarboxamide [0195] Synthesis of compound trans-( ⁇ )-10.1.
  • Example I-17 (R)-N-(3-(3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
  • Compound 17.1 was prepared from compound 15.3 and 2.3, following the procedure described in the synthesis of compound ( ⁇ )-9.5. The product his was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane). MS(ES): m/z 541.37 [M+H] + .
  • Compound I-27 was prepared from compound 27.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5.
  • the product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM).
  • Tris(dibenzylideneacetone)dipalladium(0) (0.065 g, 0.08 mmol, 0.1 equiv) was added and degassed for 5 min.
  • the reaction mixture was stirred at 100 oC for 1.5 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane) to afford ( ⁇ )-29.6 (0.25 g, 83%).
  • Example I-31-a and I-31-b 6-(cyclopropanecarboxamido)-4-((3-methoxy-5-(1-((3R,4S)-4- methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide and 6- (cyclopropanecarboxamido)-4-((3-methoxy-5-(1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)-1H- pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide [0319] Synthesis of compound 31.1.
  • Example I-37-a and I-37-b (R)-N-(3-(2-methoxy-3-(1-(2-oxopiperidin-3-yl)-1H-pyrazol-4- yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(2- methoxy-3-(1-(2-oxopiperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide [0357] Synthesis of compound ( ⁇ )-37.1.
  • the racemate was separated by chiral SFC (column CHIRALPAK IC (250 x 21 mm, 5 ⁇ m); mobile phase: (A) Liquid CO 2 , (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-38-a) and second eluting fraction (I-38-b). *The absolute configuration of the chiral center is not determined.
  • Example I-40 methyl 4-cyano-4-(3-(5-(cyclopropanecarboxamido)-1-methyl-1H-pyrazolo[3,4- c]pyridin-3-yl)-2-methoxyphenyl)piperidine-1-carboxylate [0386] Synthesis of compound 40.1. To a solution of 35.2 (0.45 g, 1.52 mmol, 1.0 equiv) and triethylamine (0.463 g, 4.57 mmol, 3.0 equiv) in DCM (5.0 mL) at 0 °C was added dropwise acetyl chloride (0.173 g, 1.83 mmol, 1.2 equiv) and stirred for 2 h.
  • Compound I-40 was prepared from compound 40.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5.
  • the product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM).
  • Example I-41 4-cyano-4-(3-(5-(cyclopropanecarboxamido)-1-methyl-1H-pyrazolo[3,4- c]pyridin-3-yl)-2-methoxyphenyl)-N,N-dimethylpiperidine-1-carboxamide [0390] Synthesis of compound 41.1. To a solution of 35.2 (0.45 g, 1.52 mmol, 1.0 equiv) and triethylamine (0.463 g, 4.57 mmol, 3.0 equiv) in DCM (5.0 mL) at 0 °C was added dimethylcarbamic chloride (0.197 g, 1.83 mmol, 1.2 equiv) and stirred for 2 h.
  • Compound I-41 was prepared from compound 41.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5.
  • the product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM).
  • Example I-42 N-(3-(3-(4-cyano-1-(2-methoxyethyl)piperidin-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0394] Synthesis of compound 42.1. To a solution of 35.2 (0.450 g, 1.52 mmol, 1.0 equiv) and triethylamine (0.63 mL, 4.57 mmol, 3.0 equiv) in DCM (10 mL) was added 1-bromo-2- methoxyethane (0.423 g, 3.05 mmol, 2.0 equiv) at 0 °C.
  • Example I-45-a and I-45-b (S)-N-(3-(2-methoxy-3-(1-((3-methoxytetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and (R)-N-(3-(2-methoxy-3-(1-((3-methoxytetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide [0409] Synthesis of compound ( ⁇ )-45.1.
  • Example I-47-a and I-47-b N-(3-(3-(1-((5R,9S)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(3-(1-((5S,9R)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0427] Synthesis of compound ( ⁇ )-47.1.
  • Example I-48 N-(3-(5-methoxy-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0437] Synthesis of compound 48.1.
  • Compound I-48 was prepared from compound 48.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5.
  • the product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM).
  • Example I-49 N-(3-(3-(1-(ethylsulfonyl)-4-(hydroxymethyl)piperidin-4-yl)-2-methoxyphenyl)- 1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0442] Synthesis of compound 49.1. To a stirred solution of I-35 (0.20 g, 0.383 mmol, 1.0 equiv) in THF at 0 °C was added diisobutylaluminum hydride (0.547 mL, 1.14 mmol, 3.0 equiv) dropwise and stirred at room temperature for 5 h.
  • diisobutylaluminum hydride 0.547 mL, 1.14 mmol, 3.0 equiv
  • Example I-50-a and I-50-b (S)-N-(3-(5-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4- yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (R)-N-(3-(5- methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide [0444] Synthesis of compound ( ⁇ )-50.1.
  • the racemate was separated by chiral HPLC (column: CHIRALPAK IB-N (250 x 21 mm, 5 ⁇ m); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in propane-2-ol: methanol (50: 50); flow rate: 17 mL/min) to afford first eluting fraction (I-50-a) and second eluting fraction (I-50-b).
  • chiral HPLC column: CHIRALPAK IB-N (250 x 21 mm, 5 ⁇ m); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in propane-2-ol: methanol (50: 50); flow rate: 17 mL/min) to afford first eluting fraction (I-50-a) and second eluting fraction (I-50-b).
  • the absolute configuration of the chiral center is not determined.
  • Compound 51.6-a was prepared from compound 51.5- a, following the procedure described in the synthesis of compound ( ⁇ )-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 387.3 [M+H] + . [0459] Synthesis of compound 51.6-b. Compound 51.6-b was prepared from compound 51.5- b, following the procedure described in the synthesis of compound ( ⁇ )-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane).
  • Compound I-52 was prepared from compound 52.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5.
  • the product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM).
  • Example I-53 N-(3-(3-(1-((1r,3r)-3-fluorocyclobutyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0469] Synthesis of compound cis-53.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (25 g, 142.05 mmol, 1.0 equiv) in methanol (250 mL), was added sodium borohydride (16.19 g, 426.13 mmol, 2.0 equiv) in portions at 0 °C.
  • Compound ( ⁇ )-55.4 was prepared from compound ( ⁇ )-55.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound ( ⁇ )-11.3.
  • the product material was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 302.22 [M+H] + .
  • Synthesis of compound ( ⁇ )-55.5 Compound ( ⁇ )-55.5 was prepared from compound ( ⁇ )-55.4, following the procedure described in the synthesis of compound ( ⁇ )-9.4.
  • Example I-57 N-(3-(2-methoxy-3-(1-((3R,6R)-6-(methoxymethyl)-2-oxopiperidin-3-yl)-1H- pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
  • Trimethylbenzeniminium dibromide (4.70 g) was added in portions. The reaction mixture was stirred at room temperature for 8 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 57.5 (4.1 g, 60%). MS(ES): m/z 312.3 and 314.3[M+H] + . [0508] Synthesis of compound 57.6.
  • Example I-58-a and I-58-b (R)-N-(3-(2-methoxy-3-(1-(5-oxo-4-azaspiro[2.5]octan-6-yl)-1H- pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(2-methoxy-3-(1-(5-oxo-4-azaspiro[2.5]octan-6-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
  • the racemate was separated by chiral SFC (column: CHIRALPAK IC (250 x 21 mm, 5 ⁇ m); mobile phase: (A) CO 2 , (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-58-a) and second eluting fraction (I-58-b). *The absolute configuration of the chiral center is not determined.
  • the racemate was separated by chiral SFC (column: CHIRALPAK IB-N (250 x 21 mm, 5 ⁇ m); mobile phase: (A) CO 2 , (B) 0.1% diethylamine IN isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-59-a) and second eluting fraction (I-59-b). *The absolute configuration of the chiral center is not determined.
  • Example I-64-a and I-64-b N-(3-(4-(1-((5R,9S)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4- yl)-3-methoxypyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(4-(1-((5S,9R)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4-yl)-3-methoxypyridin-2- yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide [0573] Synthesis of compound ( ⁇ )-64.1.
  • the remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding.
  • blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds are prepared as 111X stocks in 100% DMSO. Kds are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non- contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384- well plate. Each has a final volume of 0.02 ml.
  • the cells are spun, and the cell pellets are re-suspended with 100 ⁇ L cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 ⁇ L lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pellet. The cell lysate is shaken at 4 °C for 20 min to fully lyse the cells. The cell lysate is spun at 4 °C and 4000 rpm for 15 min, and then the supernatant is transferred into a new plate and stored at -80 °C.
  • lysis buffer with protease and phosphatase inhibitor cocktail
  • MSD Meso-scale discovery
  • PBS 40 ⁇ L/well
  • 1x MSD Wash Buffer Tris-buffered saline with 0.1% Tween® 20 detergent, TBST
  • the MSD plates are then blocked with 150 ⁇ L of blocking buffer (5% BSA in TBST) and shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • Sample lysates are then added to MSD plates (25 ⁇ L/well) and shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • Detection antibody prepared in Antibody Detection buffer, 1% BSA in 1xTBST is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • Assay Procedure The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes.
  • the stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 ⁇ M working solutions.
  • the stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 ⁇ M working solutions.
  • the final concentration of DMSO in the incubation system is 0.5%.
  • Time 0 samples are prepared by transferring 50 ⁇ L of 5 ⁇ M working solution to wells of the 96-deepwell plate, followed by the addition of 200 ⁇ L cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. At the end of the incubation, 50 ⁇ L samples from donor sides (apical compartment for Ap ⁇ Bl flux, and basolateral compartment for Bl ⁇ Ap) and receiver sides (basolateral compartment for Ap ⁇ Bl flux, and apical compartment for Bl ⁇ Ap) are transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS).
  • Lucifer Yellow leakage after 2 hour transport period stock solution of Lucifer yellow is prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 ⁇ M.100 ⁇ L of the Lucifer yellow solution is added to each Transwell® insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 ⁇ L of HBSS (10 mM HEPES, pH 7.4).
  • Hepatocyte Stability Assay 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 ⁇ M by combining 198 ⁇ L of 50% acetonitrile/50% water and 2 ⁇ L of 10 mM stock solution. Verapamil is used as positive control in the assay. Vials of cryopreserved hepatocytes are thawed in a 37 °C water bath with gently shaking. The contents are poured into the 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature.
  • Thawing medium is aspirated and hepatocytes are re-suspended with serum- free incubation medium to yield ⁇ 1.5 ⁇ 106 cells/mL.
  • Cell viability and density are counted using a Trypan Blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5 ⁇ 106 viable cells/mL.
  • a portion of the hepatocytes at 0.5 ⁇ 106 viable cells/mL are boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed.
  • Aliquots of 198 ⁇ L hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes.
  • test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard: Plasma Protein Binding Assay [0591]
  • Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 ⁇ M, and then the working solutions are spiked into plasma. The final concentration of compound is 1 ⁇ M. The final concentration of DMSO is 0.5%.
  • Ketoconazole is used as positive control in the assay.
  • Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. The dialysis set up is assembled according to the manufacturer’s instruction.

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Abstract

The present disclosure provides azaindazole compounds and compositions thereof useful for inhibiting JAK2.

Description

AZAINDAZOLES AS JAK2 INHIBITORS RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Application No. 63/478,833, filed January 6, 2023, the entire contents of which are hereby incorporated by reference in its entirety. BACKGROUND [0002] Janus kinases (JAK1, JAK2, JAK3, and TYK2) are a family of non-receptor tyrosine kinases that may have important roles in the regulation of hematopoeisis, the immune system, and cellular metabolism. JAKs can interact with certain cytokine receptors and can couple cytokine binding to cytoplasmic signaling cascades, including the signal transducers and activators of transcription (STAT) pathway. In addition to a canonical tyrosine kinase domain (JH1) located in the C-terminal region, JAK proteins also contain a pseudokinase domain (JH2). [0003] Both JH1 and JH2 contain an ATP binding site, but catalytic activity is believed to come predominantly from JH1, as JH2 lacks essential residues for phosphorylation catalysis. However, JH2 mediates critical regulatory functions in JAKs and is believed to primarily serve to inhibit basal JAK2 activity. Mutations to JH2 may therefore, in some instances, lead to kinase hyperactivity. For example, a V617F mutation to the JH2 domain of JAK2 may promote constitutive activation of the JAK-STAT pathway, and may play a causative role in various myeloproliferative disorders. The V617F mutation is found 95% of patients with polycythemia vera, as well as ~60% of patients with essential thrombocythemia and primary myelofibrosis. JAK2 hyperactivation is also associated with several leukemias and lymphomas. Disruption of ATP binding in JH2 inhibits the hyperactivity of JAK2 V617F and other pathogenic JAK2 mutants (Hammaren, H. et. al., Proc. Natl. Acad. Sci., 2015, 112 (15), 4642-4647). [0004] A modulator of JAK2 kinase activity (e.g., a JAK2 inhibitor disclosed herein) may be effective in treating a disease associated with JAK-STAT hyperactivity. Therefore, a JAK2 modulator capable of reducing JH1 activity and/or promoting JH2 regulatory function (e.g., by inhibiting ATP binding to JH2) could be useful in restoring or treating aberrant JAK2-mediated signaling, and in treating diseases associated therewith. SUMMARY [0005] The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2. [0006] In some embodiments, the present disclosure provides a compound of Formula I’:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, L2, m, n, R1, Ra, Rb, X, and Y are as defined herein. [0007] In some embodiments, the present disclosure provides a compound of Formula I:
Figure imgf000003_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, m, n, R1, Ra, Rb, X, and Y are as defined herein. DETAILED DESCRIPTION Compounds and Definitions [0008] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0009] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure. [0010] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. [0011] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight- chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule. [0012] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. [0013] Carbocyclyl: The terms “cycloaliphatic,” “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C4-C10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon- carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. [0014] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2- 10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. [0015] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl. [0016] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. [0017] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2- a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)– one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. [0018] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. [0019] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 4- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3- dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 6- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). [0020] Partially Unsaturated: As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined. [0021] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition. [0022] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,
Figure imgf000008_0001
refers to at least
Figure imgf000008_0003
refers to at least
Figure imgf000008_0002
). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above. [0023] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0– 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)(NH)R°; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; – N(OR°)R°; –C(NH)NR°2; –P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; –SiR°3; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1– 6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0024] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2, -O(haloR●), –CN, –N3, –(CH2)0– 2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NR● 2, –NO2, –SiR● 3, –OSiR● 3, -C(O)SR● , –(C1–4 straight or branched alkylene)C(O)OR●, or –SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S. [0025] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR* 2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or –S(C(R* 2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR* 2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0026] Suitable substituents on the aliphatic group of R* include halogen, –R●, -(haloR●), -OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR● 2, or –NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0027] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR† 2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR† 2, –C(S)NR† 2, –C(NH)NR† 2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0028] Suitable substituents on the aliphatic group of R† are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR● 2, or -NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0029] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. Provided Compounds [0030] In some embodiments, the present disclosure provides a compound of Formula I’:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein: X is CRx or N; Y is CRy or N; Rx and Ry are each independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; L1 is a bond or is optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; L2 is a bond or is optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; Ring A is absent or is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1 is hydrogen or optionally substituted C1-6 aliphatic; each Ra is independently -L3-Cy1, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; L3 is a bond or optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rc is independently Cy2, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rd is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; m is 0, 1, 2, 3, 4, or 5, as valency permits; n is 0, 1, 2, 3, 4, or 5, as valency permits; each p is independently 0, 1, 2, 3, 4, or 5, as valency permits; each q is independently 0, 1, 2, 3, 4, or 5, as valency permits; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R, when attached to the same nitrogen atom, are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently an optionally substituted group selected from C1-6 aliphatic and 3- to 7- membered monocyclic cycloaliphatic. [0031] In some embodiments, the present disclosure provides a compound of Formula I’:
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein: X is CRx or N; Y is CRy or N; Rx and Ry are each independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; L1 is a bond or is optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; L2 is a bond or is optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1 is hydrogen or optionally substituted C1-6 aliphatic; each Ra is independently -L3-Cy1, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; L3 is a bond or optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rc is independently Cy2, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rd is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; m is 0, 1, 2, 3, 4, or 5, as valency permits; n is 0, 1, 2, 3, 4, or 5, as valency permits; each p is independently 0, 1, 2, 3, 4, or 5, as valency permits; each q is independently 0, 1, 2, 3, 4, or 5, as valency permits; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R, when attached to the same nitrogen atom, are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently an optionally substituted group selected from C1-6 aliphatic and 3- to 7- membered monocyclic cycloaliphatic. [0032] In some embodiments, the present disclosure provides a compound of Formula I:
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: X is CRx or N; Y is CRy or N; Rx and Ry are each independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1 is hydrogen or optionally substituted C1-6 aliphatic; each Ra is independently Cy1, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rc is independently Cy2, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rd is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; m is 0, 1, 2, 3, 4, or 5, as valency permits; n is 0, 1, 2, 3, 4, or 5, as valency permits; each p is independently 0, 1, 2, 3, 4, or 5, as valency permits; each q is independently 0, 1, 2, 3, 4, or 5, as valency permits; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R, when attached to the same nitrogen atom, are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently an optionally substituted group selected from C1-6 aliphatic and 3- to 7- membered monocyclic cycloaliphatic. [0033] In some embodiments, the present disclosure provides a compound of Formula I’-A:
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L2, m, n, R, R1, Ra, and Rb are as defined above for Formula I’ or Formula I and described in classes and subclasses herein, both singly and in combination, and x is 0, 1, 2, 3, or 4. [0034] In some embodiments, the present disclosure provides a compound of Formula I’-A-1:
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L2, m, n, R1, Ra, and Rb are as defined above for Formula I’ or Formula I and described in classes and subclasses herein, both singly and in combination, x is 0, 1, 2, 3, or 4. [0035] In some embodiments, the present disclosure provides a compound of Formula I’-B:
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L2, m, n, R1, Ra, and Rb are as defined above for Formula I’ or Formula I and described in classes and subclasses herein, both singly and in combination. [0036] In some embodiments, the present disclosure provides a compound of Formula I’-B:
Figure imgf000020_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, m, n, R1, Ra, and Rb are as defined above for Formula I’ or Formula I and described in classes and subclasses herein, both singly and in combination. [0037] In some embodiments, the present disclosure provides a compound of Formula I’-C:
Figure imgf000020_0003
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy1, L1, L2, m, n, p, R1, Ra, Rb, and Rc are as defined above for Formula I’ or Formula I and described in classes and subclasses herein, both singly and in combination. [0038] In some embodiments, the present disclosure provides a compound of Formula I-A:
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, m, n, R1, Ra, and Rb are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0039] In some embodiments, the present disclosure provides a compound of Formula I-B:
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R1, Ra, Rb, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0040] In some embodiments, the present disclosure provides a compound of Formula I-B-1:
Figure imgf000021_0003
or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R1, Ra, and Rb are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0041] In some embodiments, the present disclosure provides a compound of Formula I-C:
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R1, Ra, Rb, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0042] In some embodiments, the present disclosure provides a compound of Formula I-C-1:
Figure imgf000022_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, m, n, R1, Ra, and Rb are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0043] In some embodiments, the present disclosure provides a compound of Formula II:
Figure imgf000022_0003
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy1, n, p, R1, Ra, Rb, Rc, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0044] In some embodiments, the present disclosure provides a compound of Formula II-A:
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy1, n, p, R1, Ra, Rb, and Rc are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0045] In some embodiments, the present disclosure provides a compound of Formula II-B:
Figure imgf000023_0002
or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy1, n, p, R1, Ra, Rb, Rc, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0046] In some embodiments, the present disclosure provides a compound of Formula II-B-1:
Figure imgf000024_0002
or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy1, n, p, R1, Ra, Rb, and Rc are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0047] In some embodiments, the present disclosure provides a compound of Formula II-C:
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R1, Ra, Rb, Rc, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0048] In some embodiments, the present disclosure provides a compound of Formula II-C-1:
Figure imgf000024_0003
or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R1, Ra, Rb, and Rc are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0049] In some embodiments, the present disclosure provides a compound of Formula II-D:
Figure imgf000025_0002
or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R1, Ra, Rb, Rc, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0050] In some embodiments, the present disclosure provides a compound of Formula II-D-1:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, wherein Ring B, n, p, R1, Ra, Rb, and Rc are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and m is 0, 1, 2, 3, or 4. [0051] In some embodiments, the present disclosure provides a compound of Formula III:
Figure imgf000026_0003
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy1, Cy2, n, q, R1, Ra, Rb, Rc, Rd, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0052] In some embodiments, the present disclosure provides a compound of Formula III-A:
Figure imgf000026_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, Cy1, Cy2, n, q, R1, Ra, Rb, Rc, and Rd are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0053] In some embodiments, the present disclosure provides a compound of Formula III-B:
Figure imgf000026_0001
or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy1, Cy2, n, q, R1, Ra, Rb, Rc, Rd, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0054] In some embodiments, the present disclosure provides a compound of Formula III-B- 1:
Figure imgf000027_0001
or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy1, Cy2, n, q, R1, Ra, Rb, Rc, and Rd are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0055] In some embodiments, the present disclosure provides a compound of Formula III-C:
Figure imgf000027_0002
or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy2, n, q, R1, Ra, Rb, Rc, Rd, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, or 2. [0056] In some embodiments, the present disclosure provides a compound of Formula III-C- 1:
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, wherein Ring B, Cy2, n, q, R1, Ra, Rb, Rc, and Rd are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; m is 0, 1, 2, 3, or 4; and p is 0, 1, or 2. [0057] In some embodiments of any Formulae described herein, L1 is a bond. [0058] As described herein, any methylene group within an optionally substituted C1-C6 aliphatic group of L1 (e.g., any -CH2- group) is optionally and independently replaced with -N(R)- , -O-, or -S-. In some embodiments, an optional substituent of L1 is a divalent substituent as described herein, e.g., =O (“oxo”), =S, etc. [0059] In some embodiments of any Formulae described herein, L1 is optionally substituted C1-C6 aliphatic and wherein one or more methylene groups are optionally and independently replaced with -C(O)N(R)- or -N(R)C(O)- and R is as described herein. In some embodiments of any Formulae described herein, L1 is
Figure imgf000028_0002
wherein x is 0, 1, 2, 3, or 4. In some embodiments of any Formulae described herein, L1 is
Figure imgf000028_0003
wherein x is 0, 1, 2, 3, or 4, * is a point of attachment to Ring A, and R is as described herein. In some embodiments of any Formulae described herein, L1 is
Figure imgf000028_0004
wherein x is 0, 1, 2, 3, or 4, * is a point of attachment to Ring A, and R is as described herein. In some embodiments of any Formulae described herein, L1 is
Figure imgf000028_0005
and R is as described herein. In some embodiments of any Formulae described herein, L1 is
Figure imgf000029_0002
, * is a point of attachment to Ring A, and R is as described herein. In some embodiments of any Formulae described herein, L1 is
Figure imgf000029_0003
* is a point of attachment to Ring A, and R is as described herein. In some embodiments of any Formulae described herein, L1 is
Figure imgf000029_0004
wherein x is 0, 1, 2, 3, or 4 and R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments of any Formulae described herein, L1 is
Figure imgf000029_0005
wherein x is 0, 1, 2, 3, or 4, * is a point of attachment to Ring A, and R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments of any Formulae described herein, L1 is
Figure imgf000029_0006
wherein x is 0, 1, 2, 3, or 4, * is a point of attachment to Ring A, and R is hydrogen or optionally substituted C1-6 aliphatic. [0060] In some embodiments, Ring A is absent such that in any Formulae described herein the place of Ring A is replaced with a hydrogen to satisfy valence and Ra is absent. [0061] In some embodiments, L1 is a bond and Ring A is absent such that in any Formulae described herein the entire side chain represented by
Figure imgf000029_0001
is replaced by a hydrogen to satisfy valence. In some embodiments, the present disclosure provides a compound of
Figure imgf000029_0007
or a pharmaceutically acceptable salt thereof, wherein Ring B, L2, n, R1, Rb, X, and Y are as defined in classes and subclasses herein both singly and in combination. [0062] In some embodiments of any Formulae described herein, L2 is a bond. [0063] As described herein, any methylene group within an optionally substituted C1-C6 aliphatic group of L2 (e.g., any -CH2- group) is optionally and independently replaced with -N(R)- , -O-, or -S-. In some embodiments, an optional substituent of L2 is a divalent substituent as described herein, e.g., =O (“oxo”), =S, etc. [0064] In some embodiments of any Formulae described herein, L2 is -N(R)- and R is as described herein. In some embodiments of any Formulae described herein, L2 is -N(R)- and R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments of any Formulae described herein, L2 is -NH-. [0065] In some embodiments of any Formulae described herein, L2 is optionally substituted C1-C6 aliphatic and one or more methylene groups are optionally and independently replaced with -C(O)N(R)- or -N(R)C(O)- and R is as described herein. In some embodiments of any Formulae described herein, L2 is
Figure imgf000030_0001
wherein y is 0, 1, 2, 3, or 4. In some embodiments of any Formulae described herein, L2 is
Figure imgf000030_0002
wherein y is 0, 1, 2, 3, or 4, * is a point of attachment to Ring B, and R is as described herein. In some embodiments of any Formulae described herein, L2 is
Figure imgf000030_0003
wherein y is 0, 1, 2, 3, or 4, * is a point of attachment to Ring B,, and R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments of any Formulae described herein, L2 is
Figure imgf000030_0004
wherein y is 0, 1, 2, 3, or 4, * is a point of attachment to Ring B, and R is as described herein. In some embodiments of any Formulae described herein, L2 is
Figure imgf000030_0005
wherein y is 0, 1, 2, 3, or 4, * is a point of attachment to Ring B,, and R is hydrogen or optionally substituted C1-6 aliphatic. [0066] In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0001
wherein R is as described herein. In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0002
wherein * is a point of attachment to Ring B and R is as described herein. In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0003
wherein * is a point of attachment to Ring B and R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0005
wherein * is a point of attachment to Ring B and R is as described herein. In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0004
wherein * is a point of attachment to Ring B and R is hydrogen or optionally substituted C1-6 aliphatic. [0067] In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0006
In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0007
and * is a point of attachment to Ring B. In some embodiments of any Formulae described herein, L2 is
Figure imgf000031_0008
and * is a point of attachment to Ring B. [0068] In some embodiments of any Formulae described herein, L3 is a bond. [0069] As described herein, any methylene group within an optionally substituted C1-C6 aliphatic group of L3 (e.g., any -CH2- group) is optionally and independently replaced with -N(R)- , -O-, or -S-. In some embodiments, an optional substituent of L3 is a divalent substituent as described herein, e.g., =O (“oxo”), =S, etc. [0070] In some embodiments of any Formulae described herein, L3 is optionally substituted C1-C6 aliphatic and one or more methylene groups are optionally and independently replaced with -C(O)N(R)- or -N(R)C(O)- and R is as described herein. In some embodiments of any Formulae described herein, L3 is
Figure imgf000032_0001
, wherein z is 0, 1, 2, 3, 4, or 5. In some embodiments of any Formulae described herein, L3 is
Figure imgf000032_0002
wherein z is 0, 1, 2, 3, 4, or 5 and * is a point of attachment to Ring A. In some embodiments of any Formulae described herein, L3 is
Figure imgf000032_0003
wherein z is 0, 1, 2, 3, 4, or 5 and * is a point of attachment to Ring A. [0071] In some embodiments of any Formulae described herein, L3 is
Figure imgf000032_0004
In some embodiments of any Formulae described herein, L3 is
Figure imgf000032_0005
and * is a point of attachment to Ring A. In some embodiments of any Formulae described herein, L3 is
Figure imgf000032_0006
and * is a point of attachment to Ring A. [0072] In some embodiments of any Formulae described herein, X is CH or N. In some embodiments, X is CRx. In some embodiments, X is CH. In some embodiments, X is N. [0073] In some embodiments of any Formulae described herein, Y is CH or N. In some embodiments, Y is CRy. In some embodiments, Y is CH. In some embodiments, Y is N. [0074] In some embodiments of any Formulae described herein, X is CRx and Y is CRy. In some embodiments, both X and Y are CH. [0075] In some embodiments of any Formulae described herein, Rx is hydrogen, halogen, - CN, or optionally substituted C1-6 alkyl. In some embodiments, Rx is hydrogen. In some embodiments, Rx is halogen (e.g., fluoro or chloro). In some embodiments, Rx is –CN. In some embodiments, Rx is optionally substituted C1-6 aliphatic. In some embodiments, Rx is optionally substituted C1-6 alkyl. [0076] In some embodiments of any Formulae described herein, Ry is hydrogen, halogen, - CN, or optionally substituted C1-6 alkyl. In some embodiments, Ry is hydrogen. In some embodiments, Ry is halogen (e.g., fluoro or chloro). In some embodiments, Ry is –CN. In some embodiments, Ry is optionally substituted C1-6 aliphatic. In some embodiments, Ry is optionally substituted C1-6 alkyl. [0077] In some embodiments of any Formulae described herein, Ring A is selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from phenyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered bicyclic cycloaliphatic, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from phenyl and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0078] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is phenyl. [0079] In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a pyrazole or imidazole ring. [0080] In some embodiments, Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0081] In some embodiments, Ring A is optionally substituted 3- to 7-membered monocyclic cycloaliphatic. In some embodiments, Ring A is 3- to 7-membered monocyclic cycloaliphatic. In some embodiments, Ring A is C3-7 cycloalkyl. [0082] In some embodiments, Ring A is optionally substituted 4- to 10-membered bicyclic cycloaliphatic. In some embodiments, Ring A is 4- to 10-membered bicyclic cycloaliphatic (e.g., C4-10 bicyclic cycloalkyl). In some embodiments, Ring A is 7- to 10-membered bicyclic cycloaliphatic (e.g., C7-10 bicyclic cycloalkyl). [0083] In some embodiments, Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a piperidine ring. [0084] In some embodiments, Ring A is optionally substituted 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0085] In some embodiments, Ring A substituted with m Ra groups (i.e.,
Figure imgf000035_0001
) is selected from:
Figure imgf000035_0002
[0086] In some embodiments, Ring A substituted with m Ra groups (i.e.,
Figure imgf000035_0004
) is: . In some embodiments, Ring A substituted w a
Figure imgf000035_0005
ith m R groups is:
Figure imgf000035_0006
. In some embodiments, Ring A substituted with m Ra groups is:
Figure imgf000035_0003
or
Figure imgf000036_0002
. [0087] In some embodiments, Ring A substituted with m Ra groups (i.e.,
Figure imgf000036_0001
is:
Figure imgf000036_0003
[0088] In some embodiments, Ring A substituted with m Ra groups (i.e.,
Figure imgf000037_0001
) is selected from:
Figure imgf000037_0002
[0089] In some embodiments of any Formulae described herein, Ring B is phenyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10- membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted group selected from 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered bicyclic cycloaliphatic, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted group selected from 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted group selected from 3- to 7- membered monocyclic cycloaliphatic and 4- to 10-membered bicyclic cycloaliphatic. In some embodiments, Ring B is 3- to 7-membered monocyclic cycloaliphatic or 4- to 10-membered bicyclic cycloaliphatic.
[0090] In some embodiments, Ring B is optionally substituted phenyl. In some embodiments,
Ring B is phenyl.
[0091] In some embodiments, Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0092] In some embodiments, Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0093] In some embodiments, Ring B is optionally substituted 3- to 7-membered monocyclic cycloaliphatic. In some embodiments, Ring B is 3- to 7-membered monocyclic cycloaliphatic. In some embodiments, Ring B is 3- to 5-membered monocyclic cycloaliphatic. In some embodiments, Ring B is C3-7 monocyclic cycloalkyl. In some embodiments, Ring B is C3-5 monocyclic cycloalkyl (e.g., cyclopropyl). [0094] In some embodiments, Ring B is optionally substituted 4- to 10-membered bicyclic cycloaliphatic. In some embodiments, Ring B is 4- to 10-membered bicyclic cycloaliphatic. In some embodiments, Ring B is 5- to 8-membered bicyclic cycloaliphatic. In some embodiments, Ring B is 4- to 10-membered bicyclic cycloalkyl. In some embodiments, Ring B is 5- to 8- membered bicyclic cycloalkyl. In some embodiments, Ring B is a bicyclo[3.1.0]hexane ring. [0095] In some embodiments, Ring B is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 5- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0096] In some embodiments, Ring B is optionally substituted 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0097] In some embodiments, Ring B substituted with n Rb groups (i.e.,
Figure imgf000040_0003
) is selected from:
Figure imgf000040_0002
In some embodiments, Ring B substituted with n Rb groups is
Figure imgf000040_0001
[0098] In some embodiments of any Formulae described herein, R1 is hydrogen or optionally substituted C1-6 alkyl. In some embodiments, R1 is hydrogen. In some embodiments, R1 is optionally substituted C1-6 aliphatic. In some embodiments, R1 is optionally substituted C1-6 alkyl. In some embodiments, R1 is optionally substituted C1-3 alkyl. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is C1-3 alkyl. In some embodiments, R1 is methyl. [0099] In some embodiments of any Formulae described herein, each Ra is independently Cy1, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, - N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 alkyl. In some embodiments, each Ra is independently Cy1, -OR, or optionally substituted C1-6 aliphatic. In some embodiments, one Ra is Cy1 and another Ra is –OR (e.g., -OCH3). In some embodiments, Ra is Cy1. In some embodiments, no more than one Ra is Cy1. In some embodiments, one and only one Ra is Cy1. In some embodiments, Ra is halogen (e.g., fluoro or chloro). In some embodiments, Ra is –CN, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, - OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, - N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, or -S(O)2OR’. In some embodiments, Ra is – CN. In some embodiments, Ra is -OR, -O(CH2)1-4R, -SR, or -N(R)2. In some embodiments, Ra is –OR (e.g., -OCH3). In some embodiments, at least one Ra is –OR (e.g., -OCH3). In some embodiments, Ra is optionally substituted C1-6 aliphatic. In some embodiments, Ra is optionally substituted C1-6 alkyl. In some embodiments, Ra is C1-6 alkyl optionally substituted with one or more halogen or –OR (e.g., -OH). In some embodiments, Ra is –CH3 or –CH(OH)CH3. [0100] In some embodiments of any Formulae described herein, each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 5- membered monocyclic cycloalkyl, and 5- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy1 is independently substituted with p Rc groups and is independently selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0101] In some embodiments of any Formulae described herein, each Cy1 is independently substituted with p instances of Rc groups and wherein Cy1 is a 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0102] In some embodiments, Cy1 is phenyl substituted with p Rc groups. [0103] In some embodiments, Cy1 is 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is a pyrazole ring substituted with p Rc groups (e.g., substituted with 1-2 Rc groups). In some embodiments, Cy1 is not a tetrazole ring. In some embodiments, Cy1 is 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. [0104] In some embodiments, Cy1 is 3- to 7-membered monocyclic cycloaliphatic substituted with p Rc groups. In some embodiments, Cy1 is 3- to 5-membered monocyclic cycloaliphatic substituted with p Rc groups. In some embodiments, Cy1 is 3- to 7-membered monocyclic cycloalkyl substituted with p Rc groups. In some embodiments, Cy1 is 3- to 5-membered monocyclic cycloalkyl substituted with p Rc groups. In some embodiments Cy1 is a cyclopropane or cyclobutane ring substituted with p Rc groups (e.g., 1-2 Rc groups). [0105] In some embodiments, Cy1 is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 5- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is a tetrahydrofuran ring substituted with p Rc groups (e.g., 1-2 Rc groups). In some embodiments, Cy1 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is a piperidine ring substituted with p Rc groups (e.g., 1-2 Rc groups). [0106] In some embodiments, Cy1 is 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 4- to 10-membered saturated or partially unsaturated spiro bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. In some embodiments, Cy1 is 7- to 10-membered saturated spiro bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with p Rc groups. [0107] In some embodiments, Cy1 substituted with p Rc groups is selected from:
Figure imgf000043_0001
. [0108] In some embodiments, Cy1 substituted with p Rc groups is selected from:
Figure imgf000043_0002
. [0109] In some embodiments, Cy1 substituted with p Rc groups is selected from:
Figure imgf000043_0003
[0110] In some embodiments, Cy1 substituted with p Rc groups is selected from:
Figure imgf000043_0004
. [0111] In some embodiments of any Formulae described herein, each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, - N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or an optionally substituted group selected from C1-6 alkyl, phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic. In some embodiments, Rb is halogen, -CN, or optionally substituted C1-6 aliphatic. In some embodiments, Rb is –CN, -NO2, -C(O)R’, -C(O)OR, - C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, or -S(O)2OR’. In some embodiments, Rb is -OR, -O(CH2)1-4R, -SR, or -N(R)2. In some embodiments, Rb is optionally substituted C1-6 aliphatic (e.g., optionally substituted C1-6 alkyl). In some embodiments, Rb is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7- membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0112] In some embodiments of any Formulae described herein, each Rc is independently Cy2, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, - N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 alkyl. In some embodiments, each Rc is independently Cy2, -CN, -C(O)OR, -C(O)N(R)2, -SO2R’, or optionally substituted C1-6 aliphatic. In some embodiments, each Rc is independently -CN, - C(O)OR, -C(O)N(R)2, -SO2R’, or optionally substituted C1-6 aliphatic. In some embodiments, Rc is Cy2. In some embodiments, no more than one Rc is Cy2. In some embodiments, one and only one Rc is Cy2. In some embodiments, Rc is halogen (e.g., fluoro or chloro). In some embodiments, Rc is –CN, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, - OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, - SO2N(R)2, or -S(O)2OR’. In some embodiments, Rc is –CN. In some embodiments, at least one Rc is –CN. In some embodiments, Rc is -C(O)R’, -C(O)OR, -C(O)N(R)2, -SO2R’, -SO2N(R)2, or -S(O)2OR’. In some embodiments, Rc is -C(O)OR. In some embodiments, Rc is –C(O)O(C1-6 alkyl), e.g., -C(O)OCH3. In some embodiments, Rc is -C(O)N(R)2. In some embodiments, Rc is - C(O)N(H)(C1-6 alkyl) or –C(O)N(C1-6 alkyl)2, e.g., -C(O)N(H)CH3 or –C(O)N(CH3)2. In some embodiments, Rc is -SO2R. In some embodiments, Rc is –SO2(C1-6 alkyl), e.g., -SO2CH2CH3. In some embodiments, Rc is -OR, -O(CH2)1-4R, -SR, or -N(R)2. In some embodiments, Rc is optionally substituted C1-6 aliphatic. In some embodiments, Rc is optionally substituted C1-6 alkyl. In some embodiments, Rc is C1-6 alkyl optionally substituted with one or more halogen or –OR (e.g., -OCH3). In some embodiments, Rc is –CH3, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, or – CH(CH3)CH2OCH3. In some embodiments, Rc is optionally substituted C1-6 aliphatic, wherein each substituent is independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; –NO2; –CN; –N3; -(CH2)0– 4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –(CH2)0–4C(O)R°;–(CH2)0–4C(O)OR°;–(CH2)0–4S(O)2R°; – (CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; -(CH2)0–4S(O)(NH)R°; -(CH2)0– 4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°, wherein each R° may be substituted as defined herein (see, e.g., paragraph [0024]) and is independently hydrogen, C1–6 aliphatic, –CH2Ph, – O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined herein. In some embodiments, Rc is C1-6 aliphatic optionally substituted with -C(O)OR° wherein R° is as described herein. In some embodiments, Rc is C1-6 aliphatic optionally substituted with -OR° wherein R° is as described herein. In some embodiments, Rc is C1-6 aliphatic optionally substituted with -OR° wherein R° is hydrogen or C1- 6 alkyl. In some embodiments, Rc is
Figure imgf000045_0001
optionally substituted with -C(O)OR° wherein R° is as described herein. In some embodiments, Rc is
Figure imgf000046_0001
In some embodiments, Rc is In som c c
Figure imgf000046_0002
e embodiments, R is
Figure imgf000046_0003
In some embodiments, R is
Figure imgf000046_0004
[0113] In some embodiments of any Formulae described herein, each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy2 is independently substituted with q Rd groups and is independently selected from 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered bicyclic cycloaliphatic, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy2 is independently substituted with q Rd groups and is independently selected from 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy2 is independently substituted with q Rd groups and is independently selected from 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy2 is independently substituted with q Rd groups and is independently selected from 3- to 7-membered monocyclic cycloalkyl, 4- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7- to 10-membered saturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0114] In some embodiments, Cy2 is phenyl substituted with q Rd groups. [0115] In some embodiments, Cy2 is 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. [0116] In some embodiments, Cy2 is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. [0117] In some embodiments, Cy2 is 3- to 7-membered monocyclic cycloaliphatic substituted with q Rd groups. In some embodiments, Cy2 is 3- to 5-membered monocyclic cycloaliphatic substituted with q Rd groups. In some embodiments, Cy2 is 3- to 7-membered monocyclic cycloalkyl substituted with q Rd groups. In some embodiments, Cy2 is 3- to 5-membered monocyclic cycloalkyl substituted with q Rd groups. In some embodiments Cy2 is a cyclobutane or cyclopentane ring substituted with q Rd groups (e.g., 0-2 Rd groups). [0118] In some embodiments, Cy2 is 4- to 10-membered bicyclic cycloaliphatic substituted with q Rd groups. In some embodiments, Cy2 is 6- to 9-membered bicyclic cycloaliphatic substituted with q Rd groups. In some embodiments, Cy2 is 4- to 10-membered bicyclic cycloalkyl substituted with q Rd groups. In some embodiments, Cy2 is 6- to 9-membered bicyclic cycloalkyl substituted with q Rd groups. [0119] In some embodiments, Cy2 is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 5- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is a tetrahydrofuran ring substituted with q Rd groups (e.g., 0-2 Rd groups). In some embodiments, Cy2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is a tetrahydropyran ring substituted with q Rd groups (e.g., 0-2 Rd groups). [0120] In some embodiments, Cy2 is 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 4- to 10-membered saturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 7- to 10-membered saturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 7- to 10-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is a 1,6-dioxaspiro[3.4]octane ring substituted with q Rd groups (e.g., 0-2 Rd groups). In some embodiments, Cy2 is 9-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and substituted with q Rd groups. In some embodiments, Cy2 is a 1,7-dioxaspiro[4.4]nonane ring substituted with q Rd groups (e.g., 0-2 Rd groups). [0121] In some embodiments, Cy2 substituted with q Rd groups is selected from:
Figure imgf000048_0001
. [0122] In some embodiments of any Formulae described herein, each Rd is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, - N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 alkyl. In some embodiments, each Rd is independently halogen, -CN, -OR, or optionally substituted C1-6 aliphatic. In some embodiments, Rd is halogen (e.g., fluoro or chloro). In some embodiments, Rd is –CN, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, - OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, or -S(O)2OR’. In some embodiments, Rd is –CN. In some embodiments, Rd is -OR, -O(CH2)1-4R, -SR, or -N(R)2. In some embodiments, Rd is –OR (e.g., -OCH3). In some embodiments, Rd is optionally substituted C1-6 aliphatic. In some embodiments, Rd is optionally substituted C1-6 alkyl. [0123] In some embodiments of any Formulae described herein, m is 0, 1, 2, 3, or 4, as valency permits. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. [0124] In some embodiments of any Formulae described herein, n is 0, 1, 2, 3, or 4, as valency permits. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [0125] In some embodiments of any Formulae described herein, each p is independently 0, 1, 2, 3, or 4, as valency permits. In some embodiments, each p is independently 0, 1, 2, or 3. In some embodiments, each p is independently 0, 1, or 2. In some embodiments, each p is independently 0 or 1. In some embodiments, each p is independently 1, 2, 3, 4, or 5. In some embodiments, each p is independently 1, 2, 3, or 4. In some embodiments, each p is independently 1, 2, or 3. In some embodiments, each p is independently 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. [0126] In some embodiments of any Formulae described herein, each q is independently 0, 1, 2, 3, or 4, as valency permits. In some embodiments, each q is independently 0, 1, 2, or 3. In some embodiments, each q is independently 0, 1, or 2. In some embodiments, each q is independently 0 or 1. In some embodiments, each q is independently 1, 2, 3, 4, or 5. In some embodiments, each q is independently 1, 2, 3, or 4. In some embodiments, each q is independently 1, 2, or 3. In some embodiments, each q is independently 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. [0127] In some embodiments of any Formulae described herein, each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R, when attached to the same nitrogen atom, are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 monocyclic cyloaliphatic. In some embodiments, R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl (e.g., methyl). [0128] In some embodiments of any Formulae described herein, each R’ is independently an optionally substituted group selected from C1-6 alkyl and 3- to 7-membered monocyclic cycloaliphatic. In some embodiments, R’ is optionally substituted C1-6 aliphatic. In some embodiments, R’ is optionally substituted C1-6 alkyl. In some embodiments, R’ is C1-6 alkyl (e.g., methyl or ethyl). In some embodiments, R’ is optionally substituted 3- to 7-membered monocyclic cycloaliphatic. [0129] In some embodiments of any Formulae described herein, the compound is not:
Figure imgf000051_0001
[0130] In some embodiments, the present disclosure provides a compound selected from Table
1, or a pharmaceutically acceptable salt thereof.
Table 1.
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
[0131] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds. For example, in some embodiments, provided compounds are more potent in one or more biochemical or cellular assays (e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein) and/or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases (e.g., over JAK1, JAK3, and/or TYK2), better selectivity over other pseudokinases (e.g., over JAK1-JH2 and/or Tyk2- JH2), and/or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and/or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds. Selectivity over other pseudokinases can be assessed using assays analogous to JAK2 JH2 Domain Binding Assay described in the ensuing examples, utilizing other pseudokinase constructs (e.g., over JAK1-JH2 and/or Tyk2-JH2) in place of JAK2-JH2. In some embodiments, provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds. [0132] In some embodiments, provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977). [0133] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include I’, I’-A, I’-A-1, I’-A-2, I’-B, I’- C, Formulae I-A, I-B, I-B-1, I-C, I-C-1, II, II-A, II-B, II-B-1, II-C, II-C-1, II-D, II-D-1, III, III-A, III-B, III-B-1, III-C, and III-C-1 and compound species of such formulas disclosed herein. Preparing Provided Compounds [0134] Provided compounds may generally be made by the processes described in the ensuing schemes and examples. In some embodiments, provided compounds are prepared according to the following Scheme:
Figure imgf000064_0001
wherein L1 is a leaving group, such as a halogen (e.g., bromo or iodo); L2 is a leaving group, such as a halogen (e.g., bromo or iodo); L3 is a leaving group, such as a halogen (e.g., bromo or iodo) or a cross-coupling electrophile, such as a boronic acid, boronic ester (e.g., -Bpin), or a trialkyltin moiety (e.g., -SnBu3); and Ring A, Ring B, m, n, R1, Ra, Rb, X, and Y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0135] In some embodiments, intermediate A.3 is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 under suitable coupling conditions (e.g., in the presence of a catalyst and optionally, a base and/or a ligand and/or tin compound). In some such embodiments, a suitable catalyst is a palladium catalyst, such as Pd(dppf)2Cl2 or Pd2(dba)3; or a copper catalyst, such as copper(I) iodide. In some such embodiments, a suitable base is Na2CO3 or K2CO3. In some such embodiments, a suitable ligand is a phosphine ligand, such as tri(o-tolyl)phosphine. In some such embodiments, e.g., when L3 is a halogen (such as iodo), suitable coupling conditions comprise a tin compound, such as hexadibutyltin. [0136] In some embodiments, compound A is prepared by a process comprising contacting intermediate A.3 with intermediate A.4 under suitable coupling conditions (e.g., in the presence of a catalyst and optionally, a base and/or a ligand). In some such embodiments, a suitable catalyst is a palladium catalyst, such as Pd2(dba)3. In some such embodiments, a suitable ligand is a phosphine ligand, such as Xantphos. In some such embodiments, a suitable base is Cs2CO3. In some embodiments, a process of preparing compound A further comprises a deprotection step under suitable conditions (e.g., under acidic conditions such as trifluoroacetic acid, followed by basic conditions such as triethylamine to remove a trimethylsilylethoxymethyl (SEM) group; or under H2 in the presence of Pd/C to remove a benzyl group). Compositions [0137] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I’, I’-A, I’- A-1, I’-A-2, I’-B, I’-C, I, I-A, I-B, I-B-1, I-C, I-C-1, II, II-A, II-B, II-B-1, II-C, II-C-1, II-D, II-D- 1, III, III-A, III-B, III-B-1, III-C, and III-C-1). [0138] In some embodiments, a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I’, I’-A, I’- A-1, I’-A-2, I’-B, I’-C, I, I-A, I-B, I-B-1, I-C, I-C-1, II, II-A, II-B, II-B-1, II-C, II-C-1, II-D, II-D- 1, III, III-A, III-B, III-B-1, III-C, and III-C-1) and further comprises a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art. [0139] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
[0140] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein.
Uses
[0141] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
[0142] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2.
[0143] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as JAK2 inhibitors that bind the pseudokinase (JH2) domain of JAK2. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.
[0144] JAK (e.g., JAK2) has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40) and acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (The Lancet. doi: 10.1016/80140-6736(20)30628-0). Accordingly, in some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with JAK2 in a subject in need thereof comprising administering to the subject a provided compound or composition. In some embodiments, a disease, disorder or condition is associated with overexpression of JAK2. [0145] In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof. [0146] In some embodiments, the present disclosure provides methods of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, a hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia). In some embodiments, a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma). In some embodiments, a non- Hodgkin’s lymphoma is a B-cell lymphoma. In some embodiments, a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, a hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, a hematological malignancy is myelodysplastic syndrome. [0147] In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof. [0148] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition. [0149] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care). Exemplary additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of a JAK2 inhibitor with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., et al., Blood Adv.2020, 4(10), 2213-2226). A combination of a JAK2 inhibitor with a LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, J.S., et al., HemaSphere 2018, 2(3), http://dx.doi.org/10.1097/HS9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res.2016, 5(Suppl.4), S616-S628). EXAMPLES [0150] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. [0151] Certain abbreviations utilized in the Examples below: EA = ethyl acetate; DMF = Ν,Ν-dimethylformamide; Dess-Martin periodinane =1,1-dihydro-1,1,1-triacetoxy-l,2-benzoiodooxol-3(1H)-one; DCM= Dichloromethane; THF=Tetrahydrofuran; LAH= Lithium aluminium hydride; DME=1,2-Dimethoxyethane; TEA=Triethylamine; EIPEA=Ethyldiisopropylamine; DEAD= Diethylazodicarboxylate; DIAD=Diisopropyl azodicarboxylate; HATU=2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; EDCI=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride; HOBt=1-Hydroxybenzotriazole; DIBAL-H= Diisobutylaluminium hydride; Bn= Benzyl; DMSO=Dimethyl sulfoxide; RT=room temperature; DBU= 1,8-Diazabicyclo[5.4.0]undec-7-ene; NCS= N-Chlorosuccinimide; LiHMDS= Lithium bis(trimethylsilyl)amide; DMAP=4-Dimethylaminopyridine; n-BuLi=n-Butyllithium; ACN= acetonitrile ; TCFH= Chloro-N,N,N',N'-tetramethylformamidinium Hexafluorophosphate; NMI= 1-Methylimidazole. Preparation of Provided Compounds Example I-1: (1R,5S,6r)-N-(1H-pyrazolo[3,4-c]pyridin-5-yl)bicyclo[3.1.0]hexane-6- carboxamide
Figure imgf000069_0001
[0152] Synthesis of compound I-1. To a solution of (1R,5S,6r)-bicyclo[3.1.0]hexane-6- carboxylic acid (0.05 g, 0.396 mmol, 1 equiv) in THF (5 mL) at 0 ºC were added 1H-pyrazolo[3,4- c]pyridin-5-amine (0.053 g, 0.396 mmol, 1 equiv), diisopropylamine (0.153 g, 1.19 mmol, 3 equiv), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.189 g, 0.99 mmol, 2.5 equiv). The mixture was stirred at room temperature for 12 h and poured into ice-water. The precipitations were collected by filtration, rinsed with water, and dried under vacuum to afford I-1. MS(ES): m/z 243.3 [M+H]+.1H NMR (DMSO-d6, 400 M Hz): δ 10.43 (s, 1H), 8.78 (s, 1H), 8.33 (s, 1H), 3.13 (s, 1H), 2.89 (s, 1H), 1.89 (s, 1H), 1.81-1.69 (m, 6H), 1.64-1.60 (m, 1H). Example I-2: (R)-N-(3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000070_0001
[0153] Synthesis of compound 2.1. To a solution of (S)-tetrahydrofuran-3-ol (2.0 g, 22.72 mmol, 1.0 equiv) in DCM (20 mL) was added triethylamine (8.0 mL, 56.81 mmol, 2.5 equiv) at 0 °C followed by the addition of methanesulfonyl chloride (2.1 mL, 27.27 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2 h, transferred into ice-water, stirred and extracted with DCM. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2.1. [0154] Synthesis of compound 2.2. A mixture of 2.1 (2.0 g, 12.03 mmol, 1.0 equiv), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.87 g, 9.63 mmol 0.8 equiv) and cesium carbonate (11.78 g, 36.14 mmol, 3.0 equiv) in N-Methyl-2-pyrrolidone (50 mL) was stirred at 120 °C for 6 h. The It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 2.2. MS (ES): m/z 265.2 [M+H]+. [0155] Synthesis of compound 2.3. To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4- c]pyridine (0.9 g, 2.78 mmol, 1.0 equiv) in DMF (10 mL) was added sodium hydride (0.333 g, 6.94 mmol, 2.5 equiv) in small portions at 0 °C and stirred for 30 min. To the mixture was added (2-(chloromethoxy) ethyl) trimethylsilane (0.692 g, 4.16 mmol, 1.5 equiv) and stirred at room temperature for 1 h. It was transferred into water, stirred, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 2.3. MS (ES): m/z 454.18 [M+H]+. [0156] Synthesis of compound 2.4. A mixture of 2.3 (0.5 g, 11.0 mmol, 1.0 equiv), 2.2 (0.465 g,17.6 mmol, 1.6 equiv) and sodium carbonate (0.292 g, 27.53 mmol, 2.5 equiv) in acetonitrile (8 mL) and water (2 mL) was degassed by bubbling through a stream of Argon for 10-15 min. [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.080 g, 0.11 mmol, 0.1 equiv) was added and the mixture was stirred at 80 °C for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane) to afford 2.4. MS(ES): m/z 466.44 [M+H]+. [0157] Synthesis of compound 2.5. A mixture of 2.4 (0.320 g, 0.689 mmol, 1.0 equiv), cyclopropanecarboxamide (0.293 g, 3.44 mmol, 5 equiv) and cesium carbonate (0.674 g, 2.06 mmol, 3.0 equiv) in 1, 4-dioxane (3 mL) was degassed by bubbling through a stream of Argon for 10 min.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.119 g, 0.206 mmol, 0.3 equiv) and tris(dibenzylideneacetone)dipalladium. (0.095 g, 0.103 mmol, 0.15 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 130 ºC for 3 h. It was transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane) to afford 2.5. MS(ES): m/z 469.63 [M+H]+. [0158] Synthesis of I-2. To a solution of 2.5 (0.160 g, 0.311 mmol, 1.0 equiv) in DCM (3 mL) at 0 °C was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at rt for 3 h. It was transfer into a saturated solution of sodium bicarbonate and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added methanol (3 mL), triethylamine (2 mL) and water (2 mL) and the solution was stirred at rt for 16 h. It was poured into water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM) to afford I-2. MS(ES): m/z: 339.3 [M+H]+, 1H NMR (DMSO-d6, 400MHz): δ 13.44 (s, 1H), 10.76 (s, 1H), 8.79 (s, 1H ) 8.50 (s,1H) , 8.25 (s,1H) , 7.93 (s, 1H), 5.17 (bs, 1H), 4.05-3.93 (m, 4H), 3.88-3.82 (m, 1H), 2.41-2.32 (m, 2H), 2.019 (m, 2H), 0.79 (m, 4H). Example I-3: (R)-N-(1-methyl-3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000072_0001
[0159] Synthesis of compound 3.1. To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4- c]pyridine (0.2 g, 0.617 mmol, 1 equiv) in DMF (4 mL) was added sodium hydride (0.054 g, 1.234 mmol, 2 equiv) at 0 ºC and stirred at room temperature of 15 min. Methyl iodide (0.131 g, 0.925 mmol, 1.5 equiv) was added and stirred at room temperature for 15 min. The reaction mixture was transferred into ice-water slowly, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 3.1. MS (ES): m/z 338.95 [M+H]+. [0160] Synthesis of compound 3.2. Compound 3.2 was prepared from compound 3.1 and 2.2, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 349.2 [M+H]+. [0161] Synthesis of I-3. Compound I-3 was prepared from compound 3.2, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES): m/z 353.40 [M+H]+; 1H NMR (DMSO-d6, 400 M Hz): δ 10.82 (s, 1H), 8.94 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 5.17 (bs, 1H), 4.13 (s, 3H), 3.84-3.87 (m, 1H), 3.92-3.98 (m, 3H), 2.47 (m, 2H), 2.02 (m, 1H), 0.78 (m, 4H). Example I-4: (1R,5S,6r)-N-(3-(piperidin-1-yl)-1H-pyrazolo[3,4-c]pyridin-5- yl)bicyclo[3.1.0]hexane-6-carboxamide
Figure imgf000073_0001
[0162] Synthesis of compound 4.1. A solution of 2.3 (0.7 g, 1.54 mmol, 1.0 equiv) and piperidine (0.131 g, 1.54 mmol, 1 equiv) in DMSO (10 mL) was degassed by bubbling through a stream of Argon for 10 min. Potassium carbonate (0.638 g, 4.62 mmol, 3.0 equiv), copper iodide (0.03 g, 0.15 mmol, 0.1 equiv) and L-proline (0.053 g, 0.46 mmol, 0.3 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 90 ºC temperature for 6 h. It was cooled to room temperature, transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 4.1. MS(ES): m/z 411.1 [M+H]+. [0163] Synthesis of compound 4.2. Compound 4.2 was prepared from compound 4.1 and (1R,5S,6r)-bicyclo[3.1.0]hexane-6-carboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane). MS(ES): m/z 455.68 [M+H]+. [0164] Synthesis of compound I-4. Compound I-4 was prepared from compound 4.2, following the procedure described in the synthesis of compound I-2. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 325.42 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 12.31 (s, 1H), 10.38 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 3.26 (bs, 4H), 1.86-1.73 (m, 8H), 1.67-1.58 (bs, 2H), 1.44-1.33 (bs, 2H), 1.23 (s, 2H), 1.086-1.064 (bs, 2H). Example I-5: N-benzyl-5-((1R,5S,6r)-bicyclo[3.1.0]hexane-6-carboxamido)-1H-pyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000074_0001
[0165] Synthesis of compound 5.1. A solution of 2.3 (0.7 g, 1.54 mmol, 1.0 equiv) in DMF (3.5 mL) and methanol (2.5 mL) was degassed by bubbling through a stream of carbon monoxide for 10 min. Tris(dibenzylideneacetone)dipalladium and trimethylamine (0.5 mL, 4.6 mmol, 3.0 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 80 ºC under carbon monoxide atmosphere (1 atm) for 16 h. It was cooled to room temperature, transferred into ice- water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford 5.1. MS(ES): m/z 386.32 [M+H]+. [0166] Synthesis of compound 5.2. A solution of 5.1 (350 mg, 0.909 mmol, 1.0 equiv) and lithium hydroxide (381 mg, 9.09 mmol, 10 equiv) in THF (8 mL), methanol (4 mL) and water (2 mL) was stirred at room temperature for 4 h. It was transferred into ice-water and acidify with 1 N HCl to pH 3. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5.2. MS(ES): m/z 372.29 [M+H]+. [0167] Synthesis of compound 5.3. A solution of 5.2 (230 mg, 0.6199 mmol, 1.0 equiv) and hexafluorophosphateazabenzotriazoletetramethyluronium (353 mg, 0.929 mmol, 1.5 equiv) in DMF (7 mL) was stirred at 0 °C for 30 min. To the mixture were added diisopropylethylamine (239 mg, 1.85 mmol, 3.0 equiv) and benzyl amine (79 mg, 0.743 mmol, 1.2 equiv). It was stirred for 2 h, transferred into water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane ) to afford 5.3. MS (ES): m/z 461.43 [M+H]+. [0168] Synthesis of compound 5.4. Compound 5.4 was prepared from compound 5.3 and (1R,5S,6r)-bicyclo[3.1.0]hexane-6-carboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane). MS(ES): m/z 505.69 [M+H]+. [0169] Synthesis of compound I-5. Compound I-5 was prepared from compound 5.4, following the procedure described in the synthesis of compound I-2. The product was purified by flash column chromatography on silica gel (Combiflash®, 24% ethyl acetate in hexane). MS(ES): m/z 375.43 [M+H]+; 1H NMR (DMSO-d6, 400 M Hz): δ 9.02 (s, 1H), 8.85 (s, 1H), 8.70 (s, 1H), 7.33-7.31 (m, 5H), 5.84 (m, 2H), 4.48 (m, 2H), 4.89 (s, 1H), 1.74 (m, 6H), 1.22 (m, 4H). Example I-6: N-(3-(3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000076_0001
[0170] Synthesis of compound 6.1. To a solution of 4-bromo-1H-pyrazole (5.0 g, 34.013 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60 % in mineral oil, 3.4 g, 85.034 mmol, 2.5 equiv) in portions at 0 °C and stirred for 30 min. To the mixture was added dropwise bromocyclobutane (4.6 g, 34.013 mmol, 1.1 equiv). The reaction mixture was stirred at 90 ºC overnight. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. flash column chromatography on silica gel 15.0% ethyl acetate in hexane) to afford 6.1. MS(ES): m/z: 202.28[M+H]+. [0171] Synthesis of compound 6.2. A mixture of 6.1 (2.0 g, 9.950 mmol, 1.0 equiv), 2- methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.96 g, 11.940 mmol, 1.2 equiv) and potassium carbonate (1.27 g, 29.85 mmol, 3.0 equiv) in 1,4-dioxane (8 mL) and water (2 mL) was degassed by bubbling through argon for 10 min. (1,1'- Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.404 g, 0.497 mmol, 0.05 equiv) was added to the reaction mixture and stirred at 100 °C for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®,10% ethyl acetate in hexane) to afford 6.2. MS(ES): m/z 244.5 [M+H]+. [0172] Synthesis of compound 6.3. To a stirred solution of 6.2 (2.0 g, 8.230 mmol, 1.0 equiv) in acetonitrile (20 mL) at 0 ºC was added copper (II) bromide (1.8 g, 8.230 mmol, 1.0 equiv) and tert-butyl nitrite (0.932 g, 9.053 mmol, 1.1 equiv). The reaction mixture was stirred at 0 °C for 30 min. It was transferred into water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% ethyl acetate in hexane) to afford 6.3. MS (ES): m/z 308.20 [M+H]+. [0173] Synthesis of compound 6.4. A mixture of 6.3 (1.0 g, 3.257 mmol, 1.0 equiv, bis(pinacolato)diboron (1.24 g, 4.885 mmol, 1.5 equiv) and potassium acetate (0.957 g, 9.771 mmol, 3.0 equiv) in dioxane (20 mL) was degassed by bubbling through a stream of Argon for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium (II), complex with DCM (0.132 g, 0.162 mmol, 0.05 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 90ºC for 16 h. It was cooled to room temperature, filtered through a pad of Celite. Filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 6.4. MS(ES): m/z 355.30 [M+H]+. [0174] Synthesis of compound 6.5. Compound 6.5 was prepared from compound 6.4 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane). MS(ES): m/z 439.33 [M+H]+. [0175] Synthesis of compound I-6. Compound I-6 was prepared from compound 6.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS (ES): m/z 433.5 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): 10.77 (s, 1H), 8.99 (s,1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.74 (d, J = 8.0 Hz 1H), 7.40 (d, J = 7.6 Hz 1H), 7.27-7.25 (t, J = 7.2 Hz 1H), 4.92-4.88 (t, J = 8 Hz 1H), 4.22 (s, 3H), 3.27 (s, 3H), 2.43-2.37 (bs, 3H), 2.00 (d, J = 5.6 Hz 1H), 1.81-1.77 (m, 3H), 0.78-0.77 (m, 4H). Example I-7: 4-(3-(5-(cyclopropanecarboxamido)-1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)- 1H-pyrazol-1-yl)-N,N-dimethylbenzamide
Figure imgf000078_0001
[0176] Synthesis of compound 7.1. A mixture of ethyl 4-fluorobenzoate (2.0 g, 11.892 mmol, 1.0 equiv), potassium carbonate (3.28 g, 23.78 mmol, 2.0 equiv.) and 3-bromo-1H-pyrazole (1.75 g, 11.892 mmol, 1.0 equiv) in DMF (10 mL) was stirred at 120 ºC overnight. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (15% ethyl acetate in hexane) to afford 7.1. MS(ES): m/z: 295.14[M+H]+. [0177] Synthesis of compound 7.2. To a solution of 7.1 (1.4 g, 4.7 mmol, 1.0 equiv) and lithium hydroxide (0.996 g, 23.717 mmol, 1.2 equiv) in THF (8 mL) and water (2 mL) was stirred at room temperature for 24 h. It was transferred into ice-water, acidified by 1N HCl to pH 3, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 7.2. MS(ES): m/z 267.08[M+H]+. [0178] Synthesis of compound 7.3. To a solution of 7.2 (0.900 g, 3.369 mmol, 1.0 equiv) in DMF (10 mL) at 0 ºC was added hexafluorophosphateazabenzotriazoletetramethyluronium (1.920 g, 5.054 mmol, 1.5 equiv) and stirred for 30 min. Diisopropylethylamine (1.30 g, 10.109 mmol, 3.0 equiv) and dimethylamine (0.167 g, 3.706 mmol, 1.1 equiv) were added and stirred for 2 h. It was transferred into water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM) to afford 7.3. MS (ES): m/z 294.15 [M+H]+. [0179] Synthesis of compound 7.4. A mixture of 7.3 (0.700 g, 2.379 mmol, 1.0 equiv), bis(pinacolato)diboron (0.906 g, 3.569 mmol, 1.5 equiv) and potassium acetate (0.699 g, 7.139 mmol, 3.0 equiv) in dioxane (10 mL) was degassed by bubbling through a stream of Argon for 10 min. Bis(triphenylphosphine)palladium(II) dichloride (0.209 g,0.237 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 16 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 7.4. MS(ES): m/z 341.22 [M+H]+. [0180] Synthesis of compound 7.5. Compound 7.5 was prepared from compound 7.4 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane) to afford 7.5. MS(ES): m/z 425.29 [M+H]+. [0181] Synthesis of compound I-7. Compound I-7 was prepared from compound 7.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5.0% methanol in DCM) to afford I-7. MS (ES): m/z 429.48 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): 10.806 (s, 1H), 8.99 (s,1H), 8.54 (s,1H), 8.71 (s,1H), 8.02-8.00 (d, J = 8.0 Hz 2H), 8.61-8.59 (d, J = 8.0 Hz 2H), 7.04 (s, 1H), 4.15 (s, 3H), 2.99 (s, 6H), 2.04 (m,1H), 0.78-0.77 (m, 4H). Example I-8: (R)-N-(3-(2-methoxy-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000080_0001
[0182] Synthesis of compound 8.1. A mixture of 2.2 (6.8 g, 33.66 mmol, 1.0 equiv) and 3- bromo-2-methoxyaniline (10.66 g, 40.39 mmol, 1.2 equiv) in 1,4-dioxane (68 mL) and water(20.4 mL) was degassed by bubbling through a stream of Argon for 10 min. Potassium carbonate (13.93 g, 100 mmol, 3.0 equiv) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with DCM (2.46 g, 3.36 mmol, 0.1 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 100 ºC temperature for 1 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 29% ethyl acetate in hexane) to afford 8.1. MS(ES): m/z 260.31 [M+H]+. [0183] Synthesis of compound 8.2. To a solution of 8.1 (2.95 g, 11.38 mmol, 1.0 equiv) in acetonitrile(30 mL) at 0 ºC was added copper bromide (2.5 g, 11.38 mmol, 1.0 equiv) followed by t-butyl nitrile (1.28 g, 12.4 mmol,1.1 equiv). The reaction mixture was stirred for 2 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 8.2. MS(ES): m/z 324.19 [M+H]+. [0184] Synthesis of compound 8.3. A mixture of 8.2 (1.29 g, 3.9 mmol, 1.0 equiv) and bis(pinacolato)diboron (1.21 g, 4.79 mmol, 1.2 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling through a stream of Argon for 10 min. Potassium acetate (0.78 g, 7.8 mmol, 2.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.291 g, 0.39 mmol, 0.1 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 100 ºC temperature for 16 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane) to afford 8.3. MS(ES): m/z 371.26 [M+H]+. [0185] Synthesis of compound 8.4. A mixture of 8.3 (0.3 g, 0.81 mmol, 1.0 equiv) and 3.1 (0.273 g, 0.81 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling through a stream of Argon for 10 min. Sodium carbonate (0.175 g, 1.62 mmol, 2.0 equiv), and [1,1′- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.132 g, 0.16 mmol, 0.2 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 90 ºC for 1 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane) to afford 8.4. MS(ES): m/z 455.33 [M+H]+. [0186] Synthesis of compound I-8. Compound I-8 was prepared from compound 8.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 459.30 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.88 (s, 1H), 9.01 (d, J = 1.2 Hz, 1H), 8.77 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.81 (d, J = 8 Hz, 1H), 7.56 (d, J = 1.2 Hz 1H), 7.49 (bs, 1H), 5.10 (bs, 1H), 4.22 (s, 3H), 4.04 (bs, 2H), 3.92 (s, 3H), 3.88 (m, 2H), 2.50 (m, 2H), 1.29 (m, 1H), 0.85 (m, 4H) Example I-9-a and I-9-b: (R)-N-(3-(2-methoxy-3-(1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4- yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(2- methoxy-3-(1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000082_0001
[0187] Synthesis of compound 9.1. A solution of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol, 1.0 equiv), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.51 g, 12.93 mmol, 1.5 equiv) and potassium phosphate (3.65 g, 17.24 mmol, 2.0 equiv) in dioxane (40 mL) and water (8 ml) was degassed for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.126 g, 0.17 mmol, 0.05 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 120 ºC for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 19.1. MS(ES): m/z 220.21 [M+H]+. [0188] Synthesis of compound 9.2. A mixture of 9.1 (2.1 g, 9.58 mmol, 1.0 equiv), 5-bromo- 3,4-dihydro-2H-pyran (4.69 g, 28.74 mmol, 3 equiv) and potassium carbonate (3.96 g, 28.74 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was degassed by bubbling through a stream of argon for 10 min. N, N-dimethylethylenediamine (0.253 g, 2.87 mmol, 0.3 equiv) and copper iodide (0.366 g, 1.91 mmol, 0.2 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 120 ºC for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sufhate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford 9.2. MS(ES): m/z 302.41 [M+H]+. [0189] Synthesis of compound (±)-9.3. A mixture of 10% palladium on carbon (0.2 g) and 9.2 (0.40 g, 1.49 mmol, 1.0 equiv) in methanol was stirred at rt under hydrogen atmosphere for 2 h.. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to obtain (±)-9.3. MS(ES): m/z 274.4 [M+H]+. [0190] Synthesis of compound (±)-9.4. To a solution of (±)-9.3 (3.5 g, 12.80 mmol, 1.0 equiv) in 3 N hydrochloric acid (20 mL) at -5°C was added sodium nitrite (0.958 g, 14.10 mmol, 1.1 equiv) in water (5 mL). The reaction mixture was stirred for 30 min and was added a solution of potassium iodide (6.38 g, 38.46 mmol, 3.0 equiv) in water (5 mL). It was allowed to warm at room temperature and stir for 30 min. It was transferred into ice-water, neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford (±)-9.4. MS(ES): m/z 385.2 [M+H]+. [0191] Synthesis of compound (±)-9.5. A mixture of (±)-9.5 (1.0 g, 2.60 mmol, 1.0 equiv), 3.1 (0.877 g, 2.60 mmol, 1.0 equiv), tri-o-tolyl phosphine (0.158 g, 0.52 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.119 g, 0.13 mmol, 0.05 equiv) in toluene (15 mL) was degassed by bubbling through a stream of Argon for 10 min. Hexabutylditine (0.755 g, 1.30 mmol, 0.5 equiv) was added and the reaction mixture was stirred at 100 ºC for 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford (±)-9.5. MS(ES): m/z 470.37 [M+H]+. [0192] 9.5-a and 9.5-b. The racemate was separated by SFC (column: CHIRALPAK-IC (250 x 21 mm, 5 μm); mobile phases: (A) CO2, (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (9.5-a), MS(ES): m/z 274.4 [M+H]+ and (9.5- b), MS(ES): m/z 470.37 [M+H]+. *The absolute configuration of the chiral center is not determined. [0193] Synthesis of I-9-a. Compound I-9-a was prepared from compound 9.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 473.19 [M+H]+.1H NMR (DMSO-d6, 400 M Hz): δ 10.79 (s, 1H), 9.00-8.99 (d, J = 4 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.74-7.72 (m, 1H), 7.39 (dd, J = 1.2 Hz,8.8 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 4.37-4.26 (m, 1H), 4.25 (s, 3H), 4.04-3.99 (m, 1H), 3.83-3.80 (m, 1H), 3.67-3.62 (m, 1H), 3.27 (s, 3H), 2.17-1.99 (m, 2H), 1.52-1.49 (m, 4H), 0.62-0.59 (m, 4H). [0194] Synthesis of I-9-b. Compound I-9-b was prepared from compound 9.4-b and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 473.19 [M+H]+; 1H NMR (DMSO-d6, 400 M Hz): δ 10.79 (s, 1H), 9.00-8.99 (d, J = 4 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.74-7.72 (m, 1H), 7.40 (dd, J = 1.2, 8.8 Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 4.37-4.26 (m, 1H), 4.25 (s, 3H), 4.04-3.94 (m, 1H), 3.83-3.80 (m, 1H), 3.65-3.62 (m, 1H), 3.27 (s, 3H), 2.17-1.99 (m, 2H), 1.52-1.46 (m, 4H), 0.62-0.58 (m, 4H). Example I-10: N-(3-(2-methoxy-3-(1-((1S,2S)-2-methoxycyclopentyl)-1H-pyrazol-4-yl)phenyl)- 1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(2-methoxy-3-(1- ((1R,2R)-2-methoxycyclopentyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)cyclopropanecarboxamide
Figure imgf000084_0001
Figure imgf000085_0001
[0195] Synthesis of compound trans-(±)-10.1. To a mixture of 4-bromo-1H-pyrazole (10.0 g, 68.04 mmol, 1.0 equiv), cesium carbonate (44.35 g, 136.54 mmol, 2.0 equiv) and 6- oxabicyclo[3.1.0]hexane (5.72 g, 68.04 mmol, 1.0 equiv) in DMF (120 mL) was stirred at 90 °C for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford trans-(±)-10.1. MS(ES): m/z 231.09 [M+H]+. [0196] Synthesis of compound trans-(±)-10.2. To a solution of trans-(±)-10.1 (3.5 g, 15.15 mmol, 1.0 equiv) in DMF (40 mL) was added sodium hydride (60% dispersion in mineral oil, 1.21 g, 30.30 mmol, 2.0 equiv) at 0 ºC for 15 min. Methyl iodide (1.22 mL, 19.69 mmol, 1.3 equiv) was added and stirred for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane) to afford trans-(±)-10.2. MS(ES): m/z 246.59 [M+H]+. [0197] Synthesis of compound trans-(±)-10.3. A mixture of trans-(±)-10.2 (2.5 g, 10.20 mmol, 1.0 equiv), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.82 g, 15.30 mmol, 1.5 equiv) and potassium phosphate (6.48 g, 30.61 mmol, 3.0 equiv) in 1,4-dioxane (30 mL) and water (8 mL) was degassed by bubbling through a stream of Argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.745 g, 1.02 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 1.5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 28% ethyl acetate in hexane) to afford trans-10.3. MS(ES): m/z 288.61 [M+H]+. [0198] Synthesis of compound trans-(±)-10.4. Compound trans-(±)-10.4 was prepared from compound trans-(±)-10.3, following the procedure described in the synthesis of compound (±)- 9.4. The product purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate [0199] Synthesis of compound trans-(±)-10.5. Compound trans-(±)-10.5 was prepared from compound trans-(±)-10.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane). MS(ES): m/z 483.62 [M+H]+. [0200] trans-10.5-a and trans-10.5-b. The racemate was separated by HPLC (column: CHIRALPAK-IC (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (trans-10.5-a), MS(ES): m/z 483.37 [M+H]+, and second eluting fraction (trans-10.5-b), MS(ES): m/z 483.45 [M+H]+. *The absolute configuration of the chiral center is not determined. [0201] Synthesis of I-10-a. Compound I-10-a was prepared from compound trans-10.5-a and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 487.50 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.83 (s, 1H), 8.99 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.75-7.73 (dd, 1H), 7.40- 7.38 (dd, 1H), 7.28.-7.24 (t, J = 6.8 Hz, 1H), 4.63 (bs, 1H), 4.22 (s, 3H), 4.00 (bs, 1H), 3.32 (s, 3H), 3.21 (s, 3H), 2.17 (bs, 2H), 2.06-1.99 (m, 2H), 1.75 (bs, 2H), 1.23 (bs, 1H), 0.77-0.75 (m, 4H). [0202] Synthesis of I-10-b. Compound I-10-b was prepared from compound trans-10.5-b and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 487.55 [M+H]+; 1H NMR (DMSO-d6, 400 M Hz): δ 10.79 (s, 1H), 8.99 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.75-7.73 (dd, 1H), 7.40- 7.38 (dd, 1H), 7.28.-7.24 (t, J = 6.8 Hz, 1H), 4.63 (bs, 1H), 4.22 (s, 3H), 4.00 (bs, 1H), 3.32 (s, 3H), 3.21 (s, 3H), 2.17 (bs, 2H), 2.06-1.99 (m, 2H), 1.75 (bs, 2H), 1.23 (bs, 1H), 0.77-0.75 (m, 4H). Example I-11-a and I-11-b: (R)-N-(3-(2-methoxy-3-(1-(1-methoxypropan-2-yl)-1H-pyrazol-4- yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(2- methoxy-3-(1-(1-methoxypropan-2-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000087_0001
[0203] Synthesis of compound (±)-11.1. To a stirred solution of 1-methoxypropan-2-ol (3 g, 33.29 mmol, 1.0 equiv) and triethylamine (10 g, 99.99 mmol, 3.0 equiv) in DCM at 0 ºC was added methansulfonyl chloride (5.74 g, 49.99 mmol, 1.5 equiv). The reaction mixture was stirred for 1.5 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-11.1. It was used in the next step without purification. MS(ES): m/z 168.21 [M+H]+. [0204] Synthesis of compound (±)-11.2. To a solution of (±)-11.1 (1.75 g, 11.88 mmol, 1 equiv) in dimethylformamide(20 mL) was added sodium hydride (1.7 g, 35.71 mmol, 3 equiv) at 0 ºC and stirred at room temperature of 1 h. To the mixture was added 4-bromo-1H-pyrazole (3 g, 17.83 mmol, 1.5 equiv) and stirred at room temperature for 1 h. It was added into ice-water slowly, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-11.2. MS (ES): m/z 220.08 [M+H]+. [0205] Synthesis of compound (±)-11.3. A mixture of (±)-11.2 (1.6 g, 7.3 mmol, 1.0 equiv) and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.73 g, 10.95 mmol, 1.5 equiv) in 1,4-dioxane (16 mL) and water(4 mL) was degassed for 10 min. Potassium carbonate (2.01 g, 14.60 mmol, 2.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.596 g, 0.73 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 1 h. It was cooled to room temperature, transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford (±)-11.3. MS(ES): m/z 262.32 [M+H]+. [0206] Synthesis of compound (±)-11.4. Compound (±)-11.4 was prepared from compound (±)-11.3, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 373.21 [M+H]+. [0207] Synthesis of compound (±)-11.5. Compound (±)-11.5 was prepared from compound (±)-11.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane). MS(ES): m/z 456.34 [M+H]+. [0208] 11.5-a and 11.5-b. The racemate was separated by HPLC (column: CHIRALPAK IB- N (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in isopropanol: MeCN (70: 30); flow rate: 20 mL/min) to afford first eluting fraction (11.5-a), MS(ES): m/z 456.34 [M+H]+, and second eluting fraction (11.5-b), MS(ES): m/z 456.34 [M+H]+. *The absolute configuration of the chiral center is not determined. [0209] Synthesis of compound I-11-a. Compound I-11-a was prepared from compound 11.5- a and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 461.54 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.78 (s, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.8 Hz 1H), 7.27 (t, J = 15.2 Hz, 1H), 4.61 (bs, 1H), 4.22 (s, 3H), 3.67 (m, 2H), 3.29 (s, 3H), 3.22 (s, 3H), 1.99 (bs, 1H), 1.43 (d, J = 6.8 Hz, 3H), 0.77 (m, 4H). [0210] Synthesis of compound I-11-b. Compound I-11-b was prepared from compound 11.5- b and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 461.54 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.79 (s, 1H), 8.99 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.40 (d, J = 9.2 Hz 1H), 7.27 (t, J = 15.2 Hz, 1H), 4.64 (bs, 1H), 4.22 (s, 3H), 3.69 (m, 2H), 3.31 (s, 3H), 3.22 (s, 3H), 2.01 (bs, 1H), 1.43 (d, J = 7.2 Hz, 3H), 0.77 (m, 4H). Example I-12-a and I-12-b: N-(3-(2-methoxy-3-(1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(2-methoxy-3-(1-((3S,4R)-4-methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000089_0001
Figure imgf000090_0001
[0211] Synthesis of compound (±)-12.2. To a solution of (±)-12.1 (20 g, 85.83 mmol, 1.0 equiv) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 6.86 g, 171.67 mmol, 2.0 equiv) in portions at 0 °C and stirred for 30 min. Methyl iodide (8.0 mL, 128.75 mmol, 1.5 equiv) was added dropwise to reaction mixture and stirred for 30 min at rt. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-12.2. MS(ES): m/z 248.00 [M+H]+. [0212] Synthesis of compound (±)-12.3. Compound (±)-12.3 was prepared from (±)-12.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following the procedure described in the synthesis of trans-(±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 290.15 [M+H]+. [0213] Synthesis of compound (±)-12.4. Compound (±)-12.4 was prepared from compound (±)-12.3, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 41% ethyl acetate in hexane). MS(ES): m/z 401.03 [M+H]+. [0214] Synthesis of compound (±)-12.5. Compound (±)-12.5 was prepared from compound (±)-12.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by combi-flash using 42% to 52% ethyl acetate in hexane). MS(ES): m/z 485.09 [M+H]+. [0215] Synthesis of compound (±)-I-12. Compound (±)-I-12 was prepared from compound (±)-12.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 0.5% to 1% methanol in DCM). MS(ES): m/z 489.2[M+H]+. [0216] I-12-a and I-12-b. The racemate was separated by SFC (column: CHIRALPAK AD- H (250 x 21 mm, 5 μm); mobile phases: (A) CO2, (B) 0.1% diethylamine in isopropanol: MeOH (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-12-a) and second eluting fraction (I-12-b). *The absolute configuration of the chiral center is not determined. I-12-a: MS(ES): m/z 489.5 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.33 (s, 2H), 8.04 (s, 1H), 7.75 (d, J = 8 Hz,1H), 7.40 (d, J = 8 Hz,1H), 7.27 (t, 1H), 5.09 (s, 1H), 4.22-4.16(m, 5H), 4.09-4.02(m, 2H), 3.79(d, J = 10 Hz, 1H), 3.28(s, 3H), 2.49(s, 3H), 1.99- 1.98 (m, 1H), 0.77 (s, 4H). I-12-b: MS(ES): m/z 489.5 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.33 (s, 2H), 8.04 (s, 1H), 7.75 (d, J = 7.6 Hz,1H), 7.40 (d, J = 7.6 Hz,1H), 7.27 (t, 1H), 5.05- 5.02 (m, 1H), 4.22-4.20 (m, 4H),4.18(m, 1H), 4.1-4.06(m, 1H), 4.03-4.00(m, 1H), 3.79(d, J = 10 Hz, 1H), 3.28(s, 3H), 2.47(s, 3H), 2.01-1.98 (m, 1H), 0.77-0.75 (m, 4H). Example I-13: N-(3-(2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000091_0001
[0217] Synthesis of compound 13.1. Compound 13.1 was prepared from 3-bromo-2- methoxyaniline and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure described in the synthesis of trans-(±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 204.1 [M+H]+. [0218] Synthesis of compound 13.2. Compound 13.2 was prepared from compound 13.1, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 8% ethyl acetate in hexane). MS(ES): m/z 314.99 [M+H]+. [0219] Synthesis of compound 13.3. Compound 13.3 was prepared from compound 13.2 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 399.0 [M+H]+. [0220] Synthesis of compound I-13. Compound I-13 was prepared from compound 13.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 403.1 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.78 (s, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.73-7.70 (dd, J = 8 Hz, 1H), 7.40-7.38 (dd, J = 7.6 Hz,1H), 7.25 (t, 1H), 4.22(s, 3H), 3.90(s, 3H), 3.27(s, 3H), 1.96-2.02 (m, 1H), 0.75- 0.78 (m, 4H). Example I-14: N-(3-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000092_0001
[0221] Synthesis of compound 14.1. Compound 14.1 was prepared from 3-bromo-1-methyl- 1H-pyrazole and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of trans-(±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 204.1 [M+H]+. [0222] Synthesis of compound 14.2. Compound 14.2 was prepared from compound 14.1, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 08% ethyl acetate in hexane). MS(ES): m/z 314.99 [M+H]+. [0223] Synthesis of compound 14.3. Compound 14.3 was prepared from compound 14.2 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 399.0 [M+H]+. [0224] Synthesis of compound I-14. Compound I-14 was prepared from compound 14.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 403.1 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.78 (s, 1H), 9.00 (s, 1H), 8.38 (s, 1H), 7.94-7.97 (d, J = 12 Hz,1H), 7.79 (s, 1H), 7.50-7.53 (d, J = 12 Hz,1H), 7.29 (t, 1H), 6.73 (s, 1H), 4.23 (s, 3H), 3.93 (s, 3H), 3.30 (s, 3H), 1.96-2.04 (m, 1H), 0.76-0.79 (m, 4H). Example I-15: (R)-N-(1-methyl-3-(3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000093_0001
[0225] Synthesis of compound 15.1. To a solution of 4-bromo-1H-pyrazole (5 g, 34.01 mmol, 1.0 equiv) and 2.1 (7.3 g, 44.21 mmol, 1.3 equiv) in DMF (100 mL) was added cesium carbonate (22 g, 68.02 mmol, 2.0 equiv). The reaction mixture was stirred at 90 ºC for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 15.1. MS(ES): m/z 218.32 [M+H]+. [0226] Synthesis of compound 15.2. Compound 15.2 was prepared from compound 15.1 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-9.2. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS(ES): m/z 230.28 [M+H]+. [0227] Synthesis of compound 15.3. Compound 15.3 was prepared from compound 15.2, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane. MS(ES): m/z 341.2 [M+H]+. [0228] Synthesis of compound 15.4. Compound 15.4 was prepared from compound 15.3 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate in hexane). MS(ES): m/z 425.63 [M+H]+. [0229] Synthesis of I-15. Compound I-15 was prepared from compound 15.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 429.39 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.90 (s, 1H), 9.03 (s, 1H), 8.76 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.69-7.64 (m, 2H), 7.56 (s, 1H), 5.06 (bs, 1H), 4.23 (s, 3H), 4.04-3.98 (m, 3H), 3.86-3.85 (m, 1H), 2.42-2.33 (m, 2H), 2.06 (bs, 1H), 0.85-0.80 (m, 4H). Example I-16: N-(3-(3-(1-cyclobutyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000095_0001
[0230] Synthesis of compound 16.1. Compound 16.1 was prepared from compound 6.1 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-9.2. The product was purified by flash column chromatography on silica gel (Combiflash®, 50.0% ethyl acetate in hexane). MS(ES): m/z 213.3 [M+H]+. [0231] Synthesis of compound 16.2. Compound 16.2 was prepared from compound 16.1, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane). MS (ES): m/z 324.17 [M+H]+. [0232] Synthesis of compound 16.3. Compound 16.3 was prepared from compound 16.2 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 408.30 [M+H]+. [0233] Synthesis of compound I-16. Compound I-16 was prepared from compound 16.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 412.5 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): 10.90 (s, 1H), 9.02 (s, 1H), 8.77(s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.95(s, 1H), 7.70-7.68 (d, J = 7.2 Hz 1H), 7.65-7.63 (d, J = 7.2 Hz 1H), 7.56-7.52 (m, 1H), 4.89-4.85 (m, 1H),4.23(s,3H), 2.05 (m, 1H), 1.82- 1.80 (m, 2H), 1.16(m, 4H), 0.86-0.81 (m, 4H). Example I-17: (R)-N-(3-(3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000096_0001
[0234] Synthesis of compound 17.1. Compound 17.1 was prepared from compound 15.3 and 2.3, following the procedure described in the synthesis of compound (±)-9.5. The product his was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane). MS(ES): m/z 541.37 [M+H]+. [0235] Synthesis of compound 17.2. Compound 17.2 was prepared from compound 17.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 545.37 [M+H]+. [0236] Synthesis of I-17. Compound I-17 was prepared from compound 17.2 following the procedure described in the synthesis of compound I-2. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM). MS(ES): m/z 415.19 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 13.71 (s, 1H), 10.84 (s, 1H), 8.88 (s, 1H), 8.77 (s, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8 Hz, 1H), 5.06 (bs, 1H), 4.06-3.98 (m, 3H), 3.88-3.85 (m, 1H), 2.44-2.38 (m, 2H), 2.06 (bs, 1H), 0.86-0.80 (m, 4H). Example I-18: (R)-N-(1-methyl-3-(3-(1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)phenyl)- 1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(1-methyl-3-(3-(1- (tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000097_0001
[0237] Synthesis of compound (±)-18.1. To a mixture of tetrahydro-2H-pyran-3-ol (3 g, 29.41 mmol, 1.0 equiv) and triethylamine (8.91 g, 88.23 mmol, 3.0 equiv) in dichloromethane at 0 ºC, was added dropwise methansulfonyl chloride (5.07 g, 44.11 mmol, 1.5 equiv). The reaction mixture stirred at same temperature for 1.5 h. It was transferred into ice- water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-18.1 (3 g, 56.67%). It was used in next step without purification. MS(ES): m/z 181.22 [M+H]+. [0238] Synthesis of compound (±)-18.2. A mixture of (±)-18.1 (2.44 g, 13.60 mmol, 1 equiv), 4-bromo-1H-pyrazole (3 g, 20.40 mmol, 1.5 equiv) and potassium carbonate (5.61 g, 40.66 mmol, 3 equiv) in dimethylformamide(20 mL) was stirred at 90 ºC for 16 h. It was cooled to room temperature and transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reside was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford (±)-18.2. MS (ES): m/z 232.09 [M+H]+. [0239] Synthesis of compound (±)-18.3. Compound (±)-18.3 was prepared from compound (±)-18.2 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane). MS(ES): m/z 244.31 [M+H]+. [0240] Synthesis of compound (±)-18.4. Compound (±)-18.4 was prepared from compound (±)-18.3, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 355.19 [M+H]+. [0241] Synthesis of compound (±)-18.5. Compound (±)-18.5 was prepared from compound (±)-18.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane). MS(ES): m/z 439.33 [M+H]+. [0242] 18.4-a and 18.4-b. The racemate was separated by HPLC (column: CHIRALPAK IB- N (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in isopropanol: MeCN (70: 30); flow rate: 20 mL/min) to afford first eluting fraction (18.5-a), MS(ES): m/z 439.33 [M+H]+ , and second eluting fraction (18.5-b), MS(ES): m/z 439.33 [M+H]+. *The absolute configuration of the chiral center is not determined. [0243] Synthesis of compound I-18-a. Compound I-18-a was prepared from compound 18.5- a and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 443.52 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.89 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.70 (d, J = 7.6 Hz 1H), 7.64 (t, J = 8 Hz, 1H), 7.55 (bs, 1H), 4.34-4.32 (bs, 1H), 4.23 (s, 3H), 4.07-3.42 (m, 4H), 2.22 (m, 3H), 1.51 (m, 2H), 0.86 (m, 2H), 0.63 (m, 2H). [0244] Synthesis of compound I-18-b. Compound I-18-b was prepared from compound 18.5- b and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 443.52 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.90 (s, 1H), 9.03 (s, 1H), 8.78 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.71 (d, J = 7.6 Hz 1H), 7.65-7.63 (d, J = 8 Hz, 1H), 7.57-7.51 (bs, 1H), 4.34-4.32 (bs, 1H), 4.23 (s, 3H), 4.07-4.04 (d, J = 10.4 Hz, 1H), 3.86 (d, J = 10.8 Hz, 1H), 3.68 (d, J = 19.6 Hz, 1H), 3.47-3.42 (m, 1H), 2.22 (m, 3H), 1.77-1.71 (m, 2H), 0.86-0.81 (m, 2H), 0.63-0.61 (m, 2H) Example I-19: N-(3-(2-methoxy-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000099_0001
[0245] Synthesis of compound 19.1. A solution of 9.1 (1.0 g, 4.56 mmol, 1.0 equiv), 4-bromo- 3,6-dihydro-2H-pyran (2.23 g, 13.69 mmol, 3 eq) and potassium carbonate (1.89 g, 13.69 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was degassed for 10 min. N,N-dimethylethylenediamine (0.120 g, 1.36 mmol, 0.3 equiv) and copper iodide (0.174g, 0.9mmol, 0.2eq) were added, and degassed for 5 min. The reaction mixture was stirred at 120 ºC for 16 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford 19.1. MS(ES): m/z 302.41 [M+H]+. [0246] Synthesis of compound 19.2. A mixture of 10% palladium on carbon (0.2 g) and 19.1 (0.45 g, 1.49 mmol, 1.0 equiv) in methanol was stirred at rt under hydrogen atmosphere for 2 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 19.2. MS(ES): m/z 274.4 [M+H]+. [0247] Synthesis of compound 19.3. Compound 19.3 was prepared from compound 19.2, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 385.2 [M+H]+. [0248] Synthesis of compound 19.4. Compound 19.4 was prepared from compound 19.3 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 470.37 [M+2]+. [0249] Synthesis of I-19. Compound I-19 was prepared from compound 19.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 473.19 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.77 (s, 1H), 8.99 (s, 1H), 8.33 (bs, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 4.48 (m, 1H), 4.22 (s, 3H), 3.99 (d, J = 11.2 Hz, 2H), 3.56 (s, 3H), 3.32 (d, J = 15.2 Hz 2H), 2.02 (m, 4H), 1.334 (m, 1H), 0.85- 0.83 (m, 4H). Example I-20-a and I-20-b: ((S)-N-(3-(2-(1-hydroxyethyl)-1-methyl-1H-imidazol-4-yl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (R)-N-(3-(2-(1- hydroxyethyl)-1-methyl-1H-imidazol-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000100_0001
Figure imgf000101_0001
[0250] Synthesis of compound 20.1. To a solution of methyl 4-bromo-1-methyl-1H- imidazole-2-carboxylate (3.0 g, 13.70 mmol, 1.0 equiv) in DCM (50 mL) at -78°C was added diisobutylaluminium hydride (1 M in THF, 41.09 mL, 41.09 mmol, 3.0 equiv) dropwise. The reaction mixture was stirred at -78 °C for 1 h. The reaction temperature was allowed to warm to 0 °C and slowly quenched by adding a saturated aqueous solution of potassium sodium tartrate tetra hydrate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 20.1. MS(ES): m/z 190.2[M+H]+. [0251] Synthesis of compound (±)-20.2. To a solution of 20.1 (1.6 g, 8.47 mmol, 1.0 equiv) in THF (30 mL) at -78°C was added methyl magnesium bromide (3 M in diethyl ether, 5.64 mL, 16.93 mmol, 2.0 equiv) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. It was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane) to afford (±)-20.2. MS(ES): m/z 206.2[M+H]+. [0252] Synthesis of compound (±)-20.3. To a solution of (±)-20.2 (1.2 g, 5.85 mmol, 1.0 equiv) in THF (20 mL) at 0 °C was added sodium hydride (60% in mineral oil, 0.515 g, 12.87 mmol, 2.2 equiv) and stirred for 30 min. Benzyl bromide (1.09 g, 6.43 mmol, 1.1 equiv) was added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. It was poured into crushed ice and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford (±)-20.3. MS(ES): m/z 296.18[M+H]+. [0253] Synthesis of compound (±)-20.4. A mixture of (±)-20.3 (1.0 g, 3.40 mmol, 1.0 equiv) and bis(triphenylphosphine)palladium(II) dichloride (0.240 g, 0.33 mmol, 0.1 equiv) in toluene (10 mL) was degassed by bubbling through a stream of argon for 10 min. Bis(tributyltin) (3.94 g, 6.80 mmol, 2.0 equiv) was added and the reaction mixture was stirred at 100 °C for 16 h. It was transfer into ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 16% ethyl acetate in hexane) to afford (±)-20.4. MS(ES): m/z: 506.33[M+H]+. [0254] Synthesis of compound (±)-20.5. To a solution of (±)-20.4 (0.600 g, 1.19 mmol, 1.0 equiv) and 3.1 (0.400 g, 1.19 mmol, 1.0 equiv) in toluene (10 mL) was degassed by bubbling through a stream of Argon for 10 min. Tris(dibenzylideneacetone)dipalladium (0.054 g, 0.059 mmol, 0.05 equiv) and copper iodide (0.023 g, 0.11 mmol, 3.0 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 120 ºC for 2 h. It was transferred into ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)-20.5. MS(ES): m/z: 427.32[M+H]+. [0255] Synthesis of compound (±)-20.6. Compound (±)-20.6 was prepared from compound (±)-20.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 431.51 [M+H]+. [0256] Synthesis of compound (±)-I-20. A mixture of 10% palladium on carbon (0.03 g) and (±)-20.6 (0.06 g, 0.139 mmol, 1.0 equiv) in methanol was stirred at rt under hydrogen atmosphere ( 1 atm) for 2 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford (±)-20. MS(ES): m/z 341.51 [M+H]+. [0257] I-20-a and I-20-b. The racemate was separated by HPLC (column: CHIRALPAK IB- N (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in isopropanol: MeOH (50: 50); flow rate: 20 mL/min) to afford first eluting fraction (I-20-a), and second eluting fraction (I-20-b). *The absolute configuration of the chiral center is not determined. I-20-a: MS(ES): m/z: 341.52 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.67 (s, 1H), 8.87 (s, 1H), 8.80 (s, 1H), 7.51 (s, 1H), 5.38-5.36 (d, J = 8 Hz, 1H), 4.90-4.87 (t, J = 4.6 Hz, 1H), 4.11 (s, 3H), 3.75 (s, 3H), 2.01 (m, 1H), 1.56-1.54 (d, J = 8 Hz, 3H), 0.82-0.77 (m, 4H). I-20-b: MS(ES): m/z: 436.39 [M+H]+, 1H NMR (DMSO-d6, 400 M Hz): δ 10.67 (s, 1H), 8.87 (s, 1H), 8.80 (s, 1H), 7.51 (s, 1H), 5.38-5.36 (d, J = 8 Hz, 1H), 4.90-4.87 (t, J = 4.6 Hz, 1H), 4.11 (s, 3H), 3.75 (s, 3H), 2.01 (m, 1H), 1.56-1.54 (d, J = 8 Hz, 3H), 0.82-0.77 (m, 4H). Example I-21: N-(3-(3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000103_0001
[0258] Synthesis of compound 21.1. To a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (2.5 g, 12.69 mmol, 1.0 equiv) in DMF (20 mL) was added iodine (1.07 g, 19.03 mmol, 1.5 equiv) and potassium hydroxide (4.83 g, 19.03 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 2 h. It was added ice-water and aqueous solution of sodium sulfite, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 21.1 (2.09 g, 51%). It was used in the next step without purification. MS(ES): m/z 322.8 and 324.7 [M+H]+. [0259] Synthesis of compound 21.2. To a solution of 21.1 (2.09 g, 6.47 mmol, 1.0 equiv) in DMF (20 mL) was added potassium carbonate (2.68 g, 19.42 mmol, 2.0 equiv) in portions at room temperature. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of methyl iodide (2.01 mL, 32.36 mmol, 5.0 equiv) dropwise. The reaction mixture was stirred at 110 ºC for 3 h. It was cooled to rt and added water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 21.2 (1.34 g, 61%). MS(ES): m/z 336.9 and 338.75 [M+H]+. [0260] Synthesis of compound 21.3. To a stirred solution of 6.2 (1.35 g, 5.55 mmol, 1.0 equiv) in 3 N HCl (15 mL) at 0 ºC was added sodium nitrite (0.421 g, 6.10 mmol, 1.1 equiv) and potassium iodide (1.84 g, 11.10 mmol, 2.0 equiv). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 21.3 (0.630 g, 32%). MS (ES): m/z 355.1 [M+H]+. [0261] Synthesis of compound 21.4. A mixture of 21.3 (0.580 g, 1.64 mmol, 1.0 equiv) and hexabutylditin (0.413 mL, 0.82 mmol, 0.5 equiv) in toluene (10 mL) was degassed by bubbling though a stream of argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.094 g, 0.082 mmol, 0.05 equiv) was added and degassed for 10 min. The reaction mixture was stirred at 100 ºC for 8 h. It was cooled to room temperature and filtered. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 21.4 (0.490 g, 58%). MS(ES): m/z 518.3 [M+H]+. [0262] Synthesis of compound 21.5. A mixture of 21.4 (0.285 g, 0.550 mmol, 1.0 equiv), 21.2 (0.278 g, 0.826 mmol, 1.5 equiv) and copper iodide (0.314 g, 1.65 mmol, 3.0 equiv) in 1,4- dioxane (5 mL) was degassed by bubbling though a stream of argon for 10 min. bis(triphenylphosphine)palladium(II) dichloride (0.038 g, 0.055 mmol, 0.1 equiv) was added and degassed for 10 min. The reaction mixture was stirred at 100 ºC for 2 h. It was cooled to room temperature and filtered. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane) to afford 21.5 (0.165 g, 68.5%). MS(ES): m/z 437.3 and 439.2 [M+H]+. [0263] Synthesis of compound I-21: Compound I-21 was prepared from compound 21.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 442.57 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.51 (s, 1 H), 8.65 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.82-7.81 (m, 1H), 7.28-7.27 (d, J = 4.0 Hz, 1H), 6.57(s, 1H), 4.91 (m, 1H), 3.68 (s, 3H), 3.28 (s, 3H), 2.02 (m, 1H), 1.53-1.47 (m, 4H), 1.24 (s, 1H), 0.89-0.7 (m, 2H), 0.71-0.56 (m, 4H). Example I-22: N-(3-(4-(1-cyclobutyl-1H-pyrazol-4-yl)pyridin-2-yl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000105_0001
[0264] Synthesis of compound 22.1. To a stirred solution of 4-iodo-1H-pyrazole (2.0 g, 10.30 mmol, 1.0 equiv) in DMF at 0 ºC was added sodium hydride (1.2 g, 30.92 mmol, 3.0 equiv) followed by dropwise addition of bromocyclobutane (2.07 g, 15.45 mmol, 1.5 equiv). The reaction mixture stirred at 95 °C for 5 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 22.1 (1.0 g, 39%). MS(ES): m/z 248.29 [M+H]+. [0265] Synthesis of compound 22.2. A mixture of 22.1 (1.0 g, 6.75 mmol, 1.0 equiv) and 2- bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.8 g, 10.13 mmol, 1.5 equiv) in 1,4-dioxane (25 mL) and water (5 mL) was degassed by bubbling though a stream of argon for 10 min. Cesium carbonate (4.38 g, 13.05 mmol, 2.0 equiv), and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (0.550 g, 0.675 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 1 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 22.2 (0.8 g, 71%). MS(ES): m/z 278.13 and 280.13 [M+H]+. [0266] Synthesis of compound 22.3. To a solution of 22.2 (0.8 g, 2.88 mmol, 1.0 equiv) in THF (5.0 mL) at -78° C was added n-butyllithium (1.386 mL, 3.46 mmol, 1.2 equiv) and stirred for 10 min. Tributyltin chloride (1.87 g, 5.76 mmol, 2.0 equiv) was added and stirred for 10 min. It was quenched in aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 22.3 (0.5 g, 36%). MS(ES): m/z 489.22 [M+H]+. [0267] Synthesis of compound 22.4. A mixture of 22.3 (0.50 g, 1.02 mmol, 1.0 equiv), 3.1 (0.517 g, 1.536 mmol, 1.5 equiv) and copper (1) iodide (0.039 g, 0.204 mmol, 0.2 equiv) in 1,4- dioxane (5 mL) was degassed by bubbling though a stream of argon for 10 min. bis (triphenylphosphine)palladium (II) dichloride (0.083 g, 0.102 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 1 h. It was cooled to room temperature, transferred into ice-water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 22.4 (0.2 g, 68%). MS(ES): m/z 408.07 and 410.10 [M+H]+. [0268] Synthesis of compound I-22. Compound I-22 was prepared from compound 22.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 414.42 [M+H]+ ; 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.10 (s, 1H), 9.02 (s, 1H), 8.65-8.64 (d, J = 4.8 Hz, 2H), 8.25 (s, 1H), 8.16 (s, 1H), 7.60-7.59 (d, J = 5.6 Hz, 1H), 4.92-4.90 (m, 1H), 4.27 (s, 3H), 2.05 (m, 1H), 1.84 (s, 3H), 1.25 (m, 2H), 0.86- 0.81 (m, 5H). Example I-23: (S)-N-(3-(2-methoxy-3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000107_0001
[0269] Synthesis of compound 23.1.: To a solution of (R)-tetrahydrofuran-3-ol (5.0 g, 56.75 mmol, 1.0 equiv) and trimethylamine (23.73 mL, 170.25 mmol, 3.0 equiv) in DCM (50 mL) at 0 ºC was added dropwise methanesulfonyl chloride (8.78 g, 113.5 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 4 h. It was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure 23.1 (5.6 g, 59%). MS (ES): m/z: 167.1 [M+H]+. [0270] Synthesis of compound 23.2. A mixture of 4-bromo-1H-pyrazole (5.6 g, 33.70 mmol, 1.0 equiv), cesium carbonate (32.94 g, 101.09 mmol, 3.0 equiv) and 23.2 (7.43 g, 50.54 mmol, 1.5 equiv) in DMF (50 mL) was stirred at 90 ºC for 12 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50.0% ethyl acetate in hexane) to afford 23.2 (2.9 g, 40%). MS (ES): m/z: 217.0 and 219.02 [M+H]+. [0271] Synthesis of compound 23.3. Compound 23.3 was prepared from compound 23.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 70.0% ethyl acetate in hexane). MS(ES): m/z 260.23 [M+H]+. [0272] Synthesis of compound 23.4. Compound 23.4 was prepared from compound 23.3, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane). MS (ES): m/z 371.02 [M+H]+. [0273] Synthesis of compound 23.5. Compound 23.5 was prepared from compound 23.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 454.1 and 456.1 [M+H]+. [0274] Synthesis of compound I-23. Compound I-23 was prepared from compound 23.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 459.33 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.76 (s, 1H), 8.98 (s, 1H), 8.32(s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.74-7.72 (d, J = 6.4 Hz, 1H), 7.40-7.38 (d, J = 7.2 Hz, 1H), 7.27-7.25 (d, J = 7.2 Hz 1H), 5.09 (m, 1H), 4.21 (s, 3H), 4.01-3.83 (m, 5H), 3.35 (s, 3H), 2.41-2.27 (m, 1H), 1.98 (m, 1H), 0.76 (m, 4H). Example I-24: N-(3-(1-cyclobutyl-1H-pyrazol-3-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000109_0001
[0275] Synthesis of compound 24.1. To a solution of 3-bromo-1H-pyrazole (2.0 g, 13.61 mmol, 1.0 equiv) in DMF (20 mL) and THF (20 mL) was added a solution of sodium bis(trimethylsilyl)amide (1 M THF, 4.15 mL, 20.415 mmol, 1.5 equiv) dropwise at room temperature and stirred for 30 min. To the mixture was added dropwise bromocyclobutane (1.84 g, 13.61 mmol, 1.0 equiv) and stirred at room temperature for 12 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20.0% ethyl acetate in hexane) to afford 24.1 (1.4 g, 51%). MS (ES): m/z: 201.0 and 203.01 [M+H]+. [0276] Synthesis of compound 24.2. A mixture of 24.1 (0.10 g, 0.497 mmol, 1.0 equiv), bis(pinacolato)diboron (0.631 g, 2.49 mmol, 5.0 equiv) and potassium acetate (0.146 g, 1.49 mmol, 3.0 equiv) in 1,4-dioxane (8 mL) was degassed by bubbling though a stream of argon for 10 min. (1,1'-Bis(diphenylphosphino)ferrocene) palladium(II) dichloride (0.036 g, 0.0497 mmol, 0.1 equiv) was added and degassed for 10 min. The mixture was stirred at 100 °C for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50.0% ethyl acetate in hexane) to afford 24.2 (0.080 g, 65%). MS(ES): m/z 249.13 [M+H]+. [0277] Synthesis of compound 24.3. Compound 24.3 was prepared from compound 24.2 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane). MS (ES): m/z 332.1 and 334.0 [M+H]+. [0278] Synthesis of compound I-24. Compound I-24 was prepared from compound 24.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM).1H NMR (DMSO-d6, 400 MHz): δ 10.74 (s, 1H), 8.93 (s, 1H), 8.83 (s, 1H), 7.95 (s, 1H), 6.68-6.67 (s, 1H), 4.94-4.89 (m, 1H), 4.15 (s, 3H), 2.03-2.02 (m, 1H), 1.83-1.82 (m, 3H), 1.53-1.47 (m, 1H), 0.83-0.76 (m, 4H), 0.62-0.60 (m, 2H). Example I-25: N-(3-(4-cyano-1-cyclobutyl-1H-pyrazol-3-yl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000110_0001
[0279] Synthesis of compound 25.1. A mixture of 5-amino-1H-pyrazole-4-carbonitrile (5 g, 46.25 mmol, 1.0 equiv), bromocyclobutane (12.49 g, 92.50 mmol, 2.0 equiv) and cesium carbonate (30.0 g, 92.50 mmol, 2.0 equiv) in DMF was stirred at 80 °C for 16 h. It was transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (35% ethyl acetate in hexane) to afford 25.1 (2.5 g, 33%), MS(ES): m/z 163.5[M+H]+. [0280] Synthesis of compound 25.2. To a solution of 25.1 (2.5 g, 15.41 mmol, 1.0 equiv) in 3 N Hydrochloric acid in water (35 mL) was added dropwise sodium nitrite solution (1.36 g, 20.03 mmol, 1.3 equiv) in water at 0 °C and stirred for 20 min. A solution of potassium iodide (7.67 g, 46.23 mmol, 3.0 equiv)) in water was added dropwise to reaction mixture at 0 °C and stirred for 1 h at room temperature. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 25.2 (1.0 g, 24%). MS(ES): m/z 274.3 [M+H]+. [0281] Synthesis of compound 25.3. Compound 25.3 was prepared from compound 25.2 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane). MS(ES): m/z 357.3 [M+H]+ and 359.4 [M+H]+. [0282] Synthesis of compound I-25. Compound I-25 was prepared from compound 25.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 362.20 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.83 (s, 1H), 9.04 (s, 1H), 8.85-8.84 (d, J = 4.0 Hz, 2H), 5.02-4.98 (m, 1H), 4.24 (s, 3H), 2.60-2.48 (m, 4H), 2.06-2.03 (m, 1H), 1.90-1.97 (m, 2H), 0.86-0.81 (m, 4H). Example I-26-a and I-26-b: N-(3-(2-methoxy-3-(1-((3R,4R)-4-methoxytetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(2-methoxy-3-(1-((3S,4S)-4-methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000111_0001
Figure imgf000112_0001
[0283] Synthesis of compound (±)-26.1. To a solution of (±)-12.1 (6 g, 25.74 mmol, 1.0 equiv) in THF (100 mL) at 0 °C was added 4-nitrobenzoic acid (6.45 g, 38.62 mmol, 1.5 equiv) followed by triphenylphosphine (10.15 g, 38.62 mmol, 1.5 equiv) and diethylazodicarboxylate (6.72 g, 38.62mol, 1.5 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate in hexane) to afford (±)-26.1 (4.0 g, 41%), MS(ES): m/z 383.6[M+H]+. [0284] Synthesis of compound (±)-26.2. To a solution of (±)-26.1 (4 g, 10.47 mmol, 1.0 equiv) in methanol (40 mL) was added potassium carbonate (7.22 g, 52.35 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford (±)- 26.2 (2.1 g, 86%). MS(ES): m/z 233.3 [M+H]+ and 235.2 [M+H]+. [0285] Synthesis of compound (±)-26.3. To a solution of (±)-26.2 (2.1 g, 9.01 mmol, 1.0 equiv) in DMF (30 mL) at 0 °C was added 60% sodium hydride in mineral oil (0.540 g, 13.15 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at 0 °C for 30 min. Methyl iodide (1.9 g, 13.15 mmol, 1.5 equiv) was added dropwise at 0 °C and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane) to afford (±)- 26.3 (1.9 g, 85%). MS(ES): m/z 247.5 [M+H]+ and 249.2 [M+H]+. [0286] Synthesis of compound (±)-26.4. Compound (±)-26.4 was prepared from compound (±)-26.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 290.6 [M+H]+. [0287] Synthesis of compound (±)-26.5. Compound (±)-26.5 was prepared from compound (±)-26.4, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane). MS(ES): m/z 401.5 [M+H]+. [0288] Synthesis of compound (±)-26.6. Compound (±)-26.6 was prepared from compound (±)-26.5 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane). MS(ES): m/z 484.2 [M+H]+ and 486.3 [M+H]+. [0289] Synthesis of compound (±)-I-26. Compound (±)-I-26 was prepared from compound (±)-26.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM). MS(ES): m/z 489.1 [M+H]+ . [0290] I-26-a and I-26-b. The racemate was separated by SFC (column: CHIRALPAK IG (250 x 21 mm, 5 μm); mobile phases: mobile phase: (A) CO2, (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-26-a) and second eluting fraction (I-26-b). *The absolute configuration of the chiral center is not determined. I-26-a: MS(ES): m/z: 489.14 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.02 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.78-7.76 (d, J = 6.4 Hz, 1H), 7.43-7.38 (m, 1H), 7.30-7.28 (d, J = 7.6 Hz, 1H), 5.18-5.13 (m, 1H), 4.62-4.52 (m, 1H), 4.24 (s, 3H), 4.04-4.00 (m, 2H), 3.85-3.82 (m, 2H), 3.29 (s, 3H), 3.11 (s, 3H), 2.00-1.95 (m, 1H), 0.79-0.77 (m, 4H). I-26-b: MS(ES): m/z: 489.43 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.01 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.78-7.76 (d, J = 6.4 Hz, 1H), 7.43-7.37 (m, 1H), 7.30-7.28 (d, J = 7.6 Hz, 1H), 5.16-5.13 (m, 1H), 4.61-4.50 (m, 1H), 4.23 (s, 3H), 4.05-4.00 (m, 2H), 3.83-3.80 (m, 2H), 3.30 (s, 3H), 3.12 (s, 3H), 2.01-1.95 (m, 1H), 0.78-0.76 (m, 4H). Example I-27: N-(3-(1-cyclobutyl-5-methoxy-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000114_0001
[0291] Synthesis of compound 27.1. A mixture of 4-nitro-1H-pyrazole (5.0 g, 8.09 mmol, 1 equiv), bromocyclobutane (1.18 g, 8.09 mmol, 1.3 equiv) and potassium carbonate (7.9 g, 24.2 mmol, 2.5 equiv) in DMSO (50 mL) was stirred at 60 ºC for 16 h. It was cooled to room temperature and transferred into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 27.1 (3.9 g, 53%). MS (ES): m/z 168.19 [M+H]+. [0292] Synthesis of compound 27.2. To a solution of 27.1 (3.9 g, 48.0 mmol, 1 equiv) in THF (40 mL) was added lithium tri-tert-butoxyaluminum hydride in THF (1 M, 48 mL, 48.0 mmol, 1 equiv) at -78ºC. The reaction mixture was stirred for 45 min. Hexachloroethane (3.9 g, 48.0 mmol, 1 equiv) was added and the mixture was stirred at room temperature for 16 h. It was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 27.2 (2.5 g, 53%). MS (ES): m/z 202.2 [M+H]+. [0293] Synthesis of compound 27.3. To a solution of 27.2 (2.5 g, 36.11 mmol, 1.0 equiv) in DMF (10 mL) was added sodium hydride (36.11 mL, 36.11 mmol, 1.0 equiv) at 0 ºC and stirred for 30 min. methanol (36.11 mL, 36.11 mmol, 1.0 equiv) was added at 0 ºC and stirred at room temperature for 1 h. It was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 28% ethyl acetate in hexane) to afford 27.3 (1.9 g, 78%). MS(ES): m/z 198.31 [M+H]+. [0294] Synthesis of compound 27.4. A mixture of 27.3 (1.9 g, 22.2 mmol, 1.0 equiv) and 10% palladium in charcoal (0.85 g, 44.4 mmol, 50%w/w) in methanol (18 mL) was stirred under hydrogen atmosphere (1 atm) for 2 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.2% methanol in DCM) to afford 27.4 (1.5 g, 94%). MS(ES): m/z 168.3 [M+H]+. [0295] Synthesis of compound 27.5. To a stirred solution of 27.4 (1.5 g, 3.63 mmol, 1.0 equiv) in acetonitrile (18 mL) was added tert-butyl nitrite (0.37 g, 5.44 mmol, 1.5 equiv). The reaction mixture was stirred at rtt for 30 min. To the mixture was added copper iodide (1.8 g, 10.89 mmol, 3 equiv) and stirred for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 21% ethyl acetate in hexane) to afford 27.5 (0.45 g, 18%). MS(ES): m/z 279.6 [M+H]+. [0296] Synthesis of compound 27.6. Compound 27.6 was prepared from compound 27.5 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 71% ethyl acetate in hexane). MS(ES): m/z 363.5 [M+H]+. [0297] Synthesis of compound I-27. Compound I-27 was prepared from compound 27.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 367.53 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 8.93 (s, 1H), 8.51 (s, 1H), 7.74 (s, 1H), 4.89 (m, 1H), 4.15 (s, 3H), 3.82 (s, 1H), 2.50-2.36 (m, 5H), 2.02 (m, 2H), 1.83 (m, 2H), 0.82-0.63 (m, 4H). Example I-28-a and I-28-b: (R)-N-(3-(3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)- N-(3-(3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000116_0001
[0298] Synthesis of compound (±)-28.1. To a solution of cyclopentanone (10 g, 119.0, 1.0 equiv) in DCM (100 mL) was added N-bromosuccinimide (21.19 g, 119.0 mmol, 1.0 equiv) at room temperature and stirred for 16 h. It was filtered through a pad of Celite®. The filtrate was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-28.1 (11 g, 57%). It was used in the next step without purification. [0299] Synthesis of compound (±)-28.2. A mixture of (±)-28.1 (11 g, 67.48 mmol, 1.0 equiv), potassium carbonate (27.93 g, 202.45 mmol, 3.0 equiv) and 4-bromo-1H-pyrazole (9.2 g, 67.48 mmol, 1.0 equiv) in acetonitrile (50 mL) was stirred at room temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 16% ethyl acetate in hexane) to afford (±)-28.2 (2.5 g, 71%). MS(ES): m/z 229.0 and 231.0 [M+1]+. [0300] Synthesis of compound (±)-28.3. To a solution of (±)-28.2 (2.5 g, 10.91 mmol, 1.0 equiv) in benzene (20 mL) was added ethylene glycol (0.67 g, 10.91 mmol, 1.0 equiv) followed by boron trifluoride diethyl etherate (0.77 g, 5.45 mmol, 0.5 equiv). The reaction mixture was stirred for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-28.3 (1.4 g, 48%). MS(ES): m/z 273.01 and 275.0 [M+1]+. [0301] Synthesis of compound (±)-28.4. Compound (±)-28.4 was prepared from compound (±)-28.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES), m/z 316.2 [M+H]+. [0302] Synthesis of compound (±)-28.5. Compound (±)-28.5 was prepared from compound (±)-28.4, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in DCM). MS(ES): m/z 427.1 [M+H]+. [0303] Synthesis of compound (±)-28.6. Compound (±)-28.6 was prepared from compound (±)-28.5 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane). MS(ES): m/z 510.2 and 512.2 [M+H]+. [0304] Synthesis of compound (±)-I-28. Compound (±)-I-28 was prepared from compound (±)-28.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). [0305] I-28-a and I-28-b. The racemate was separated by chiral HPLC (column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in isopropanol: methanol (50: 50); flow rate = 20 mL/min) to afford first eluting fraction (I-28-a) and second eluting fraction (I-28-b). *The absolute configuration of the chiral center is not determined. I-28-a: MS(ES): m/z 515.14 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.76-7.74 (d, J = 7.2 Hz, 1H), 7.41-7.40 (d, J = 6.8 Hz, 1H), 7.29-7.27 (m, 1H), 4.61 (m, 1H), 4.23 (s, 3H), 3.80-3.78 (m, 4H), 3.28 (s, 3H), 2.31-2.24 (m, 2H), 1.99-1.87 (m, 3H), 1.72 (m, 1H), 1.23-1.09 (m, 1H), 0.79-0.72 (m, 4H). I-28-b: MS(ES): m/z 515.14 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.76-7.74 (d, J = 7.2 Hz, 1H), 7.41-7.40 (d, J = 6.8 Hz, 1H), 7.29-7.27 (m, 1H), 4.61 (m, 1H), 4.23 (s, 3H), 3.80-3.78 (m, 4H), 3.28 (s, 3H), 2.31-2.24 (m, 2H), 1.99-1.87 (m, 3H), 1.72 (m, 1H), 1.23-1.09 (m, 1H), 0.79-0.71 (m, 4H). Example I-29-a and I-29-b: (R)-N-(3-(3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N- (3-(3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000118_0001
Figure imgf000119_0001
[0306] Synthesis of compound (±)-29.1. To a solution of cyclobutanone (5 g, 71.34 mmol, 1.0 equiv) in chloroform (100 mL) at 0 °C was added a solution of bromine (11.35 g, 71.34 mmol, 1.0 equiv) in chloroform (60 mL) dropwise. The result solution was stirred at room temperature for 16 h. It was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-29.1 (5 g, 47%). It was used in the next step without purification. [0307] Synthesis of compound (±)-29.2. A mixture of (±)-29.1 (5 g, 34.02 mmol, 2.0 equiv), potassium carbonate (9.3 g, 67.56 mmol, 4.0 equiv) and 4-bromo-1H-pyrazole (2.5 g, 17.01 mmol, 1.0 equiv) in acetonitrile (50 mL) was stirred at room temperature for 72 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 16% ethyl acetate in hexane) to afford (±)-29.2 (0.68 g, 19%). MS(ES): m/z 215.09 and 216.79 [M+1]+. [0308] Synthesis of compound (±)-29.3. To a solution of (±)-29.2 (0.68 g, 3.16 mmol, 1.0 equiv) and ethylene glycol (0.196 g, 3.16 mmol, 1.0 equiv) in benzene (10 mL) was added boron trifluoride diethyl etherate (0.222 g, 1.6 mmol, 0.5 equiv). The reaction mixture was stirred at 100 °C for 16 h. It was cooled to room temperature and transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)- 29.3 (0.40 g, 49%). MS(ES): m/z 258.01 and 260.10 [M+1]+. [0309] Synthesis of compound (±)-29.4. Compound (±)-29.4 was prepared from compound (±)-29.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES), m/z 302.41 [M+H]+. [0310] Synthesis of compound (±)-29.5. Compound (±)-29.5 was prepared from compound (±)-29.4, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in DCM). MS(ES): m/z 413.03 [M+H]+. [0311] Synthesis of compound (±)-29.6. A mixture of (±)-29.5 (0.30 g, 0.728 mmol, 1.0 equiv), bis(pinacolato)diboron (0.203 g, 0.80 mmol, 1.1 equiv), triethylamine (0.220 g, 2.18 mmol, 3.0 equiv) and dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.065 g, 0.16 mmol, 0.2 equiv) in toluene (5.0 mL) was degassed by bubbling though a stream of argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (0.065 g, 0.08 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 1.5 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane) to afford (±)-29.6 (0.25 g, 83%). MS(ES), m/z 413.1 [M+H]+. [0312] Synthesis of compound (±)-29.7. Compound (±)-29.7 was prepared from compound (±)-29.6 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES), m/z 497.30 [M+H]+. [0313] Synthesis of compound (±)-I-29. Compound (±)-I-29 was prepared from compound (±)-29.7 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). [0314] I-29-a and I-29-b. The racemate was separated by chiral HPLC (column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in isopropanol: MeOH (50: 50); flow rate = 20 mL/min) to afford first eluting fraction (I-29-a) and second eluting fraction (I-29-b). *The absolute configuration of the chiral center is not determined. I-29-a: MS(ES): m/z 501.16 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 8.99 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.77-7.75 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.29-7.25 (t, J = 7.6 Hz, 1H), 4.96-4.91 (m, 1H), 4.22 (s, 3H), 3.81-3.77 (m, 2H), 3.28 (s, 3H), 3.02-3.01 (m, 1H), 2.40-2.38 (m, 2H), 2.33-2.18 (m, 3H), 2.03-1.97 (m, 1H), 1.23 (m, 1H), 0.77-0.75 (m, 3H). I-29-b: MS(ES): m/z 501.19 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.00 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.77-7.76 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42-7.40 (d, J = 6.0 Hz, 1H), 7.29-7.25 (t, J = 7.6 Hz, 1H), 4.95-4.92 (m, 1H), 4.22 (s, 3H), 3.81-3.80 (m, 2H), 3.28 (s, 3H), 3.02-3.80 (m, 2H), 2.29-2.18 (m, 3H), 2.07-1.98 (m, 1H), 1.23 (m, 1H), 0.77- 0.62 (m, 3H). Example I-30: N-(3-(3-(1-cyanocyclopropyl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000121_0001
[0315] Synthesis of compound 30.1. To a solution of 2-(3-bromo-2- methoxyphenyl)acetonitrile (0.70 g, 3.10 mmol, 1.0 equiv) in DMF (15 mL) was added sodium hydride (60 wt%, 0.371 g, 9.29 mmol, 3.0 equiv) in portions at 0 °C and stirred for 30 min. To the mixture was added dropwise 1,2-dibromoethane (1.16 g, 6.19 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford 30.1 (0.530 g, 68%). MS (ES): m/z: 252.1 and 254.03 [M+H]+. [0316] Synthesis of compound 30.2. A mixture of 30.1 (0.530 mg, 2.10 mmol, 1.0 equiv), bis(pinacolato)diboron (1.6 g, 6.31 mmol, 3.0 equiv) and potassium acetate (0.619 g, 6.31 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling through a stream of argon for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro- palladium(II) DCM complex (0.171 g, 0.210 mmol, 0.1 equiv) was added and degassed for 5 min. The mixture was stirred at 100 ºC for 1 h. It was filtrated through a pad of Celite® and rinsed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane) to afford 30.2 (0.345 g, 55%). MS (ES): m/z 300.18 [M+H]+. [0317] Synthesis of compound 30.3. A mixture of 30.2 (0.345 g, 1.15 mmol, 1.0 equiv), 3.1 (0.779 g, 2.31 mmol, 2.0 equiv) and potassium carbonate (0.478 g, 3.46 mmol, 3.0 equiv) in 1,4- dioxane (10 mL) was degassed by bubbling through a stream of argon for 15 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (1:1) (0.093 g, 0.115 mmol, 0.1 equiv) was added and degassed for 10 min. The reaction mixture was stirred at 100 ºC for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (70.0% ethyl acetate in hexane) to afford 30.3 (0.067 g, 15%). MS (ES): m/z: 383.2 and 385.1 [M+H]+. [0318] Synthesis of compound I-30. Compound I-30 was prepared from compound 30.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 388.44 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.01 (s, 1H), 8.33 (s, 1H), 7.59-7.56 (d, J = 7.6 Hz, 1H), 7.46-7.44 (d, J = 7.6 Hz, 1H), 7.29- 7.23 (t, J = 7.6 Hz, 1H), 4.28 (s, 3H), 3.47 (s, 3H), 2.03-1.97 (m, 1H), 1.71-1.68 (m, 2H), 1.50- 1.43 (m, 2H), 0.79-0.74 (m, 4H). Example I-31-a and I-31-b: 6-(cyclopropanecarboxamido)-4-((3-methoxy-5-(1-((3R,4S)-4- methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide and 6- (cyclopropanecarboxamido)-4-((3-methoxy-5-(1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)-1H- pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide
Figure imgf000123_0001
[0319] Synthesis of compound 31.1. To a solution of 3-methoxypyridin-2-amine (10 g, 80.64 mmol, 1.0 equiv) in trifluoroaceticacid (100 mL) were added in portions N-bromosuccinimide (28.7 g, 161.29 mmol, 2 equiv) at 0 ºC. The reaction mixture was allowed to warm to rt and stirred for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (26% ethyl acetate in hexane) to afford 31.1 (5.9 g, 36%). MS(ES): m/z 205.2 and 206.1 [M+H]+. [0320] Synthesis of compound 31.2. To a solution of 31.1 (5.9 g, 29.06 mmol, 1.0 equiv) in DMF (60 mL) was added sodium hydride (5.58 g, 139.5 mmol, 4.8 equiv) in portions at 0 °C and stirred for 40 min. To the mixture was added 4-methoxybenzyl chloride (21.8 g, 139.5 mmol, 4.8 equiv) at 0 ºC. The reaction mixture was allowed to warm to rt and stirred for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (18% ethyl acetate in hexane) to afford 31.2 (3.1 g, 24%). MS(ES): m/z 445.6 and 446.5[M+H]+. [0321] Synthesis of compound 31.3. A mixture of 31.3 (3.1 g, 6.99 mmol, 1.0 equiv), bis(pinacolato)diboron (3.55 g, 13.99 mmol, 2.0 equiv) and potassium acetate (2.057 g, 20.99 mmol, 3.0 equiv) in dioxane (50 mL) was degassed by bubbling through a stream of argon for 15 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.63 g, 0.699 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 120 ºC for 2 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (35% ethyl acetate in hexane) to afford 31.3 (1.1 g, 32%). MS(ES): m/z 491.6 [M+H]+. [0322] Synthesis of compound (±)-31.4. A mixture of 31.3 (1.1 g, 2.24 mmol, 1.0 equiv), (±)- 12.2 (0.83 g, 3.36 mmol, 1.5 equiv) and tripotassium phosphate (1.42 g, 6.72 mmol, 3.0 equiv) in dioxane (10 mL) and water (4 mL) was degassed by bubbling through a stream of argon for 15 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.16 g, 0.224 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 2 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (48% ethyl acetate in hexane) to afford (±)-31.4 (0.504 g, 42%). MS(ES): m/z 531.8 [M+H]+. [0323] Synthesis of compound (±)-31.5. To a solution of (±)-31.4 (0.504 g, 0.95 mmol, 1.0 equiv) in DCM (10 mL) were added trifluoromethanesulfonic acid (2 mL) at 0 °C. It was stirred at 50 ºC for 15 min, transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.5% methanol in DCM) to afford (±)-31.5 (0.256 g, 92%). MS(ES): m/z 291.6 [M+H]+. [0324] 31.5-a and 31.5-b. The racemate was separated by chiral SFC (column: CHIRALPAK IG (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (31.5-a) (0.101 g, 48%), MS(ES): m/z 291.6 [M+H]+ and second eluting fraction (31.5-b) (0.108 g, 47%). MS(ES): m/z 291.6 [M+H]+. *The absolute configuration of the chiral center is not determined. [0325] Synthesis of compound 31.6-a. To a solution of 31.5-a (0.101 g, 0.347 mmol, 1.0 equiv) and 4,6-dichloronicotinamide (0.079 g, 0.417 mmol, 1.2 equiv) in THF (7 mL) at 0 °C was added sodium bis(trimethylsilyl)amide (2 M in THF, 0.34 mL, 0.694 mmol, 2.0 equiv) and stirred at 0 ºC for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.5% methanol in DCM) to afford 31.6-a (0.045 g, 29%). MS(ES): m/z 445.96 [M+H]+. [0326] Synthesis of compound 31.6-b. Compound 31.6-b was prepared from 31.5-a following the procedure described in the synthesis of 31.6-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.5% methanol in DCM). MS(ES): m/z 445.96 [M+H]+. [0327] Synthesis of compound I-31-a. Compound I-31-a was prepared from compound 31.6- a and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM). MS(ES): m/z 494.5 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 12.17 (s, 1H), 10.73 (s, 1H), 9.57 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.21 (bs, 1H), 8.15 (s, 1H), 8.00-7.99 (d, J = 5.2 Hz, 1H), 7.58 (bs, 1H), 7.25-7.24 (d, J = 5.2 Hz, 1H), 5.75 (s, 1H), 5.05 (bs, 1H), 4.23-4.16 (m, 2H), 4.10-4.00 (m, 2H), 3.71 (s, 3H), 3.34 (s, 3H), 2.08-2.03 (m, 1H), 0.84-0.80 (m, 4H). [0328] Synthesis of compound I-31-b. Compound I-31-b was prepared from compound 31.6- b and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM). MS(ES): m/z 494.5 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 12.17 (s, 1H), 10.73 (s, 1H), 9.57 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.21 (bs, 1H), 8.13 (s, 1H), 8.00-7.99 (d, J = 5.2 Hz, 1H), 7.58 (bs, 1H), 7.25-7.24 (d, J = 5.2 Hz, 1H), 5.74 (s, 1H), 5.05 (m, 1H), 4.23-4.15 (m, 2H), 4.10-4.01 (m, 2H), 3.71 (s, 3H), 3.35 (s, 3H), 2.08-2.03 (m, 1H), 0.84-0.80 (m, 4H). Example I-32-a and I-32-b: N-(3-(2-methoxy-3-(1-((3S,4R)-3-methoxytetrahydro-2H-pyran-4- yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and N-(3-(2-methoxy-3-(1-((3R,4S)-3-methoxytetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000126_0001
[0329] Synthesis of compound (±)-32.1 and (±)-32.2. To a solution of 4-iodo-1H-pyrazole (6.0 g, 30.93 mmol, 1.0 equiv) in DMF (60 mL) at 0 °C was added 60% sodium hydride in mineral oil (1.85 g, 46.39 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C for 30 min and 3,7- dioxabicyclo[4.1.0]heptane (6.19 g, 61.86 mmol, 2.0 equiv) was added dropwise. The reaction mixture was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate in hexane) to afford mixture of (±)-32.1 and (±)-32.2 (4.0 g, 44%), MS(ES): m/z 295.2 [M+H]+. [0330] Synthesis of compound (±)-32.3 and (±)-32.4. A mixture of (±)-32.1 and (±)-32.2 (4.0 g, 13.60 mmol, 1.0 equiv) in DMF (40 mL) at 0 °C was added 60% sodium hydride in mineral oil (0.816 g, 20.4 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C for 30 min. Methyl iodide (2.8 g, 20.4 mmol, 1.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate in hexane) and followed by preparative HPLC to afford (±)- 32.4 (0.82 g, 20%), MS(ES): m/z 309.3[M+H]+. [0331] Synthesis of compound (±)-32.5. Compound (±)-32.5 was prepared from compound (±)-32.4 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 304.5 [M+H]+. [0332] Synthesis of compound (±)-32.6. Compound (±)-32.6 was prepared from compound (±)-32.5, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 415.2 [M+H]+ . [0333] Synthesis of compound (±)-32.7. Compound (±)-32.7 was prepared from compound (±)-32.6 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES): m/z 498.2 [M+H]+ and 500.3 [M+H]+ . [0334] Synthesis of compound (±)-I-32. Compound (±)-I-32 was prepared from compound (±)-32.7 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 503.2 [M+H]+ . [0335] I-32-a and I-32-b. The racemate was separated by chiral SFC (column: CHIRALPAK AD-H (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 100% methanol; flow rate: 80 mL/min) to afford first eluting fraction (I-32-a) and second eluting fraction (I-32-b). *The absolute configuration of the chiral center is not determined. I-32-a. MS(ES): m/z: 503.19 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 8.99 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.75-7.73 (d, J = 8.0 Hz, 1H), 7.41-7.39 (d, J = 6.8 Hz, 1H), 7.28-7.26 (t, J = 7.6 Hz, 1H), 4.34-4.31 (m, 1H), 4.22 (s, 3H), 4.15-4.14 (m, 1H), 3.93- 3.91 (m, 1H), 3.64-3.58 (m, 1H), 3.28 (s, 3H), 3.17-3.12 (m, 2H), 3.03 (s, 3H), 2.04-2.01 (m, 2H), 1.33-1.32 (m, 1H), 0.77-0.74 (m, 4H). I-32-b. MS(ES): m/z: 503.19 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 8.99 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.75-7.73 (d, J = 8.0 Hz, 1H), 7.41-7.39 (d, J = 6.8 Hz, 1H), 7.28-7.26 (t, J = 7.6 Hz, 1H), 4.34-4.31 (m, 1H), 4.22 (s, 3H), 4.15-4.14 (m, 1H), 3.93- 3.91 (m, 1H), 3.64-3.58 (m, 1H), 3.28 (s, 3H), 3.17-3.12 (m, 2H), 3.03 (s, 3H), 2.04-2.01 (m, 2H), 1.33-1.32 (m, 1H), 0.77-0.74 (m, 4H). Example I-33: (R)-N-(3-(2-methoxy-3-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000128_0001
[0336] Synthesis of compound 33.1. Compound 33.1 was prepared from compound 2.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 29% ethyl acetate in hexane). MS(ES): m/z 260.31 [M+H]+. [0337] Synthesis of compound 33.2. To a solution of 33.1 (0.7 g, 2.7 mmol, 1.0 equiv) in acetonitrile(7 mL) at 0 ºC was added copper iodide (0.005 g, 0.02 mmol, 0.01 equiv), p- toluenesulfonic acid (0.557 g, 3.2 mmol,1.2 equiv), t-butyl nitrite (0.417 g, 4.0 mmol, 1.5 equiv) and tetra-n-butylammonium iodide (1.99 g, 5.4 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 33.2 (0.34 g, 342%). MS(ES): m/z 371.19 [M+H]+. [0338] Synthesis of compound 33.3. A mixture of 33.2 (0.34 g, 0.530 mmol, 1.0 equiv), 3.1 (0.37 g, 1.102 mmol, 1.2 equiv) and sodium carbonate (0.240 g, 2.29 mmol, 2.5 equiv) in acetonitrile (4 mL) and water (1 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.067 g, 0.0918 mmol, 0.1 equiv) was added and the mixture was stirred at 80 °C for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane) to afford 33.3 (0.080 g, 19.18%). MS(ES): m/z 455.2 [M+H]+. [0339] Synthesis of compound I-33. Compound I-33 was prepared from compound 33.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 460.12 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.76-7.74 (d, J = 7.6 Hz, 1H), 7.41-7.39 (d, J = 7.6 Hz, 1H), 7.29-7.25 (t, J = 7.2 Hz, 1H), 5.119 (m, 1H), 4.23 (s, 3H), 4.03-3.85 (m, 3H), 3.24(s, 3H), 2.41-2.39 (m, 2H), 1.97-2.03 (m, 2H), 0.85-0.78 (m, 4H) Example I-34: (R)-N-(3-(3-(7-cyano-1,4-dioxaspiro[4.4]nonan-7-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(3-(7-cyano-1,4- dioxaspiro[4.4]nonan-7-yl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000130_0001
[0340] Synthesis of compound 34.1 A solution of chromium trioxide (4.57 g, 75.75 mmol,3.5 equiv) and sulfuric acid (8.5 mL) in water (62 mL) at 0 °C was added dropwise with a solution of 1,4-dibromobutan-2-ol (5.0 g, 21.64 mmol,1.0 equiv) in acetone (150 mL). The reaction mixture was stirred at room temperature for 24 h. It was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 34.1(2.4 g, 48%).1H NMR (CDCL3, 400 MHz): δ 3.92 (s, 2H), 3.61-3.57 (m, 2H), 3.30-3.27 (m, 2H). It was used in the next step without purification. [0341] Synthesis of compound 34.2. To a solution of 34.1 (2.4 g, 10.48mol, 1.0 equiv) in ethylene glycol was added trimethylsilyl chloride (0.339 g, 3.14 mmol, 0.3 equiv) at 0 °C dropwise and the reaction mixture was stirred for 24 h at room temperature. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. which was purified by silica gel column chromatography (25% ethyl acetate in hexane) to afford 34.2 (1.1 g, 38%). 1H NMR (CDCl3, 400 MHz): δ 4.11 (m, 4H), 3.44 (m, 2H), 3.39 (s, 2H), 2.47 (m, 2H). [0342] Synthesis of compound (±)-34.3. To a solution of 34.2 (0.907 g, 4.02 mmol, 1.0 equiv) in DMF (5 mL) was added sodium hydride (60% in mineral oil, 0.241 g, 6.04 mmol, 1.5 equiv) at 0 ºC and stirred for 30 min. To the mixture was added 2-(3-bromo-2-methoxyphenyl)acetonitrile (1.1 g, 4.02 mmol, 1.2 equiv) at 0 ºC and stirred at 60 °C for 1 h. It was transferred into cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The residue was purified by column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-34.3 (0.40 g, 30%). MS(ES): m/z 337.9 and 339.9[M+H]+. [0343] Synthesis of compound (±)-34.4. A mixture of (±)-34.3 (0.400 g, 1.02 mmol, 1.0 equiv). bis(pinacolato)diboron (0.449 g, 1.77 mmol, 1.5 equiv) and potassium acetate (0.347 g, 3.55 mmol, 3.0 equiv) in 1,4-dioxane (4 mL) was degassed by bubbling though a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM (0.745 g, 1.02 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ºC for 5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-34.4 (0.40 g, 88%). It was use in next step without purification. [0344] Synthesis of compound (±)-34.5. Compound (±)-34.5 was prepared from compound 3.1 and (±)-34.4, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 75.0% ethyl acetate in hexane). MS(ES): m/z 469.2 and 471.2 [M+H]+. [0345] Synthesis of compound (±)-I-34. Compound (±)-I-34 was prepared from compound (±)-34.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 474.13 [M+H]+. [0346] I-34-a and I-34-b. The racemate was separated by chiral SFC (column CHIRALPAK IH (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in propane-2- ol:acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction ( I-34-a) and second eluting fraction (I-34-b). I-34-a: MS(ES): m/z 474.13 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.02 (s, 1H), 8.34 (s, 1H), 7.58 -7.56 (d, J = 7.2 Hz, 1H), 7.48 - 7.46 (d, J = 7.2 Hz, 1H), 7.28 - 7.26 (t, J = 7.2 Hz, 1H), 4.23 (s, 3H), 3.90 (m, 4H), 3.28 (s, 3H), 2.89- 2.86 (m, 2H), 2.32-2.29 (m, 2H), 2.12-2.11 (m, 2H), 2.00-1.98 (m, 1H), 0.77 (m, 4H). I-34-b: MS(ES): m/z 474.39 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.02 (s, 1H), 8.34 (s, 1H), 7.58 -7.56 (d, J = 7.2 Hz, 1H), 7.48 - 7.46 (d, J = 7.2 Hz, 1H), 7.28 - 7.26 (t, J = 7.2 Hz, 1H), 4.23 (s, 3H), 3.90 (m, 4H), 3.28 (s, 3H), 2.89- 2.86 (m, 2H), 2.32-2.29 (m, 2H), 2.12-2.11 (m, 2H), 2.00-1.98 (m, 1H), 0.77 (m, 4H). Example I-35: N-(3-(3-(4-cyano-1-(ethylsulfonyl)piperidin-4-yl)-2-methoxyphenyl)-1-methyl- 1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000132_0001
Figure imgf000133_0001
[0347] Synthesis of compound 35.1. To a solution of 2-(3-bromo-2- methoxyphenyl)acetonitrile (1.5 g, 6.635 mmol, 1.0 equiv) in DMF (15 mL) was added sodium hydride (60% in mineral oil, 0.955 g, 19.905 mmol, 3.0 equiv) in portions at 0 °C and stirred for 30 min. To the mixture was added dropwise tert-butyl bis(2-chloroethyl)carbamate (2.409 g, 9.952 mmol, 1.5 equiv) at 0 °C The reaction mixture was stirred at 80 ºC overnight. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate in hexane) to afford 35.1 (0.740 g, 46%). MS (ES): m/z: 395.2 and 397.1 [M+H]+. [0348] Synthesis of compound 35.2. To a stirred solution of 35.1 (0.740 mg, 1.871 mmol, 1.0 equiv) in DCM (10 mL) at 0 ºC was dropwise added trifluoroacetic acid (10 mL) and stirred at same temperature for 1 h. Most trifluoroacetic acid was removed under reduced pressure and the residue was diluted by DCM and washed by saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM) to afford 35.2 (0.460 g, 83%). MS (ES): m/z 295.1 and 297.0 [M+H]+. [0349] Synthesis of compound 35.3. To a solution of 35.2 (0.460 g, 1.558 mmol, 1.0 equiv) and triethylamine (0.6 mL, 4.675 mmol, 3.0 equiv) in DCM (5 mL) was added at 0 °C was added dropwise ethanesulfonyl chloride (0.300 g, 2.337 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 15 min. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50.0% ethyl acetate in hexane) to afford 35.3 (0.180 g, 30%). MS (ES): m/z: 387.2 and 389.1 [M+H]+. [0350] Synthesis of compound 35.4. Compound 35.4was prepared from compound 35.3, following the procedure described in the synthesis of compound 6.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 435.36 [M+H]+. [0351] Synthesis of compound 35.5. Compound 35.5 was prepared from compound 35.4 and 3.1, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane). MS(ES): m/z 518.3 and 520.2 [M+H]+. [0352] Synthesis of compound I-35. Compound I-35 was prepared from compound 35.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 523.62 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.81 (s, 1H), 9.02 (s, 1H), 8.34 (s, 1H), 7.60-7.58 (d, J = 7.2 Hz, 1H), 7.47-7.45 (d, J = 7.2 Hz, 1H), 7.32- 7.30 (d, J = 8.0 Hz, 1H), 4.24 (s, 3H), 3.85-3.81 (d, J = 13.2 Hz, 2H), 3.33-3.28 (m, 3H), 3.23-3.18 (m, 2H), 2.09-2.00 (m, 4H), 1.27-1.23 (m, 5H), 1.10-1.07 (m, 1H), 0.78-0.76 (m, 4H). Example I-36: N-(3-(3-(1-acetyl-4-cyanopiperidin-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000134_0001
[0353] Synthesis of compound 36.1: To a solution of 35.1 (0.250 g, 0.846 mmol, 1.0 equiv) and triethylamine (0.35 mL, 2.54 mmol, 3.0 equiv) in DCM (10 mL) was added acetyl chloride (0.12 mL, 1.69 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexane) to afford 36.1 (0.190 g, 67%). MS (ES): m/z: 337.1 and 339.1 [M+H]+. [0354] Synthesis of compound 36.2. A mixture of 36.1 (0.190 g, 2.82 mmol, 1.0 equiv), bis(pinacolato)diboron (0.715 g, 2.82 mmol, 5.0 equiv) and potassium acetate (0.165 g, 1.69 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling through a stream of argo for 10 min. (1,1'-Bis(diphenylphosphino)ferrocene) palladium(II) dichloride DCM complex (0.230 g, 0.282 mmol, 0.1 equiv) was added to the reaction mixture and degassed for 10 min. The mixture was stirred at 100 °C for 1 h under argon in a seal tube. It was filtrated through a pad of Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane) to afford 36.2 (0.170 g, 79%). MS(ES): m/z 385.1 [M+H]+. [0355] Synthesis of compound 36.3. Compound 36.3 was prepared from compound 36.4 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane). MS(ES): m/z 468.23 and 470.2 [M+H]+. [0356] Synthesis of compound I-36. Compound I-36 was prepared from compound 36.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 473.39 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.81 (s, 1H), 9.02 (s, 1H), 8.33 (s, 1H), 7.59-7.58 (d, J = 6.8 Hz, 1H), 7.43-7.42 (d, J = 7.2 Hz, 1H), 7.29 (m, 1H), 4.63- 4.59 (m, 1H), 4.24 (s, 3H), 4.05-4.02 (m, 1H), 3.29 (s, 3H), 2.07 (s, 3H), 2.06-2.00 (m, 2H), 1.86 (m, 2H), 2.01 (m, 1H), 0.85 (m, 1H), 0.78-0.76 (m, 4H), 0.62-0.60 (m, 1H). Example I-37-a and I-37-b: (R)-N-(3-(2-methoxy-3-(1-(2-oxopiperidin-3-yl)-1H-pyrazol-4- yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(2- methoxy-3-(1-(2-oxopiperidin-3-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000136_0001
[0357] Synthesis of compound (±)-37.1. To a solution of 5-bromopentanoic acid (20 g, 110.48 mmol, 1.0 equiv) in DCM (200 mL) at 0 °C was added oxalyl chloride (16.8 g, 132.57 mmol, 1.2 equiv) followed by cat. amount of DMF. The reaction mixture was stirred at 0 °C for 3 h. Most solvent was removed under reduced pressure. The residue was dissolved in 1, 2- dichloroethane and added N-bromosuccinimide (19.0 g, 121.52 mmol, 1.10 equiv) at room temperature. The reaction mixture was refluxed for 2 h and then cooled to 0 ºC. To reaction mixture was added to a solution of triethylamine and 4-methoxybenzylamine (22.7 g, 165.72 mmol, 1.50 equiv) in anhydrous THF (60 mL) at 0 ºC and the reaction mixture was stirred at room temperature for 16 h. It was poured into aqueous sodium thiosulfate solution (50 mL) and the product was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate filtered and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 19% ethyl acetate in hexane) to afford (±)-37.1 (14 g, 33%), MS(ES): m/z 379.2 and 381.1 [M+H]+. [0358] Synthesis of compound (±)-37.2. To a solution of (±)-37.1 (7.5 g, 19.78 mmol, 1.0 equiv) in DMF (80 mL) at 0 °C was added 60% sodium hydride in mineral oil (1.18 g, 29.68 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at room temperature for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford (±)-37.2 (3.5 g, 59%). MS(ES): m/z 298.1 and 300.1[M+H]+. [0359] Synthesis of compound (±)-37.3. A mixture of 4-iodo-1H-pyrazole (2.0 g, 10.31 mmol, 1.0 equiv), (±)-37.2 (3.38 g, 11.34mol, 1.1 equiv) and cesium carbonate (10.10 g, 31.08mol, 3.0 equiv) in DMF was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate in hexane) to afford (±)-37.3 (1.2 g, 28%), MS(ES): m/z 412.7[M+H]+. [0360] Synthesis of compound (±)-37.4. Compound (±)-37.4 was prepared from compound (±)-37.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 407.4 [M+H]+. [0361] Synthesis of compound (±)-37.5. Compound (±)-37.5 was prepared from compound (±)-37.4, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane). MS(ES): m/z 517.3 [M+H]+. [0362] Synthesis of compound (±)-37.6. Compound (±)-37.6 was prepared from compound (±)-37.5 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES): m/z 601.2 and 603.2 [M+H]+ [0363] Synthesis of compound (±)-37.7. Compound (±)-37.6 was prepared from compound (±)-37.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 606.22 [M+H]+ . [0364] Synthesis of compound (±)-I-37. To a solution of (±)-37.7 (0.095 g, 0.158 mmol, 1.0 equiv) in methanesulfonic acid (1 mL) was stirred at 60 ºC for 3 h. It was cooled to room temperature, transferred into water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford (±)-I-37 (0.020 g, 26%). MS(ES): m/z 486.26 [M+H]+ . [0365] I-37-a and I-37-b. The racemate was separated by chiral HPLC (column: CHIRALPAK OX-H (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane (B) 0.1% diethylamine in isopropanol: MeCN (70:30); flow rate: 20 mL/min) to afford first eluting fraction (I-37-a) and second eluting fraction (I-37-b). *The absolute configuration of the chiral center is not determined. I-37-a: MS(ES): m/z: 486.2 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.00 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.76-7.74 (dd, J = 7.6 Hz, 6.0 Hz, 1H), 7.41-7.39 (dd, J = 7.6 Hz, 6.0 Hz, 1H), 7.29-7.25 (t, J = 7.6 Hz, 1H), 5.04-5.00 (m, 1H), 4.23 (s, 3H), 3.93-3.91 (m, 1H), 3.35 (s, 3H), 3.17-3.16 (d, J = 4 Hz, 1H), 2.29-2.19 (m, 1H), 2.00-1.99 (m, 2H), 1.90-1.79 (m, 1H), 1.18-1.14 (m, 1H), 0.79-0.75 (m, 4H). I-37-b: MS(ES): m/z: 486.1 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.00 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.76-7.74 (dd, J = 7.6 Hz, 6.0 Hz, 1H), 7.41-7.39 (dd, J = 7.6 Hz, 6.0 Hz, 1H), 7.29-7.25 (t, J = 7.6 Hz, 1H), 5.04-5.00 (m, 1H), 4.23 (s, 3H), 3.93-3.91 (m, 1H), 3.35 (s, 3H), 3.17-3.16 (d, J = 4 Hz, 1H), 2.29-2.19 (m, 1H), 2.00-1.99 (m, 2H), 1.90-1.79 (m, 1H), 1.18-1.14 (m, 1H), 0.79-0.75 (m, 4H). Example I-38: N-(3-(3-(1-((2R,3R)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(3-(1-((2S,3S)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000139_0001
[0366] Synthesis of compound 38.1. To a solution of 3,4-dihydro-2H-pyran (50 g, 595.23 mmol, 1.0 equiv) in N,N,N′,N′-tetramethylethylenediamine (62 mL) was added dropwise n- butyllithium (2.5 M in hexane, 175 mL) at 0 ºC and stirred for 24 h. Paraformaldehyde (45 g) was added at 0 ºC and stirred at room temperature for 24 h. It was transferred into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The organic layer was separated, poured over an aqueous solution of copper(II) sulfate pentahydrate (100 g) in 500 mL water and stirred vigorously for 30 min. The organic layer was then separated and washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum distillation (100 mbar, 30 ºC) to afford 38.1 (40 g). It was used in the next step without purification. [0367] Synthesis of compound 38.2. To a solution of 38.1 (40 g, 350.87 mmol, 1.0 equiv) in DMF (500 mL) was added sodium hydride (60% dispersion in mineral oil, 35.08 g, 877.19 mmol, 2.5 equiv) at 0 ºC and stirred for 30 min. Benzyl bromide (90.00 g, 526.31 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 1.5 h. It was added into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% ethyl acetate in hexane) to afford 38.2 (26 g, 36%). MS(ES): m/z 205.52 [M+H]+. [0368] Synthesis of compound (±)-38.3. To a solution of 38.2 (26.0 g, 127.45 mmol, 1.0 equiv) in THF (300 mL) at 0 °C was added borane dimethyl sulfide complex (10.5 mL). The reaction mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was again cooled to 0 ºC and was added hydrogen peroxide (15 mL) and 10% solution of sodium hydroxide (15 mL). The mixture was stirred for 1 h. It was transferred into ice-water and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 22% ethyl acetate in hexane) to afford (±)-38.3 (21.3 g, 75%). MS(ES): m/z 223.42 [M+H]+. [0369] Synthesis of compound (±)-38.4. To a solution of (±)-38.3 (21.3 g, 95.94 mmol, 1.0 equiv) in acetone (250 mL) at 0 °C was added freshly prepared Jones’s reagent (40 mL). The reaction mixture was allowed to warm to room temperature and stir for 2 h. It was transferred into ice-water and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (±)-38.4 (19.0 g). MS(ES): m/z 221.64 [M+H]+. [0370] Synthesis of compound (±)-38.5. To a solution of (±)-38.4 (19.0 g, 86.36 mmol, 1.0 equiv) in THF (220 mL) at 0 °C was added L-selectride (95 mL). The reaction mixture was allowed to warm to room temperature and stir for 1.5 h. It was transferred into ice-water and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford (±)- 38.5 (12.5 g, 65%). MS(ES): m/z 223.22 [M+H]+. [0371] Synthesis of compound (±)-38.6. To a solution of (±)-38.5 (12.5 g, 56.30 mmol, 1.0 equiv) in benzene (125 mL) at 0 °C was added triethylamine (15.66 mL, 112.61 mmol, 2.0 equiv) and methanesulfonyl chloride (7.70 g, 67.56 mmol, 1.2 equiv). The reaction mixture was allowed to warm to room temperature and stir for 1 h. It was transferred into ice-water and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-38.6 (12.0 g). MS(ES): m/z 301.72 [M+H]+. [0372] Synthesis of compound (±)-38.7. To a solution of 4-iodo-1H-pyrazole (7.0 g, 36.08 mmol, 1.0 equiv) in DMF (150 mL) was added (±)-38.6 (12.0 g, 39.69 mmol, 1.1 equiv) and cesium carbonate (35.28 g, 108.2 mmol, 3.0 equiv). The reaction mixture was allowed to stir at 90 ºC for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (36% ethyl acetate in hexane) to afford (±)-38.7 (6.3 g, 40%). MS(ES): m/z 399.13 [M+H]+. [0373] Synthesis of compound (±)-38.8. Compound (±)-38.8 was prepared from compound (±)-38.7 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 47% ethyl acetate in hexane). MS(ES): m/z 394.91 [M+H]+. [0374] Synthesis of compound (±)-38.9. Compound (±)-38.9 was prepared from compound (±)-38.8, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate in hexane). MS(ES): m/z 505.38 [M+H]+. [0375] Synthesis of compound (±)-38.10. Compound (±)-38.10 was prepared from compound (±)-38.9 and 3.1, following the procedure described in the synthesis of compound (±)- 9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate in hexane). MS(ES): m/z 588.3 and 590.3 [M+H]+. [0376] Synthesis of compound (±)-38.11. Compound (±)-38.11 was prepared from compound (±)-38.10 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 593.67 [M+H]+. [0377] Synthesis of compound (±)-I-38. A mixture of (±)-38.11 (0.09 g, 0.15 mmol, 1.0 equiv) and 10% palladium on charcoal (0.075 g) in methanol (8 mL) was stirred under hydrogen atmosphere (1 atm) at room temperature for 5 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford (±)-I-38 (0.04 g, 52%). MS(ES): m/z 503.23 [M+H]+. [0378] I-38-a and I-38-b. The racemate was separated by chiral SFC (column CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) Liquid CO2, (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-38-a) and second eluting fraction (I-38-b). *The absolute configuration of the chiral center is not determined. I-38-a: MS(ES): m/z: 503.20 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.74-7.73 (d, J = 6.4 Hz, 1H), 7.41-7.39 (d, J = 6.0 Hz, 1H), 7.29-7.25 (t, J = 7.2 Hz, 1H), 4.61 (m, 1H), 4.23 (s, 3H), 3.96-3.93 (m, 1H), 3.63 (m, 1H), 3.28 (s, 3H), 3.18-3.11 (m, 1H), 2.93-2.91 (m, 1H), 2.18-2.14 (m, 2H), 2.01 (m, 1H), 1.76 (m, 1H), 1.24 (m, 1H), 1.18-1.60 (m, 2H), 0.85-0.78 (m, 4H). I-38-b: MS(ES): m/z: 503.22 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.74-7.73 (d, J = 6.4 Hz, 1H), 7.41-7.39 (d, J = 6.0 Hz, 1H), 7.29-7.25 (t, J = 7.2 Hz, 1H), 4.61 (m, 1H), 4.23 (s, 3H), 3.96-3.93 (m, 1H), 3.63 (m, 1H), 3.28 (s, 3H), 3.18-3.11 (m, 1H), 2.93-2.91 (m, 1H), 2.18-2.14 (m, 2H), 2.01 (m, 1H), 1.76 (m, 1H), 1.24 (m, 1H), 1.18-1.60 (m, 2H), 0.85-0.78 (m, 4H). Example I-39: 1-((4-(3-(5-(cyclopropanecarboxamido)-1-methyl-1H-pyrazolo[3,4-c]pyridin-3- yl)-2-methoxyphenyl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylic acid
Figure imgf000143_0001
[0379] Synthesis of compound 39.1. To a solution of ethyl 1-(hydroxymethyl)cyclopropane- 1-carboxylate (6 g, 10.40 mmol, 1.0 equiv) and triethylamine (3.1 g, 31.2 mmol, 3.0 equiv) in DCM (20 mL) at 0 °C was added methanesulfonyl chloride (1.77 g, 15.6 mmol, 1.5 equiv) dropwise and the reaction mixture was stirred at room temperature for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 39.1 (1.7 g, 73.5%). It was used in the next step without purification. [0380] Synthesis of compound 39.2. To a solution of 4-iodo-1H-pyrazole (1 g, 5.16 mmol, 1.0 equiv) in DMF (40 mL) was added 39.1 (1.7 g, 7.73 mmol, 1.5 equiv) followed by cesium carbonate (5.0 g, 15.48 mmol, 3.0 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (23% ethyl acetate in hexane) to afford 39.2 (1.0 g, 61%), MS(ES): m/z 321.3[M+H]+. [0381] Synthesis of compound 39.3. Compound 39.3 was prepared from compound 39.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 316.6 [M+H]+. [0382] Synthesis of compound 39.4. Compound 39.4 was prepared from compound 39.3, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 28% ethyl acetate in hexane). MS(ES): m/z 427.5 [M+H]+ . [0383] Synthesis of compound 39.5. Compound 39.5 was prepared from compound 39.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES): m/z 510.4 [M+H]+ and 512.5 [M+H]+ . [0384] Synthesis of compound 39.6. Compound 39.6 was prepared from compound 39.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 515.2 [M+H]+. [0385] Synthesis of I-39. To a solution of 39.6 (0.060 g, 0.11 mmol, 1.0 equiv) in THF (4 mL) and water (3 mL) was added lithium hydroxide (0.023 g, 0.55 mmol, 5.0 equiv). The reaction mixture was stirred at 50 ºC for 3 h. It was concentrated under reduced pressure. This was diluted with water and acidified by 2 N HCl solution. Precipitates were collected by filtration and dried under reduced pressure to afford I-39 (0.035 g, 61%). MS(ES): m/z 515.24 [M+H]+ , 1H NMR (DMSO-d6, 400 MHz): δ 12.49 (s, 1H), 10.78 (s, 1H), 8.99 (s, 1H), 8.34-8.22 (m, 1H), 7.95 (s, 1H), 7.73-7.72 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.40-7.38 (d, J = 6.8 Hz, 1H), 7.28-7.26 (m, 1H), 6.74 (s, 1H), 4.38 (s, 1H), 4.22 (s, 3H), 3.28 (s, 3H), 1.50-1.49 (m, 1H), 1.23-1.09 (m, 4H), 0.78- 0.62 (m, 4H). Example I-40: methyl 4-cyano-4-(3-(5-(cyclopropanecarboxamido)-1-methyl-1H-pyrazolo[3,4- c]pyridin-3-yl)-2-methoxyphenyl)piperidine-1-carboxylate
Figure imgf000145_0001
[0386] Synthesis of compound 40.1. To a solution of 35.2 (0.45 g, 1.52 mmol, 1.0 equiv) and triethylamine (0.463 g, 4.57 mmol, 3.0 equiv) in DCM (5.0 mL) at 0 °C was added dropwise acetyl chloride (0.173 g, 1.83 mmol, 1.2 equiv) and stirred for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. which was purified by silica gel column chromatography (25% ethyl acetate in hexane) to afford 40.1 (0.310 g, 58%). MS(ES): m/z 353.16 and 355.11 [M+H]+. [0387] Synthesis of compound 40.2. A mixture of 40.1 (0.310 g, 0.877 mmol, 1.0 equiv), potassium acetate (0.258 g, 2.63 mmol, 3.0 equiv) and bis(pinacolato)diboron (0.894 g, 3.52 mmol, 4.0 equiv) in 1,4-dioxane (5 mL) was degassed by bubbling though a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex (0.072 g, 0.08801 mmol, 0.1 equiv) was added and stirred at 100 °C for 24 h. It was filtered through a pad of Celite® bed and the filtrate was concentrated under reduced pressure to afford 40.2 (0.280 g, 80%). MS(ES): m/z 401.20 [M+H]+. It was used in the next step without purification. [0388] Synthesis of compound 40.3. Compound 40.3 was prepared from compound 40.2 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 80.0% ethyl acetate in hexane). MS(ES): m/z 484.02 and 486.02 [M+H]+. [0389] Synthesis of compound I-40. Compound I-40 was prepared from compound 40.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM). MS (ES): m/z 489.19 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.012 (s, 1H), 8.321 (s, 1H), 7.57-7.55 (d, J = 7.2 Hz, 1H), 7.43-7.41 (d, J = 7.2 Hz, 1H), 7.29-7.27 (d, J = 7.2 Hz, 1H), 4.22 (s, 3H), 3.62 (s, 3H), 3.27 (s, 3H), 3.17 (m, 3H), 2.39 (m, 2H), 1.97-1.95 (m, 4H), 0.77 (s, 4H). Example I-41: 4-cyano-4-(3-(5-(cyclopropanecarboxamido)-1-methyl-1H-pyrazolo[3,4- c]pyridin-3-yl)-2-methoxyphenyl)-N,N-dimethylpiperidine-1-carboxamide
Figure imgf000146_0001
[0390] Synthesis of compound 41.1. To a solution of 35.2 (0.45 g, 1.52 mmol, 1.0 equiv) and triethylamine (0.463 g, 4.57 mmol, 3.0 equiv) in DCM (5.0 mL) at 0 °C was added dimethylcarbamic chloride (0.197 g, 1.83 mmol, 1.2 equiv) and stirred for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. which was purified by silica gel column chromatography (25% ethyl acetate in hexane) to afford 41.1 (0.30 g, 58%). MS(ES): m/z 366.03 and 368.03 [M+H]+. [0391] Synthesis of compound 41.2. A mixture of 41.1 (0.30 g, 0.819 mmol, 1.0 equiv), potassium acetate (0.121 g, 2.45 mmol, 3.0 equiv) and bis(pinacolato)diboron (0.832 g, 3.27 mmol, 4.0 equiv) in 1,4-dioxane (5 mL) was degassed by bubbling though a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex (0.067 g, 0.0819 mmol, 0.1 equiv) was added and the mixture was stirred at 100 °C under argon for 24 h. It was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to afford 41.2 (0.270 g, 80%). MS(ES): m/z 414.20[M+H]+. It was used in the next step without purification. [0392] Synthesis of compound 41.3. Compound 41.3 was prepared from compound 41.2 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 80.0% ethyl acetate in hexane). MS(ES): m/z 497.10 and 499.10[M+H]+. [0393] Synthesis of compound I-41. Compound I-41 was prepared from compound 41.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS (ES): m/z 502.24 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.81 (s, 1H), 9.01 (s, 1H), 8.32 (s, 1H), 7.58-7.57 (d, J = 6.4 Hz, 1H), 7.46-7.44 (d, J = 6.8 Hz, 1H), 7.30- 7.28 (t, J = 7.6 Hz, 1H), 4.23(s, 3H), 3.73-3.70 (m, 2H), 3.28 (s, 3H), 3.10 (m, 2H), 2.77 (s, 6H), 2.41-2.37 (m, 2H), 2.02-1.98 (m, 3H), 0.77 (m, 4H). Example I-42: N-(3-(3-(4-cyano-1-(2-methoxyethyl)piperidin-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000147_0001
[0394] Synthesis of compound 42.1. To a solution of 35.2 (0.450 g, 1.52 mmol, 1.0 equiv) and triethylamine (0.63 mL, 4.57 mmol, 3.0 equiv) in DCM (10 mL) was added 1-bromo-2- methoxyethane (0.423 g, 3.05 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexane) to afford 42.1 (0.290 g, 54%). MS (ES): m/z: 353.2 and 355.2 [M+H]+. [0395] Synthesis of compound 42.2. A mixture of 42.2 (0.290 g, 0.820 mmol, 1.0 equiv), bis(pinacolato)diboron (1.04 g, 4.10 mmol, 5.0 equiv) and potassium acetate (0.241 g, 2.46 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling though a stream of argon for 10 min. (1,1'-Bis(diphenylphosphino)ferrocene) palladium(II) dichloride DCM complex (0.066 g, 0.0820 mmol, 0.1 equiv) were added to the reaction mixture and degassed for 10 min. and stirred at 100 °C for 1 h. It was filtrated through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane) to afford 42.2 (0.210 g, 64%). MS(ES): m/z 401.21 [M+H]+. [0396] Synthesis of compound 42.3. Compound 42.3 was prepared from compound 42.2 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane). MS(ES): m/z 484.2 and 486.2 [M+H]+. [0397] Synthesis of compound I-42. Compound I-42 was prepared from compound 42.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 489.25 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.01 (s, 1H), 8.32 (s, 1H), 7.58-7.56 (d, J = 7.2 Hz, 1H), 7.44 (m, 1H), 7.28 (m, 1H), 4.23 (s, 3H), 3.48 (s, 3H), 3.32 (s, 3H), 3.31-3.27 (m, 5H), 3.02 (m, 3H), 2.47-2.32 (m, 2H), 1.99 (m, 3H), 0.78 (m, 4H). Example I-43: N-(3-(3-(1-(ethylsulfonyl)piperidin-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000148_0001
Figure imgf000149_0001
[0398] Synthesis of compound 43.1. A mixture of 1,3-dibromo-2-methoxybenzene (1.00 g, 3.76 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.400 g, 4.51 mmol, 1.2 equiv) and sodium carbonate (1.2 g, 11.28 mmol, 3.0 equiv) in 1,4-dioxane (20 mL) and water (4 mL) w was purged with argon gas for 15 min. Bis(diphenylphosphino)ferrocene palladium dichloride (0.306 g, 0.376 mmol, 0.1 equiv) was added and the mixture was stirred at 90 ºC for 3 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 16% ethyl acetate in hexane) to afford 43.1 (0.508 g, 37%). MS(ES): m/z 370.24 and 371.24 [M+H]+. [0399] Synthesis of compound 43.2. A mixture of 43.1 (0.508 g, 1.38 mmol, 1.0 equiv) and platinum oxide (0.50 g,) in ethyl acetate (25 mL) was stirred under hydrogen atmosphere for 16 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 43.2 (0.412 g, 81%). MS(ES): m/z 372.15 and 373.15[M+H]+. [0400] Synthesis of compound 43.3. A stirred solution of 43.2 (0.412 g, 1.11 mmol, 1 equiv) in DCM (12 mL) at 0 °C was added trifluoroacetic acid (1.5 mL). The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture diluted with DCM and quenched with saturated sodium bicarbonate solution, The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.8% methanol in DCM) to afford 43.3 (0.286 g, 95%). MS(ES): m/z 270.0 and 272.0 [M+H]+. [0401] Synthesis of compound 43.4. A stirred solution of 43.3 (0.286 g, 1.06 mmol, 1 equiv) and trimethylamine (0.321 g, 3.18 mmol, 3.0 equiv) in DCM (8 mL) was added ethanesulfonyl chloride (0.149 g, 1.16 mmol, 1.1 equiv) at 0 °C. The reaction mixture was allowed to stir at room temperature for 2 h. It was diluted with DCM and washed with saturated sodium bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.8% methanol in DCM) to afford 43.4 (0.192 g, 50%). MS(ES): m/z 362.1 and 364.09 [M+H]+. [0402] Synthesis of compound 43.5. Compound 43.5 was prepared from compound 43.4, following the procedure described in the synthesis of compound 6.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane). MS(ES): m/z 410.35 [M+H]+. [0403] Synthesis of compound 43.6. A mixture of 3.1 (0.230 g, 0.65 mmol, 1.0 equiv), 43.5 (0.40 g, 0.976 mmol, 1.5 equiv) and potassium carbonate (0.27 g, 1.95 mmol, 3.0 equiv) in 1,4- dioxane (12 mL) and water (3 mL) was added degassed by bubbling though a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.053 g, 0.065 mmol, 0.1 equiv) was added and degassed for 10 min. The reaction mixture was stirred at 110 °C for 1 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 45.0% ethyl acetate in hexane) to afford 43.6 (0.06 g, 18.68%). MS(ES): m/z 494.42 [M+H]+. [0404] Synthesis of compound I-43. Compound I-43 was prepared from compound 43.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS (ES): m/z 498.19 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): 10.77 (s, 1H), 8.99 (s,1H), 8.35 (s, 1H), 7.46-7.44 (d, J = 8.0 Hz, 1H), 7.42-7.40 (d, J = 8.0 Hz, 1H), 7.26-7.24 (d, J = 8.0 Hz, 1H), 4.21 (s, 3H), 3.76 (s, 3H), 3.18-3.09 (m, 6H).3.03-2.97 (m, 1H).2.08-2.04 (m, 1H).1.87-1.72 (m, 4H), 1.27-1.25 (t, J = 8.0 Hz, 3H), 0.78 (m, 4H). Example I-44: 6-((3-(3-(4-cyano-1-(ethylsulfonyl)piperidin-4-yl)-2-methoxyphenyl)-1-methyl- 1H-pyrazolo[3,4-c]pyridin-5-yl)amino)picolinonitrile
Figure imgf000151_0001
[0405] Synthesis of compound 44.1. To a solution of 35.2 (0.50 g, 1.693 mmol, 1.0 equiv) and triethylamine (0.7 mL, 5.081 mmol, 3.0 equiv) in DCM (5 mL) at 0 °C was added dropwise ethanesulfonyl chloride (0.326 g, 2.540 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 15 min. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50.0% ethyl acetate in hexane) to afford 44.1 (0.320 g, 49%). MS (ES): m/z: 387.2 and 389.2 [M+H]+. [0406] Synthesis of compound 44.2. A mixture of 44.2 (0.320 g, 0.826 mmol, 1.0 equiv), bispinacolatodiboron (0.314 g, 1.239 mmol, 1.5 equiv) and potassium acetate (0.202 g, 2.065 mmol, 2.5 equiv) in 1,4-dioxane (4 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'-Bis (diphenylphosphino)ferrocene]palladium (II) dichloride (0.060 g, 0.0826 mmol, 0.1 equiv) were added to the reaction mixture and degassed for 10 min. The mixture was stirred at 100 °C for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 44.2 (0.265 g, 74%). It was used in the next step without purification. MS(ES): m/z 435.13 [M+H]+. [0407] Synthesis of compound 44.3. Compound 44.3 was prepared from compound 44.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 518.3 and 520.3 [M+H]+. [0408] Synthesis of compound I-44. A mixture of 44.3 (0.089 g, 0.171 mmol, 1.0 equiv), 6- aminopicolinonitrile (0.030 g, 0.257 mmol, 1.5 equiv), cesium carbonate (0.167 g, 0.515 mmol, 3.0 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.019 g, 0.034 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.015 g, 0.0171 mmol, 0.1 equiv) in 1,4-dioxane (6 mL) was degassed by bubbling through a stream of argon for 5 min. The reaction mixture was stirred at 130 °C for 1 h. It was cooled to room temperature, quenched by water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM) to afford I-44 (0.028 g, 29%). MS (ES): m/z 557.64 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.20 (s, 1H), 9.03 (s, 1H), 8.32 (s, 1H), 7.81- 7.77 (t, J = 7.6 Hz 1H), 7.71-7.69 (d, J = 7.6 Hz, 1H), 7.57-7.55 (d, J = 7.6 Hz, 1H), 7.49-7.47 (d, J = 7.6 Hz, 1H), 7.41-7.40 (d, J = 7.6 Hz, 1H), 7.33-7.32 (m, 1H), 4.25 (s, 3H), 3.90-3.86 (d, J = 12.8 Hz, 2H), 3.22-3.16 (m, 5H), 2.63-2.60 (m, 4H), 2.13-2.10 (m, 2H), 1.27-1.24 (m, 3H). Example I-45-a and I-45-b: (S)-N-(3-(2-methoxy-3-(1-((3-methoxytetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and (R)-N-(3-(2-methoxy-3-(1-((3-methoxytetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000152_0001
Figure imgf000153_0001
[0409] Synthesis of compound (±)-45.1. To a stirred solution of dimethyl 2-methoxymalonate (15 g, 92.59 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (4.7 g, 185.1 mmol, 2.0 equiv) at 0 °C. After 1 h, sodium iodide (3 g, 92.59 mmol, 1.0 equiv) and 1-bromo-2- fluoroethane (8.9 g, 92.59 mmol, 1.0 equiv) were added at 0 °C. The reaction mixture stirred at room temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford (±)-45.1 (10 g, 52%). MS(ES): m/z 209.22 [M+H]+. [0410] Synthesis of compound (±)-45.2. To a solution of (±)-45.1 (10 g, 48.0 mmol, 1 equiv) in THF (80 mL) was added a solution of lithium tri-t-butoxyaluminum hydride in THF (1 M, 48 mL, 48.0 mmol, 1 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was cooled to room temperature, quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution followed by citric acid solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-45.2 (6.5 g, 75%). MS (ES): m/z 181.19 [M+H]+. [0411] Synthesis of compound (±)-45.3. To a solution of (±)-45.2 (6.5 g, 36.11 mmol, 1.0 equiv) in THF (25 mL) and methanol (5 mL) was added 1 N sodium hydroxide solution in water (36.11 mL, 36.11 mmol, 1.0 equiv) at room temperature. It was stirred at room temperature for 16 h. It was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.4% methanol in DCM) to afford (±)-45.3 (3.25 g, 62%). MS(ES): m/z 147.31 [M+H]+. [0412] Synthesis of compound (±)-45.4. To a stirred solution of (±)-45.3 (3.25 g, 22.2 mmol, 1.0 equiv) in THF (18 mL) was added lithium aluminum hydride (1 M in THF, 44.4 g, 44.4 mmol, 2 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was quenched with 1 N HCl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM) to afford (±)-45.4 (1.6 g, 54%). MS(ES): m/z 133.31 [M+H]+. [0413] Synthesis of compound (±)-45.5. To a stirred solution of (±)-45.4 (1.6 g, 12.1 mmol, 1.0 equiv) and triethylamine (5.0 mL, 36.3 mmol, 3 equiv) in DCM (18 mL) at 0 °C was added methanesulfonyl chloride (2.0 g, 18.1 mmol, 1.5 equiv). It was stirred for 1 h, transferred into sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-45.5 (1.7 g, 67%). It was used in the next step without further purification. MS(ES): m/z 211.22 [M+H]+. [0414] Synthesis of compound (±)-45.6. A mixture of (±)-45.5 (1.7 g, 8.09 mmol, 1 equiv), 4-bromo-1H-pyrazole (1.18 g, 8.09 mmol, 1 equiv) and cesium carbonate (7.9 g, 24.2 mmol, 3 equiv) in DMF (20 mL) was stirred at 80 °C for 16 h. It was cooled to room temperature and transferred into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)-45.6 (1.5 g, 71%). MS (ES): m/z 262.19 [M+H]+. [0415] Synthesis of compound (±)-45.7. Compound (±)-45.7 was prepared from compound (±)-45.6 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane). MS(ES): m/z 304.41 [M+H]+. [0416] Synthesis of compound (±)-45.8. Compound (±)-45.8 was prepared from compound (±)-45.7, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 415.6 [M+H]+. [0417] Synthesis of compound (±)-45.9. Compound (±)-45.9 was prepared from compound (±)-45.8 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane). MS(ES): m/z 499.5 [M+H]+. [0418] Synthesis of compound (±)-I-45. Compound (±)-I-45 was prepared from compound (±)-45.9 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). [0419] I-45-a and I-45-b. The racemate was separated by chiral HPLC (column: CHIRALPAK IC (250 x 21 mm,5 μm); mobile phase: (A) 0.1% diethylamine in n- hexane, (B) 0.1% diethylamine in isopropanol: CAN (70:30); flow rate: 20 mL/min) to afford first eluting fraction (I-45-a) and second eluting fraction (I-45-b). *The absolute configuration of the chiral center is not determined. I-45-a: MS(ES): m/z 503.51 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 8.86 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 4.56-4.43 (m, 2H), 4.25 (s, 3H), 3.96-3.88 (m, 2H), 3.81 (s, 3H), 3.39 (s, 3H), 2.16-1.91 (m, 3H), 1.38-1.18 (m, 2H), 098-0.90 (m, 4H). I-45-b: MS(ES): m/z 503.5 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 8.86 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 4.56-4.43 (m, 2H), 4.25 (s, 3H), 3.96-3.88 (m, 2H), 3.81 (s, 3H), 3.39 (s, 3H), 2.16-2.03 (m, 3H), 1.20-1.18 (m, 2H), 0.97-0.88 (m, 4H). Example I-46-a and I-46-b: N-(3-(2-methoxy-3-(1-((2R,3R)-2-(methoxymethyl)tetrahydro-2H- pyran-3-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and N-(3-(2-methoxy-3-(1-((2S,3S)-2-(methoxymethyl)tetrahydro- 2H-pyran-3-yl)-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000156_0001
[0420] Synthesis of compound (±)-46.1. To a solution of (±)-38.9 (25 g, 62.77 mmol, 1.0 equiv) in DCM (275 mL) was added triflic acid (41 mL) dropwise at 0 °C and stirred for 20 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-46.1 (8.3 g, 43%). MS(ES): m/z 309.18 [M+H]+. [0421] Synthesis of compound (±)-46.2. To a solution of (±)-46.1 (8.3 g, 26.93 mmol, 1.0 equiv) in DMF (70 mL) was added sodium hydride (60% dispersion in mineral oil, 2.15 g, 53.87 mmol, 2.0 equiv) at 0 °C for 15 min. Methyl iodide (4.97gm, 35.01 mmol, 1.3 equiv) was added and again stirred for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane) to afford (±)-46.2 (6.22 g, 72%). MS(ES): m/z 323.59 [M+H]+. [0422] Synthesis of compound (±)-46.3. Compound (±)-46.3 was prepared from compound (±)-46.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane). MS(ES): m/z 318.36 [M+H]+. [0423] Synthesis of compound (±)-46.4. Compound (±)-46.4 was prepared from compound (±)-46.3, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 31% ethyl acetate in hexane). MS(ES): m/z 429.56 [M+H]+. [0424] Synthesis of compound (±)-46.5. Compound (±)-46.5 was prepared from compound (±)-46.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane). MS(ES): m/z 512.2 and 514.2 [M+H]+. [0425] Synthesis of compound (±)-I-46. Compound (±)-I-46 was prepared from compound (±)-46.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in Dichloromethane). MS(ES): m/z 517.45 [M+H]+. [0426] I-46-a and I-46-b. The racemate was separated by chiral SFC (column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) Liquid CO2, (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-46-a) and second eluting fraction (I-46-b). *The absolute configuration of the chiral center is not determined. I-46-a: MS(ES): m/z: 517.35 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.00 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.75-7.73 (d, J = 7.6 Hz, 1H), 7.41-7.40 (d, J = 7.6 Hz, 1H), 7.28-7.52 (t, J = 7.6 Hz, 1H), 4.22 (s, 1H), 3.93-3.91 (m, 1H), 3.75-3.73 (m, 1H), 3.28 (s, 3H), 3.13 (s, 3H), 3.04-3.02 (m, 1H), 2.92-2.91 (m, 1H), 2.20 (m, 2H), 2.00 (m, 2H), 1.74 (m, 1H), 1.23 (m, 2H), 1.18-1.14 (m, 2H), 0.86-0.77 (m, 4H). I-46-b: MS(ES): m/z: 517.34 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.75-7.73 (d, J = 7.6 Hz, 1H), 7.41-7.40 (d, J = 7.6 Hz, 1H), 7.28-7.52 (t, J = 7.6 Hz, 1H), 4.22 (s, 1H), 3.93-3.91 (m, 1H), 3.75-3.73 (m, 1H), 3.28 (s, 3H), 3.13 (s, 3H), 3.04-3.02 (m, 1H), 2.92-2.91 (m, 1H), 2.20 (m, 2H), 2.00 (m, 2H), 1.74 (m, 1H), 1.23 (m, 2H), 1.18-1.14 (m, 2H), 0.85-0.77 (m, 4H). Example I-47-a and I-47-b: N-(3-(3-(1-((5R,9S)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(3-(1-((5S,9R)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000158_0001
Figure imgf000159_0001
[0427] Synthesis of compound (±)-47.1. To a solution of (±)-12.1 (58.0 g, 248.86 mmol, 1.0 equiv) in toluene (580 mL) at 0 °C was added Dess-Martin periodinane (159 g, 376.62 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at room temperature for 16 h. It at 0 °C was quenched by adding saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexane) to afford (±)-47.1 (40.0 g, 70%). MS(ES): m/z 231.0 [M+H]+& 233.0 [M+H]+. [0428] Synthesis of compound (±)-47.2. To a solution of (±)-47.1 (40.0 g, 173.12 mmol, 1.0 equiv) in THF (400 mL) at 0 °C was added vinyl magnesium bromide (1 M in THF, 346 mL, 346.25 mmol, 2.0 equiv) dropwise. The reaction mixture was stirred at 0 °C for 2 h. It was quenched with saturated ammonium chloride solution and product was extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (22% ethyl acetate in hexane) to afford (±)-47.2 (5.5 g, 12%). MS(ES): m/z 259.1 and 261.1 [M+H]+. [0429] Synthesis of compound (±)-47.3. To a solution of (±)-47.1 (5.0 g, 19.30 mmol, 1 equiv) in DMF (50 mL) was added sodium hydride (55% in mineral oil) (1.68 g, 38.59 mmol, 2 equiv) at 0 °C and stirred for 15 min. Allyl bromide (3.5 g, 28.95 mmol, 1.5 equiv) was added to the reaction mixture was stirred at 0 °C for 15 min. It added into ice-water slowly, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-47.3 (3.0 g, 52%). MS(ES): m/z 299.08 and 301.08 [M+H]+. [0430] Synthesis of compound (±)-47.4. To a solution of (±)-47.3 (3.0 g, 10.03 mmol, 1 equiv) in DCM (50 mL) was added [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichlo (phenyl methylene) (Tricyclohexylphosphine)ruthenium (2.55 g, 3.01 mmol, 0.3 equiv) at room temperature and stirred for 5 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-47.4 (1.6 g, 59%). MS(ES): m/z 271.02 and 273.02 [M+H]+. [0431] Synthesis of compound (±)-47.5. Compound (±)-47.5 was prepared from compound (±)-47.4 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product material was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 314.08 [M+H]+. [0432] Synthesis of compound (±)-47.6. A mixture of compound (±)-47.5 (1.1 g, 1.36 mmol, 1.0 equiv) and 20% palladium on carbon (0.600 g) in methanol (20 mL) was stirred under hydrogen (1 atm) for 4 h. It was filtered through a pad of Celite® and rinsed with 10% methanol in DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane) to afford (±)-47.6 (0.90 g, 81%). MS(ES): m/z 316.10 [M+H]+. [0433] Synthesis of compound (±)-47.7. Compound (±)-47.7 was prepared from compound (±)-47.6, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane). MS(ES): m/z 427.04 [M+H]+. [0434] Synthesis of compound (±)-47.8. Compound (±)-47.8 was prepared from compound (±)-47.7 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 510.2 and 512.27 [M+H]+. [0435] Synthesis of compound (±)-I-47. Compound (±)-I-47 was prepared from compound (±)-47.8 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM). MS(ES): m/z 515.52 [M+H]+. [0436] I-47-a and I-47-b. The racemate was separated by chiral SFC (column: CHIRALPAK IH (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in propane-2- ol:acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-47-a) and second eluting fraction (I-47-b). *The absolute configuration of the chiral center is not determined. I-47-a: MS(ES): m/z 515.22 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.76 -7.74 (d, J = 7.6 Hz, 1H), 7.42 - 7.40 (d, J = 7.6 Hz, 1H), 7.29 - 7.27 (t, J = 7.6 Hz, 1H), 4.85 (m, 1H), 4.85-4.84 (m, 1H), 4.32-4.30 (m, 1H), 4.28 (s, 3H), 3.92-3.85 (m, 2H), 3.81-3.76 (m, 2H), 3.27 (s, 3H), 1.99-1.96 (m, 2H), 1.54-1.48 (m, 2H), 1.33 (m, 1H), 0.079-0.73 (m, 4H). I-47-b: MS(ES): m/z 515.44 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 8.99 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.76 -7.74 (d, J = 7.6 Hz, 1H), 7.42 - 7.40 (d, J = 7.6 Hz, 1H), 7.29 - 7.27 (t, J = 7.6 Hz, 1H), 4.85 (m, 1H), 4.85 (m, 1H), 4.32-4.28 (m, 1H), 4.22 (s, 3H), 3.92-3.87 (m, 2H), 3.81-3.79 (m, 2H), 3.27 (s, 3H), 1.83-1.79 (m, 2H), 1.52-1.49 (m, 2H), 1.20-1.15 (m, 1H), 0.77 (m, 4H). Example I-48: N-(3-(5-methoxy-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000161_0001
[0437] Synthesis of compound 48.1. To a solution of 2-oxaspiro[3.3]heptan-6-ol (4.0 g, 35.04 mmol, 1.0 equiv) and triethylamine (14.65 mL, 105.13 mmol, 3.0 equiv) in DCM (50 mL) was methanesulfonyl chloride (5.42 mL, 70.09 mmol, 2.0 equiv) dropwise at 0 °C and stirred at room temperature for 3 h. It was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 48.1 (4.0 g, 59%). MS (ES): m/z: 193.23[M+H]+. [0438] Synthesis of compound 48.2 and 48.3. A mixture of 48.1 (4.0 g, 20.81 mmol, 1.0 equiv), 5-methoxy-1H-pyrazole (2.25 g, 22.89 mmol, 1.1 equiv) in DMF (40 mL) and cesium carbonate (20.34 g, 62.43 mmol, 3.0 equiv) was stirred at 80 °C for 12 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30.0% ethyl acetate in hexane) and repurified by HPLC to afford 48.2 (0.203 g, 4.5%) and 48.3 (0.235 g, 5.81%). MS(ES): m/z 195.23 [M+H]+. [0439] Synthesis of compound 48.4. To a stirred solution of 48.3 (0.235 g, 1.21 mmol, 1.0 equiv) in acetonitrile (10 mL) was added N-iodosuccinimide (0.816 g, 3.63 mmol, 3.0 equiv) and the reaction mixture was stirred at 70 °C for 4 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 48.4 (0.132 g, 34%). MS (ES): m/z 321.13 [M+H]+. [0440] Synthesis of compound 48.5. Compound 48.5 was prepared from compound 48.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 404.1 and 406.1 [M+H]+. [0441] Synthesis of compound I-48. Compound I-48 was prepared from compound 48.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 409.27 [M+H]+, LCMS purity: 95.81%, HPLC purity: 95.28%, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 8.93 (s, 1H), 8.50 (s, 1H), 7.72 (s, 1H), 4.79- 4.75 (m, 1H), 4.68 (s, 2H), 4.58 (s, 2H), 4.14 (s, 3H), 3.80 (s, 3H), 2.74-2.67 (m, 4H), 2.01 (m, 1H), 0.80-0.78 (m, 4H). Example I-49: N-(3-(3-(1-(ethylsulfonyl)-4-(hydroxymethyl)piperidin-4-yl)-2-methoxyphenyl)- 1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000162_0001
[0442] Synthesis of compound 49.1. To a stirred solution of I-35 (0.20 g, 0.383 mmol, 1.0 equiv) in THF at 0 °C was added diisobutylaluminum hydride (0.547 mL, 1.14 mmol, 3.0 equiv) dropwise and stirred at room temperature for 5 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane) to afford 49.1 (0.10 g, 39%). MS(ES): m/z 526.20 [M+H]+. [0443] Synthesis of compound I-49. To a stirred solution of 49.1 (0.1 g, 0.190 mmol, 1.0 equiv) in methanol (2.0 mL) at 0 °C was added in portions sodium borohydride (10.85 g, 0.285 mmol, 1.5 equiv) and stirred at room temperature for 10 min. It was quenched in water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford I-49 (0.025 g, 49.5%). MS(ES): m/z 527.22 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 8.97 (s, 1H), 8.30 (s, 1H), 7.42 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 4.76 (m, 1H), 4.21(s, 3H), 3.54 (m, 2H), 3.47 (m, 2H), 3.11 (s, 3H), 3.01-2.99 (m, 2H), 2.92-2.87 (m, 2H), 1.98 (m, 2H), 1.82 (m, 2H), 1.16-1.12 (m, 2H), 1.08-1.07 (m, 2H), 0.77 (m, 4H). Example I-50-a and I-50-b: (S)-N-(3-(5-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4- yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (R)-N-(3-(5- methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000163_0001
Figure imgf000164_0001
[0444] Synthesis of compound (±)-50.1. A mixture of 4-nitro-1H-pyrazole (10.0 g, 88.44 mmol, 1.0 equiv), cesium carbonate (86.44 g, 265.31 mmol, 3.0 equiv) and tetrahydro-2H-pyran- 3-yl methanesulfonate (31.88 g, 176.87 mmol, 2.0 equiv) in dimethyl sulfoxide (100 mL) was stirred at 40 °C for 12 h. It cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30.0% ethyl acetate in hexane) to afford (±)-50.1 (6.3 g, 36%). MS (ES): m/z: 198.19[M+H]+. [0445] Synthesis of compound (±)-50.2. To a stirred solution of (±)-50.1 (6.3 g, 31.95 mmol, 1.0 equiv) in THF (100 mL) was added dropwise lithium bis(trimethylsilyl)amide (1.0 M in THF, 96 mL, 95.85 mmol, 3.0 equiv) at -70 ºC and stirred for 1 h. Hexachloroethane (7.23 mL, 63.9 mmol, 2.0 equiv) was added and the reaction mixture was allowed to warm to rt and stirred for 3 h. It was transferred into water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)-50.2 (3.4 g, 46%). MS (ES): m/z 232.64 [M+H]+. [0446] Synthesis of compound (±)-50.3. To a solution of (±)-50.2 (3.4 g, 14.68 mmol, 1.0 equiv) in DMF (20 mL) was added sodium hydride (60% in mineral oil, 1.76 g, 44.03 mmol, 3.0 equiv) at 0 ºC and dropwise added methanol (5.94 mL, 146.78 mmol, 10.0 equiv). Then reaction mixture was stirred for 12 h at room temperature. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30.0% ethyl acetate in hexane) to afford (±)- 50.3 (2.4 g, 72%). MS(ES): m/z 228.22 [M+H]+. [0447] Synthesis of compound (±)-50.4. A mixture of (±)-50.3 (2.4 g, 10.56 mmol, 1.0 equiv) and palladium on carbon (2.4 g) in methanol (20 mL) was stirred under hydrogen pressure atmosphere for 2 h at room temperature. It was filtered through a pad of Celite® and rinsed eith methanol. The filtrate was concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 70.0% ethyl acetate in hexane) to afford (±)- 50.4 (1.3 g, 62%). MS(ES): m/z 198.2 [M+H]+. [0448] Synthesis of compound (±)-50.5. To a stirred solution of (±)-50.4 (1.3 g, 6.59 mmol, 1.0 equiv) in acetonitrile: water (20 mL, 1:1) at 0 °C was added sodium nitrite (0.454 g, 6.59 mmol, 1.0 equiv) and potassium iodide (4.38 g, 26.36 mmol, 4.0 equiv). The reaction mixture was stirred at 0 °C for 15 min and was added sulfuric acid (1.77 mL, 32.96 mmol, 5.0 equiv) dropwise at 0 ºC. The mixture was stirred for 1 h, transferred into water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane) to afford (±)-50.5 (0.390 g, 19%). MS (ES): m/z 309.12 [M+H]+. [0449] Synthesis of compound (±)-50.6. Compound (±)-50.6 was prepared from compound (±)-50.5 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 392.1 and 394.1 [M+H]+. [0450] Synthesis of compound (±)-I-50. Compound (±)-I-50 was prepared from compound (±)-50.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 397.3 [M+H]+. [0451] I-50-a and I-50-b. The racemate was separated by chiral HPLC (column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in propane-2-ol: methanol (50: 50); flow rate: 17 mL/min) to afford first eluting fraction (I-50-a) and second eluting fraction (I-50-b). *The absolute configuration of the chiral center is not determined. I-50-a: MS(ES): m/z: 397.34 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.71 (s, 1H), 8.88 (s, 1H), 8.62 (s, 1H), 8.04 (s, 1H), 4.21-4.19 (m, 1H), 4.10 (s, 3H), 4.00-3.97 (m, 1H), 3.90 (s, 3H), 3.80-3.78 (m, 1H), 3.65-3.60 (m, 1H), 3.45-3.40 (m, 1H), 2.12-2.01 (m, 3H), 1.71-1.65 (m, 2H) 0.81-0.77 (m, 4H). I-50-b: MS(ES): m/z: 397.37 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.72 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 8.04 (s, 1H), 4.21-4.19 (m, 1H), 4.10 (s, 3H), 4.00-3.97 (m, 1H), 3.90 (s, 3H), 3.80-3.78 (m, 1H), 3.65-3.60 (m, 1H), 3.45-3.40 (m, 1H), 2.12-2.01 (m, 3H), 1.71-1.65 (m, 2H) 0.81-0.77 (m, 4H). Example I-51-a and I-51-b: N-(3-(3-(1-((1R,2R)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2- methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3- (3-(1-((1S,2S)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000166_0001
Figure imgf000167_0001
[0452] Synthesis of compound (±)-51.1. To a solution of 4-bromo-1H-pyrazole (20 g, 136.05 mmol, 1.0 equiv) in DMF (200 mL) were added 6-oxabicyclo[3.1.0]hexane (11.42 g, 136.05 mmol, 1.0 equiv) and cesium carbonate (88.67 g, 272.10 mmol, 2.0 equiv). The reaction mixture was stirred at 120 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (19% ethyl acetate in hexane) to afford (±)-51.1 (15 g, 48%). MS(ES): m/z 232.09 [M+H]+. [0453] Synthesis of compound (±)-51.2. To a solution of (±)-51.1 (15 g, 64.93 mmol, 1.0 equiv) and 4-nitrobenzoic acid (21.68 g, 129 mmol, 1.2 equiv) in THF (120 mL) at 0 °C was added triphenyl phosphine (37.42 g, 142.84 mmol, 2.2 equiv) and diisopropyl azodicarboxylate (28.85 g, 142.84 mmol, 2.2 equiv). The reaction mixture was stirred at room temperature for 24 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12% ethyl acetate in hexane) to afford (±)-51.2 (19.6 g, 79%). MS(ES): m/z 381.2 [M+H]+. [0454] Synthesis of compound (±)-51.3. A mixture of (±)-51.2 (19.6 g, 51.57 mmol, 1.0 equiv) and potassium carbonate (21.35 g, 154.7 mmol, 3 equiv) in methanol (300 mL) was stirred at room temperature for 16 h. It was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (17% ethyl acetate in hexane) to afford (±)-51.3 (6.4 g, 54%). MS(ES): m/z 232.09 [M+H]+. [0455] Synthesis of compound (±)-51.4. To a solution of (±)-51.3 (6.4 g, 027.27 mmol, 1.0 equiv) in THF (64 mL) at 0 °C was added diethylaminosulfur trifluoride (13.38 g, 083 mmol, 3 equiv) in portions. The reaction mixture was stirred at room temperature for 48 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-51.4 (5.2 g, 35%). MS(ES): m/z 234.08 [M+H]+. It was used in the next step without purification. [0456] Synthesis of compound (±)-51.5. Compound (±)-51.5 was prepared from (±)-51.4 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following the procedure described in the synthesis of trans-(±)-10.3. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexane). MS(ES): m/z 276.33 [M+H]+. [0457] 51.5-a and 51.5-b. The racemate was separated by chiral HPLC (column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 20 mL/min) to afford first eluting fraction (51.5-a), MS(ES): m/z 276.3 [M+H]+ and second eluting fraction (51.5-b). MS(ES): m/z 276.3 [M+H]+. *The absolute configuration of the chiral center is not determined. [0458] Synthesis of compound 51.6-a. Compound 51.6-a was prepared from compound 51.5- a, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 387.3 [M+H]+. [0459] Synthesis of compound 51.6-b. Compound 51.6-b was prepared from compound 51.5- b, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 387.3 [M+H]+. [0460] Synthesis of compound 51.7-a. Compound 51.7-a was prepared from compound 51.6- a and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 469.09 and 471.09 [M+H]+. [0461] Synthesis of compound 51.7-b. Compound 51.7-b was prepared from compound 51.6- b and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 469.09 and 471.09 [M+H]+. [0462] Synthesis of compound I-51-a. Compound I-51-a was prepared from compound 51.7- a and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS (ES): m/z 475.47 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.00 (s,1H), 8.34-8.33 (s, 1H), 8.03 (s, 1H), 7.76-7.74 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.41- 7.40 (d, J = 4.0 Hz, 1H), 7.29-7.25 (t, J = 8.0 Hz, 1H), 6.76 (s, 1H), 5.36 (m, 1H), 5,22 (m, 1H), 4.96-4.91 (m, 1H), 4.23 (s, 3H), 3.28 (s, 3H), 2.33-2.29 (m, 1H), 2.18-2.14 (m, 1H), 2.09-2.00 (m, 2H), 1.51-1.48 (m, 1H), 0.77 (m, 2H), 0.60 (m, 2H). [0463] Synthesis of compound I-51-b. Compound I-51-b was prepared from compound 51.7- b and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS (ES): m/z 475.44 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.75-7.74 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.41-7.39 (d, J = 7.2 Hz, 1H), 7.28-7.25 (t, J = 8.0 Hz, 1H), 6.75 (s, 1H), 5.35-5.21 (s, JHF = 52.8 Hz, 1H), 4.95-4.90 (m, 1H), 4.22 (s, 3H), 3.28 (s, 3H), 2.32-2.28 (m, 1H), 2.17-1.87 (m, 5H), 0.77-0.62 (m, 4H). Example I-52: (S)-N-(3-(5-methoxy-1-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000169_0001
[0464] Synthesis of compound 52.1. To a solution of (R)-3-methoxypyrrolidine (20.0 g, 198.01 mmol, 1.0 equiv) and triethylamine (40 g, 396.1 mmol, 2.0 equiv) in THF (200 mL) at 0 °C was added 2-chloroacetyl chloride (22.17 g, 198.01 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 52.1 (11.4 g, 65.06%). It was used in the next step without purification. [0465] Synthesis of compound 52.2 and 52.3. A mixture of 52.1 (11.4 g, 64.18 mmol, 1.0 equiv), cesium carbonate (61.62 g, 192.56 mmol, 3.0 equiv) and 5-methoxy-1H-pyrazole (6.29 g, 64.25 mmol, 1.1 equiv) in DMF (70 mL) was stirred at 80 °C for 7 h. It was transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (column: SUNFIRE C18 (250 x 50 mm, 5 μm); mobile phase: (A) 0.1% TFA in water, (B) 100% acetonitrile; flow rate: 60 mL/min) to afford first eluting fraction (52.2) and second eluting fraction (52.3). MS(ES): m/z 240.2 [M+1]+. [0466] Synthesis of compound 52.4. To a solution of 52.3 (0.26 g, 1.087 mmol, 1.0 equiv) and N-iodosuccinimide (0.24 g, 1.087 mmol, 1.0 equiv) in acetonitrile (2 mL) was stirred at 70 °C for 16 h. It was filtered. The filtrate was transferred into ice-cold saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 52.4 (0.23 g, 56%). MS(ES): m/z 366.1 [M+1]+. [0467] Synthesis of compound 52.5. Compound 52.5 was prepared from compound 52.4 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 449.2 and 451.2 [M+H]+. [0468] Synthesis of compound I-52. Compound I-52 was prepared from compound 52.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 454.43 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 7.97 (s, 1H), 4.53 (bs, 2H), 4.20 (s, 3H), 4.02 (m, 1H), 3.93 (s, 3H), 3.36 (s, 3H), 3.21-3.10 (m, 2H), 2.22 (m, 1H), 2.14-2.11 (m, 1H), 2.01-1.92 (m, 2H), 1.19 (m, 1H), 0.91-0.90 (m, 4H). Example I-53: N-(3-(3-(1-((1r,3r)-3-fluorocyclobutyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000171_0001
[0469] Synthesis of compound cis-53.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (25 g, 142.05 mmol, 1.0 equiv) in methanol (250 mL), was added sodium borohydride (16.19 g, 426.13 mmol, 2.0 equiv) in portions at 0 °C. The reaction mixture was stirred at room temperature for 3 h. It was transferred into ice-cold water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford cis-53.1 (21 g, 83%). MS (ES): m/z 179.3 [M+H]+. [0470] Synthesis of compound trans-53.2. To a solution of cis-53.1 (21 g, 117.91 mmol, 1.0 equiv) in DCM (210 mL) was added diethylaminosulfur trifluoride (37.98 g, 235.95 mmol, 3.0 equiv) in portions at 0 ºC. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice- water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3% ethyl acetate in hexane) to afford trans-53.2 (5.3 g, 25%). MS (ES): m/z 181.22 [M+H]+. [0471] Synthesis of compound trans-53.3. A mixture of trans-53.2 (5.3 g, 117.91 mmol, 1.0 equiv) and 10% palladium on charcoal (140 mg) in methanol (10 mL) was stirred under hydrogen (1 atm) at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford trans-53.3 (2.3 g, 25%). The product was used without further purification. MS (ES): m/z 91.10 [M+H]+. [0472] Synthesis of compound cis-53.4. To a solution of trans-53.3 (2.3 g, 25.55 mmol, 1.0 equiv) and 4-nitrobenzoic acid (4.69 g, 28.11 mmol, 1.1 equiv) in THF (23 mL) was added triphenylphonine (8.70 g, 33.22 mmol, 2.0 equiv) and diisopropyl azodicarboxylate (6.71 g, 33.22 mmol, 2.0 equiv). The mixture was stirred at rt for 6 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford cis-53.4 (2.2 g, 32%). MS(ES): m/z 240.20 [M+H]+. [0473] Synthesis of compound cis-53.5. A solution of cis-53.4 (2.2 g, 117.91 mmol, 1.0 equiv) in methanol (10 mL) was added potassium carbonate (2.5 g, 18.41 mmol, 2.0 equiv) and stirred at rt for 12 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford cis-53.5 (0.79 g, 96%). [0474] Synthesis of compound cis-53.6. A solution of cis-53.5 (0.79 g, 8.77 mmol, 1.0 equiv) and pyridine (2.08 g, 26.33 mmol, 3.0 equiv) at 0 °C in DCM (10 mL) was added p- toluenesulfonic anhydride (3.4 g, 10.53 mmol, 1.2 equiv) and stirred for 2 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford cis-53.6 (0.49 g, 23%). [0475] Synthesis of compound trans-53.7. A mixture of trans-53.6 (0.81 g, 3.33 mmol, 1.0 equiv), 4-bromo-1H-pyrazole (0.49 g, 3.33 mmol, 1.1 equiv) and cesium carbonate (2.7 g, 8.33 mmol, 2.5 equiv) in DMF (10 mL) was stirred at 80 °C for 2 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford trans-53.7 (0.45 g). MS(ES): m/z 220.06 [M+H]+. It was used in the next step without purification. [0476] Synthesis of compound trans-53.8. Compound trans-53.8 was prepared from compound trans-53.7 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane). MS(ES): m/z 262.30 [M+H]+. [0477] Synthesis of compound trans-53.9. Compound trans-53.9 was prepared from compound trans-53.8, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS(ES): m/z 373.18 [M+H]+. [0478] Synthesis of compound trans-53.10. Compound trans-53.10 was prepared from compound trans-53.9 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 39% ethyl acetate in hexane). MS(ES): m/z 456.3 and 458.3[M+H]+. [0479] Synthesis of compound I-53. Compound I-53 was prepared from compound trans- 53.10 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM). MS(ES): m/z 461.18 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.00 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.75-7.73 (d, J = 7.2 Hz, 1H), 7.41-7.39 (d, J = 7.2 Hz, 1H), 7.29-7.27 (t, J = 7.6 Hz, 1H), 5.54-5.39 (m, 1H), 5.20 (m, 1H), 4.23(s, 3H), 3.28 (s, 3H), 2.78 (m, 4H), 2.00 (m, 1H), 0.78 (s, 4H). Example I-54: N-(3-(3-(6-cyano-2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2- methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000174_0001
[0480] Synthesis of compound 54.1. To a solution of tert-butyl 3,3- bis(bromomethyl)azetidine-1-carboxylate (3.0 g, 8.74 mmol, 1.0 equiv) in DMF (30 mL) was added sodium hydride (60% in mineral oil, 1.05 g, 26.23 mmol, 3.0 equiv) in portions at 0 °C and stirred for 30 min. To the mixture was added dropwise 2-(3-bromo-2-methoxyphenyl)acetonitrile (2.97 g, 13.12 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford 54.1 (0.850 g, 24%). MS (ES): m/z: 407.2 and 409.2 [M+H]+. [0481] Synthesis of compound 54.2. A mixture of 54.1 (0.850 g, 2.09 mmol, 1.0 equiv) and bis(pinacolato)diboron (2.65 g, 10.43 mmol, 5.0 equiv) and potassium acetate (0.614 g, 6.26 mmol, 3.0 equiv) in 1,4-dioxane (20 mL) was degassed by bubbling though a stream of argon for 10 min. (1,1'-Bis(diphenylphosphino)ferrocene) palladium(II) dichloride DCM complex (0.65 g, 0.795 mmol, 0.1 equiv) were added to the reaction mixture and further degassed for 10 min. and stirred at 100 °C for 1 h. It was filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 54.2 (0.850 g, 90%). MS(ES): m/z 455.23 [M+H]+. [0482] Synthesis of compound 54.3. Compound 54.3 was prepared from compound 54.2 and 3.1, following the procedure described in the synthesis of compound 2.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane). MS(ES): m/z 538.3 and 540.3 [M+H]+. [0483] Synthesis of compound 54.4. To a solution of 54.3 (0.290 g, 0.538 mmol, 1.0 equiv) in DCM (20 mL) was added trifluoroacetic acid (0.123 mL, 1.614 mmol, 3.0 equiv) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. It was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane) to afford 54.4 (0.250 g, 100%). MS(ES): m/z 439.3 [M+H]+. [0484] Synthesis of compound 54.5. To a solution of 54.4 (0.250 g, 0.570 mmol, 1.0 equiv) and triethylamine (0.23 mL, 1.71 mmol, 3.0 equiv) in DCM (20 mL) was added methanesulfonyl chloride (0.088 mL, 1.14 mmol, 2.0 equiv) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h. It was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane) to afford 54.5 (0.085 g, 29%). MS(ES): m/z 516.2 and 518.2 [M+H]+. [0485] Synthesis of compound I-54. Compound I-54 was prepared from compound 54.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS (ES): m/z 521.61 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.02 (s, 1H), 8.32 (s, 1H), 7.57-7.56 (d, J = 6.8 Hz, 1H), 7.41-7.39 (d, J = 7.2 Hz, 1H), 7.29- 7.27 (d, J = 7.6 Hz, 1H), 4.23 (s, 3H), 4.21 (s, 2H), 3.82(s, 2H), 3.14-3.11(m, 3H), 3.02 (s, 3H), 2.94-2.91 (m, 3H), 2.00 (m, 1H), 1.49 (m, 1H), 0.78 (m, 4H). Example I-55-a and I-55-b: N-(3-(3-(1-((4R,8S)-1,6-dioxaspiro[3.4]octan-8-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(3-(1-((4S,8R)-1,6-dioxaspiro[3.4]octan-8-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000176_0001
[0486] Synthesis of compound (±)-55.1. To a solution of (±)-47.2 (5.7 g, 22.00 mmol, 1.0 equiv) in THF (60 mL) was added 9-borabicyclo[3.3.1]nonane (1 M in THF, 66.0 mL 66.00 mmol, 3.0 equiv). The reaction mixture was stirred at 70 ℃ for 2 h. It was treated with 10% sodium hydroxide solution in water (5.7 mL) and hydrogen peroxide (5.7 mL) for 1 h at room temperature and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue material was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-55.1 (1.4 g, 23%). MS(ES): m/z 276.96 and 278.96 [M+H]+. [0487] Synthesis of compound (±)-55.2. To a solution of (±)-55.1 (1.4 g, 5.05 mmol, 1.0 equiv) and pyridine (1.19 g,1.51 mmol, 3.0 equiv) in DCM (25 mL) at 0 °C was added 4- toluenesulfonyl chloride (1.44gm,7.58 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 6 h. It was transfer into ice-water and product was extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue material was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-55.2 (0.85 g, 39%). MS(ES): m/z: 431.17 and 433.17 [M+H]+. [0488] Synthesis of compound (±)-55.3. To a solution of (±)-55.2 (0.85 g, 1.97 mmol, 1.0 equiv) in DMF (10 mL) at 0 °C and added sodium hydride(60% dispersion in mineral oil, 0.118 g, 2.95 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C for 30 min. It was transfer into ice-water and product was extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue material was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford (±)-55.3 (0.45 g, 88%). MS(ES): m/z:258.96 and 260.96 [M+H]+. [0489] Synthesis of compound (±)-55.4. Compound (±)-55.4 was prepared from compound (±)-55.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product material was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 302.22 [M+H]+. [0490] Synthesis of compound (±)-55.5. Compound (±)-55.5 was prepared from compound (±)-55.4, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS(ES): m/z 413.23 [M+H]+. [0491] Synthesis of compound (±)-55.6. Compound (±)-55.6 was prepared from compound (±)-55.5 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES): m/z 496.02 and 497.9[M+H]+. [0492] Synthesis of compound (±)-I-55. Compound (±)-I-55 was prepared from compound (±)-55.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 501.15 [M+H]+. [0001] I-55-a and I-55-b. The racemate was separated by chiral SFC (column: CHIRALPAK IH (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-55-a) and second eluting fraction (I-55-b). *The absolute configuration of the chiral center is not determined. I-55-a: MS(ES): m/z: 501.15 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 8.07 (m,1H), 7.78-7.76(d, J = 7.2 Hz, 1H), 7.43-7.41 (d, J = 7.2 Hz, 1H), 7.30-7.28 (t, J = 7.6 Hz, 1H), 5.17 (m, 1H), 4.42 (m, 2H), 4.23 (s, 3H), 4.14 (m, 2H), 3.97 (m, 1H), 3.29 (s, 3H), 2.89 (s, 1H), 2.01 (bs, 1H) 1.33 (s, 1H), 1.15 (s, 1H), 0.77 (s, 4H) I-55-b: MS(ES): m/z: 501.13 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 8.073 (s, 1H), 7.77-7.58 (d, J = 7.2 Hz, 1H), 7.43-7.41 (d, J = 7.2 Hz, 1H), 7.30-7.28 (t, J = 7.6 Hz, 1H), 5.17 (bs, 1H), 4.41 (m, 2H), 4.23 (s, 3H), 4.14 (m, 2H), 3.97 (m, 1H),3.29 (s, 3H), 2.89 (s, 1H), 2.01 (bs, 1H) 1.33 (s, 1H), 1.15 (s, 1H), 0.77 (s, 4H) Example I-56-a and I-56-b: (R)-N-(3-(5-methoxy-1'-(tetrahydro-2H-pyran-3-yl)-1'H-[1,4'- bipyrazol]-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(5-methoxy-1'-(tetrahydro-2H-pyran-3-yl)-1'H-[1,4'-bipyrazol]-4-yl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000178_0001
Figure imgf000179_0001
[0493] Synthesis of compound (±)-56.1. To a stirred solution of 4-nitro-1H-pyrazole (20.0 g, 176.99 mmol, 1.0 equiv) and tetrahydro-2H-pyran-3-ol (19.85 g, 194.69 mmol, 1.1 equiv) in THF (200 mL) at room temperature was added diisopropylazodicarboxylate (50.05 g, 247.78 mmol, 1.4 equiv) and triphenylphosphine (64.91 g, 247.78 mmol, 1.4 equiv) in portions. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice-water, neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.1% methanol in Dichloromethane) to afford (±)-56.1 (13 g, 37%). MS(ES): m/z 198.0 [M+H]+. [0494] Synthesis of compound (±)-56.2. A mixture of (±)-56.1 (13.0 g, 65.98 mmol, 1.0 and palladium on carbon (2 g) equiv) in methanol (260 mL) was stirred under hydrogen (1 atm) for 5 h at room temperature. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-56.2 (9.0 g, 81%). MS(ES): m/z 168.1 [M+H]+. [0495] Synthesis of compound (±)-56.3. To a stirred solution (±)-56.2 (9.0 g, 53.25 mmol, 1.0 equiv) in concentrated hydrochloric acid 20 mL at 0 °C was added an aq. solution of sodium nitrite (4.40 g, 63.9 mmol, 1.2 equiv) followed a solution of tin chloride (36.05 g, 159.75 mmol, 3.0 equiv) in hydrochloric acid (25 mL). The reaction mixture was stirred for 45 min. It was transferred into ice-water and basified with aq. sodium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-56.3 (9.0 g). MS(ES): m/z 183.2 [M+H]+. It was used without purification. [0496] Synthesis of compound (±)-56.4. To a stirred solution of (±)-56.3 (9.0 g, 49.45 mmol, 1.0 equiv) and diethyl 2-(ethoxymethylene)malonate (10.68 g, 49.45 mmol, 1.0 equiv) in water (50 mL) was added potassium carbonate (6.82 g, 49.45 mmol, 1.0 equiv). The reaction mixture was stirred at 100 °C for 4 h. It was transferred into ice-water and acidify with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-56.4 (3.20 g, 21%). MS(ES): m/z 307.2 [M+H]+. It was used in the next step without purification. [0497] Synthesis of compound (±)-56.5. To a stirred solution of (±)-56.4 (3.20 g, 10.45 mmol, 1.0 equiv) in ethyl acetate (25 mL) and methanol (25 mL) at 0 °C was added trimethylsilyldiazomethane (3.81 g, 33.46 mmol, 3.2 equiv) dropwise. The reaction mixture was stirred for 5 h at room temperature. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)- 56.5 (2.1 g, 63%). MS(ES): m/z 321.3 [M+H]+. [0498] Synthesis of compound (±)-56.6. To a stirred solution (±)-56.5 (2.1 g, 6.56 mmol, 1.0 equiv) in THF: water: methanol (1: 1: 1) at room temperature was added an aqueous solution of lithium hydroxide (2.62 g, 65.62 mmol, 10.0 equiv) and stirred at room temperature for 16 h. It was transferred into ice-water and acidify with concentrated hydrochloric acid. The solids precipitated were collected by filtration and dried under vacuum to afford (±)-56.6 (1.0 g, 15%). It was used in the next step without purification. MS(ES): m/z 293.2 [M+H]+. [0499] Synthesis of compound (±)-56.7. To a solution of (±)-56.6 (1.0 g, 3.42 mmol, 1.0 equiv) in acetonitrile (20 mL) at 0 °C was added sodium bicarbonate (0.86 g, 10.26 mmol, 3.0 equiv) and N-idosuccenamide (1.54 g, 6.84 mmol, 1.2 equiv) in portions. The reaction mixture was stirred for 10 min. It was transferred into ice-water, neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 52% ethyl acetate in hexane) to afford (±)-56.7 (0.70 g, 55%). MS(ES): m/z 375.1 [M+H]+. [0500] Synthesis of compound (±)-56.8. Compound (±)-56.8 was prepared from compound (±)-56.7 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 93% ethyl acetate in hexane). MS(ES): m/z 460.0 [M+H]+. [0501] Synthesis of compound (±)-I-56. Compound (±)-I-56 was prepared from compound (±)-56.8 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.7% methanol in DCM). MS(ES): m/z 463.2 [M+H]+. [0502] I-56-a and I-56-b. The racemate was separated by chiral SFC (column: CHIRALPAK- IC (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-56-a) and (I-56-b). *The absolute configuration of the chiral center is not determined. I-56-a: MS(ES): m/z 463.20 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.84 (s, 1H), 8.98(s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 4.40-4.37 (m, 1H), 4.19 (s, 3H), 4.04- 4.01 (m, 1H), 3.89 (s, 3H), 3.84-3.82 (m, 1H), 3.70-3.65 (m, 1H), 3.48-3.42 (m, 1H), 2.91-2.89 (m, 1H), 2.18-2.12 (m, 1H), 2.03-2.02 (m, 1H), 1.70-1.66 (m, 2H), 0.84-0.79 (m, 4H). I-56-b: MS(ES): m/z 463.53 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.82 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 4.38 (m, 1H), 4.17 (s, 3H), 4.02-4.01 (m, 1H), 3.87 (s, 3H), 3.83-3.80 (m, 1H), 3.68-3.63 (m, 1H), 3.46-3.41 (m, 1H), 2.16-2.14 (m, 2H), 2.02 (m, 1H), 1.74-1.68 (m, 2H), 1.17-1.13 (m, 1H), 0.82-0.78 (m, 4H). Example I-57: N-(3-(2-methoxy-3-(1-((3R,6R)-6-(methoxymethyl)-2-oxopiperidin-3-yl)-1H- pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000181_0001
Figure imgf000182_0001
[0503] Synthesis of compound 57.1. To a solution of (R)-2-aminohexanedioic acid (50.0 g, 310.55 mmol, 1.0 equiv) in ethanol (500 mL) at 0 °C was added dropwise thionyl chloride (110.8 g, 931.67 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 2 h and at 90 °C for 1 h. It was concentrated, quenched by an aqueous solution of sodium hydroxide and extracted with DCM. The combined organic layers were washed with sodium bi carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure 57.1 (29 g, 54%). MS(ES): m/z 172.15 [M+H]+. [0504] Synthesis of compound 57.2. To a solution of 57.1 (29.0 g, 28.67 mmol, 1.0 equiv) in DCM (290 mL) at 0 °C was added lithiumborohydride (2 M in THF, 65 mL, 28.67 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was quenched by 5 N hydrochloric acid solution to adjust pH ~7-8. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7% methanol in DCM) to afford 57.2 (19.0 g, 87%). MS(ES): m/z 130.13 [M+H]+. [0505] Synthesis of compound 57.3. To a solution of 57.2 (14.0 g, 108.52 mmol, 1.0 equiv) in THF (140 mL) was added sodium hydride (60% in mineral oil, 13.5 g, 271.31 mmol, 2.5 equiv) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Methyl iodide (15.5 g, 108.52 mmol, 1.0 equiv) was added dropwise and stirred for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7% methanol in DCM) to afford 57.3 (6.78 g, 43%). MS(ES): m/z 144.12 [M+H]+. [0506] Synthesis of compound 57.4. To a solution of 57.3 (6.7 g, 40 mmol, 1.0 equiv) in DMF (60 mL) at 0 °C was added sodium hydride (60% in mineral oil, 4.5 g, 80 mmol, 2.0 equiv) followed by benzyl bromide (9.96 g, 60 mmol, 1.5 equiv). The reaction mixture stirred at room temperature for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane as a eluent to afford 57.4 (5.1 g, 47%). MS(ES): m/z 234.3 [M+H]+. [0507] Synthesis of compound 57.5. To a solution of 57.4 (5.1g 27.79 mmol, 1.0 equiv) in chloroform (60 mL) and triethylamine (20 mL) at 0 °C was added trimethylsilyl trifluoromethanesulfonate (31 mL) dropwise and stirred for 1 h. Trimethylbenzeniminium dibromide (4.70 g) was added in portions. The reaction mixture was stirred at room temperature for 8 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 57.5 (4.1 g, 60%). MS(ES): m/z 312.3 and 314.3[M+H]+. [0508] Synthesis of compound 57.6. A mixture of 57.5 (4.1 g, 13.14 mmol, 1.0 equiv), cesium carbonate (8.54 g, 26.28 mmol, 2.0 equiv) and 4-bromo-1H-pyrazole (2.3 g, 15.76 mmol, 1.2 equiv) in DMF (50 mL) was stirred at 100 °C for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 57.6 (1.6 g, 32%). MS(ES): m/z 378.3 and 380.3 [M+H]+. [0509] Synthesis of compound 57.7. Compound 57.7 was prepared from compound 57.6 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-10.3. The product was purified by column chromatography on silica gel (Combiflash®, 3.3% methanol in DCM). MS(ES): m/z 421.4 [M+H]+. [0510] Synthesis of compound 57.8. Compound 57.8 was prepared from compound 57.7, following the procedure described in the synthesis of compound (±)-9.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 532.3 [M+H]+. [0511] Synthesis of compound 57.9. Compound 57.9 was prepared from compound 57.8 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 615.2 and 617.2 [M+H]+. [0512] Synthesis of compound 57.10. To a solution of 57.9 (0.118 g, 0.19 mmol, 1.0 equiv) in DCM (4 mL) at 0 °C was added trifluoromethanesulfonic acid (4 mL). The reaction mixture was stirred at 80 °C for 20 min. It was transfer into saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.3% methanol in DCM) to afford 57.10 (0.070 g, 70%). MS(ES): m/z 525.2 and 527.2[M+H]+. [0513] Synthesis of compound I-57. Compound I-57 was prepared from compound 57.10 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 530.54 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.00 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.74-7.72 (m, 2H), 7.40 (s, 1H), 7.27 (s, 1H), 4.97-5.07 (m, 1H), 4.23 (s, 3H), 3.33-3.32 (s, 6H), 2.09-1.91 (m, 5H), 1.24-1.23 (m, 3H), 0.79-0.76 (m, 4H). Example I-58-a and I-58-b: (R)-N-(3-(2-methoxy-3-(1-(5-oxo-4-azaspiro[2.5]octan-6-yl)-1H- pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(2-methoxy-3-(1-(5-oxo-4-azaspiro[2.5]octan-6-yl)-1H-pyrazol-4-yl)phenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000185_0001
[0514] Synthesis of compound 58.1 To a solution of 4-azaspiro[2.5]octan-5-one (5.0 g, 40 mmol, 1.0 equiv) in DMF (60 mL) at 0 °C was added sodium hydride (60% in mineral oil, 4.5 g,
80 mmol, 2.0 equiv) and stirred for 20 min. To the mixture was added benzyl bromide (9.96 g, 60 mmol, 1.5 equiv). The reaction mixture stirred at room temperature for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 58.1 (4.8 g, 56%). MS(ES): m/z 216.10 [M+H]+. [0515] Synthesis of compound (±)-58.2. To a solution of 58.1 (4.8 g, 22.32 mmol, 1.0 equiv) and triethylamine (20 mL) in chloroform (60 mL) at 0 °C was added trimethylsilyl trifluoromethanesulfonate (31 mL) and stirred for 1 h. Trimethyl-benzeniminium-tribromide (4.70 g) was added in portions. The reaction mixture was stirred at room temperature for 8 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)-58.1 (3.2 g, 49%). MS(ES): m/z 294.3 and 296.3[M+H]+. [0516] Synthesis of compound (±)-58.3. A mixture of (±)-58.2 (3.2 g, 10.92 mmol, 1.0 equiv), cesium carbonate (7.09 g, 21.84 mmol, 2.0 equiv) and 4-iodo-1H-pyrazole (2.07 g, 10.92 mmol, 1.0 equiv) was stirred at 80 °C for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)- 58.3 (2.4 g, 54%). MS(ES): m/z 408.07 [M+H]+. [0517] Synthesis of compound (±)-58.4. A mixture of (±)-58.4 (2.4 g, 33.66 mmol, 1.0 equiv) and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline5 (10.66 g, 40.39 mmol, 1.2 equiv) in 1,4-dioxane (25 mL) and water (5 mL) was degassed by bubbling though a stream of argon for 10 min. Cesium carbonate (13.93 g, 100 mmol, 3.0 equiv) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (2.46 g, 3.36 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.3% methanol in DCM) to afford (±)-58.4 (1.5 g, 63%). MS(ES): m/z 403.31 [M+H]+. [0518] Synthesis of compound (±)-58.5. To a mixture of (±)-58.4 (1.5 g, 3.73 mmol, 1.0 equiv), camphor sulfonic acid (1.03 g, 4.47 mmol, 1.2 equiv), tetra-butylammonium bromide (1.43 g, 4.47 mmol, 1.2 equiv) and copper bromide (0.249 g, 1.11 mmol, 0.3 equiv) in acetonitrile (25 mL) was added t-butylnitrile (0.460 g, 4.47 mmol,1.2 equiv) at room temperature for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford (±)-58.5 (0.70 g, 40%). MS(ES): m/z 466.21 and 468.2 [M+H]+. [0519] Synthesis of compound (±)-58.6. A mixture of (±)-58.5 (0.70 g, 1.50 mmol, 1.0 equiv), bis(pinacolato)diboron (0.570 g, 2.25 mmol, 1.5 equiv) and potassium acetate (0.441 g, 4.50 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling though a stream of argon for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (0.122 g, 0.15 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 16 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)- 58.6 (0.650 g, 84%). MS(ES): m/z 514.5 [M+H]+. [0520] Synthesis of compound (±)-58.7. A mixture of (±)-58.6 (0.650 g, 1.26 mmol, 1.0 equiv) and 3.1 (0.471 g, 1.39 mmol, 1.1 equiv) in acetonitrile (12 mL) and water (4 mL) was degassed by bubbling though a stream of argon for 10 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (0.102 g, 0.12 mmol, 0.1 equiv) and sodium carbonate (0.396 g, 3.78 mmol, 3.0 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 29% ethyl acetate in hexane) to afford (±)-58.7 (0.430 g, 57%). MS(ES): m/z 597.3 and 599.3 [M+H]+. [0521] Synthesis of compound (±)-58.8. To a solution of (±)-58.7 (0.430 g, 0.72 mmol, 1.0 equiv) in DCM (4 mL) at 0 °C was added trifluoromethanesulfonic acid (4 mL). The reaction mixture was stirred at 80 °C for 20 min. It was transfer into saturated sodium bicarbonate solution and product was extract with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.3% methanol in DCM) to afford (±)-58.8 (0.210 g, 57.5%). MS(ES): m/z 507.2 and 509.2[M+H]+. [0522] Synthesis of compound (±)-I-58. Compound (±)-I-58 was prepared from compound (±)-58.8 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 512.3[M+H]+. [0523] I-58-a and I-58-b. The racemate was separated by chiral SFC (column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-58-a) and second eluting fraction (I-58-b). *The absolute configuration of the chiral center is not determined. I-58-a: MS(ES): m/z 512.3 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 8.99 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.76-7.74 (t, J = 7.6 Hz, 1H), 7.41-7.39 (t, J = 6.0 Hz, 1H), 7.28-7.24 (t, J = 7.6 Hz, 1H), 5.14-5.10 (m, 1H), 4.23 (s, 3H), 3.39 (s, 3H), 2.42 (m, 1H), 2.32-2.23 (m, 1H), 2.05-1.99 (m, 1H), 1.66-1.63 (m, 1H), 1.15-1.18 (m, 1H), 0.78- 0.76 (m, 4H), 0.74-0.71 (m, 4H). I-58-b: MS(ES): m/z 512.3 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.00 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.93(s, 1H), 7.77-7.75 (d, J = 6.0 Hz, 1H), 7.42-7.40 (d, J = 6.0 Hz 1H), 7.29-7.25 (t, J = 7.6 Hz 1H), 5.14-5.10 (m, 1H), 4.23 (s, 3H), 3.29 (s, 3H), 2.31-2.23 (m, 1H), 2.13-1.99 (m, 2H), 1.66-1.63 (m, 1H), 1.15-1.18 (m, 1H), 0.78-0.76 (m, 4H), 0.74-0.71 (m, 4H). Example I-59-a and I-59-b: N-(3-(3-methoxy-4-(1-((3S,4R)-4-methoxytetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)pyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and N-(3-(3-methoxy-4-(1-((3R,4S)-4-methoxytetrahydrofuran-3- yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000188_0001
Figure imgf000189_0001
[0524] Synthesis of compound (±)-59.1. To a solution of (±)-12.1 (7.1 g, 30.73 mmol, 1.0 equiv) in DMF (70 mL) at 0 °C was added 60% sodium hydride (1.59 g, 39.95 mmol, 1.3 equiv) in portions. The reaction mixture stirred for 20 min at 0 °C. Methyl iodide (5.67 g, 39.95 mmol, 1.3 equiv) was added and the mixture was stirred at room temperature for 2 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexane) to afford (±)-59.1. (6.2 g, 83%). MS(ES): m/z 246.12 [M+H]+. [0525] Synthesis of compound (±)-59.2. A mixture of (±)-59.1 (6.2 g, 25.30 mmol, 1.0 equiv), bis(pinacolato)diboron (9.61 g, 37.95 mmol, 1.5 equiv) and potassium acetate (7.44 g, 75.91 mmol, 3.0 equiv) in 1,4-dioxane (60 mL) was degassed by bubbling through a stream of argon for 20 min. (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.206 g, 0.253 mmol, 0.01 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 2 h. It was filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was added water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue material was further washed with hexane to afford (±)-59.2 (6.01 g, 81%). MS(ES): m/z 293.19[M+H]+. [0526] Synthesis of compound (±)-59.3. To a solution of 4-bromopyridin-3-ol (10 g, 57.47 mmol, 1.0 equiv) in concentrated sulfuric acid (98%, 60 mL) were added concentrated nitric acid (70%, 5.42 g, 86.20 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1.5% methanol in DCM) to afford (±)-59.3 (3.1 g, 25%). MS(ES): m/z 219.99 [M+H]+. [0527] Synthesis of compound (±)-59.4. To a mixture of (±)-59.3 (3.1 g, 14.16 mmol, 1.0 equiv) and potassium carbonate (5.86 g, 42.48 mmol, 3.0 equiv) in DMF (60 mL) was added methyl iodide (3.01 g, 21.24 mmol, 1.5 equiv) dropwise at 0 ºC. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12% ethyl acetate in hexane) to afford (±)-59.4 (1.6 g, 48.5%). MS(ES): m/z 234.02[M+H]+. [0528] Synthesis of compound (±)-59.5. Compound (±)-59.5 was prepared from compound (±)-59.2 and 59.4, following the procedure described in the synthesis of compound (±)-10.3. The product was purified by column chromatography on silica gel (35% ethyl acetate in hexane). MS(ES): m/z 321.30 [M+H]+. [0529] Synthesis of compound (±)-59.6. A mixture of (±)-59.5 (0.440 g, 1.37 mmol, 1.0 equiv) and 10% palladium on charcoal (0.220 g) in methanol (15 mL) was stirred under hydrogen (1 atm) for 3 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-59.6 (0.25 g, 63%). MS(ES): m/z 291.32 [M+H]+. [0530] Synthesis of compound (±)-59.7. To a solution of (±)-59.6 (2.1 g, 7.23 mmol, 1.0 equiv) in 48% hydrobromic acid (21 mL) at 0 °C was added bromine (3.47 g, 22.41 mmol, 3.1 equiv) and stirred for 30 min. To the mixture was added sodium nitrite (1.47 g, 2 .69 mmol, 3 equiv) in portions. The reaction mixture was stirred at 50 °C for 1 h. It was poured into ice-water and adjusted pH~10 using sodium hydroxide solution. It was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexane) to afford (±)-59.7 (1.4 g, 55%). MS(ES): m/z 356.18 and 357.18 [M+H]+ [0531] Synthesis of compound (±)-59.8. Compound (±)-59.8 was prepared from compound (±)-59.7 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by column chromatography on silica gel (2.6% methanol in DCM). MS(ES): m/z 487.28 and 488.28 [M+H]+. [0532] Synthesis of compound (±)-I-59. Compound (±)-I-59 was prepared from compound (±)-59.8 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 490.18 [M+H]+. [0533] I-59-a and I-59-b. The racemate was separated by chiral SFC (column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine IN isopropanol: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-59-a) and second eluting fraction (I-59-b). *The absolute configuration of the chiral center is not determined. I-59-a: MS(ES): m/z 490.18 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 9.01 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 8.45-8.44 (d, J = 5.2 Hz, 1H), 8.23 (s, 1H), 7.73-7.71 (d, J = 4.8 Hz, 1H), 5.06 (s, 1H), 4.25 (s, 3H), 4.21-4.17 (m, 1H), 4.11-4.03 (m, 2H), 3.81-3.78 (d, J = 12.4 Hz, 1H), 3.60 (s, 3H), 3.34 (s, 3H), 2.01-2.00 (m, 1H), 1.12-1.10 (m, 1H), 0.80-0.77 (m, 4H). I-59-b: MS(ES): m/z 490.18 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.01 (s, 1H), 8.77 (s, 1H), 8.56 (s, 1H), 8.45-8.44 (d, J = 5.3 Hz, 1H), 8.23 (s, 1H), 7.73-7.72 (d, J = 5.2 Hz, 1H), 5.07 (s, 1H), 4.25 (s, 3H), 4.21-4.17 (m, 1H), 4.11-4.03 (m, 2H), 3.81-3.78 (d, J = 12.4 Hz, 1H), 3.60 (s, 3H), 3.34 (s, 3H), 2.02 (m, 1H), 1.23 (m, 1H), 0.81-0.80 (m, 4H). Example I-60-a and I-60-b: N-(3-(3-(1-((1R,4R)-5,8-dioxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(3-(1-((1S,4S)-5,8-dioxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000192_0001
[0534] Synthesis of compound (±)-cis-60.1 and (±)-trans-60.1. To a solution of 2-(4-bromo- 1H-pyrazol-1-yl)cyclobutan-1-one (67 g, 311.56 mmol, 1.0 equiv) in THF (30 mL) and water (700 mL) at 0 °C was added tetrabutylammonium cyanide (108.54 g, 405.08 mmol, 1.3 equiv) followed by sodium bisulphite (32.4 g, 311.56 mmol, 1.0 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate in hexane) and the isomers were isolated by preparative HPLC to afford (±)-trans-60.1 (4.4 g, 5.83%), MS(ES): m/z 242.3[M+H]+ and 244.5[M+H]+. [0535] Synthesis of compound (±)-trans-60.2. To a solution of (±)-trans-60.1 (4.1 g, 10.47 mmol, 1.0 equiv) in concentrated hydrochloric acid (40 mL) was stirred at 80 °C for 2 h. It was concentrated under reduced pressure. The residue was purified by preparative HPLC purification to afford (±)-trans-60.2 (1.6 g, 34%). MS(ES): m/z 261.2 [M+H]+ and 263.2 [M+H]+. [0536] Synthesis of compound (±)-trans-60.3. To a solution of (±)-trans-60.2 (1.6 g, 6.13 mmol, 1.0 equiv) in THF (25 mL) at 0 °C was added borane dimethyl sulfide (0.931 g, 12.26 mmol, 2.0 equiv) dropwise. The reaction mixture was stirred at 60 °C for 2 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford (±)-trans-60.3 (0.9 g, 59%). MS(ES): m/z 247.1 [M+H]+ and 249.2 [M+H]+. [0537] Synthesis of compound (±)-trans-60.4. To a solution of (±)-trans-60.3 (0.9 g, 3.64 mmol, 1.0 equiv) in 1,2-dichloroethane (10 mL) was added tetrabutylammonium bromide (0.234 g, 0.72 mmol, 0.2 equiv), followed by sodium hydroxide (8.73 g, 218.4 mmol, 60.0 equiv) in water (10 mL). The reaction mixture was stirred at 50 °C for 72 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane) to afford (±)- trans-60.4 (0.28 g, 28%). MS(ES): m/z 273.2 [M+H]+ and 275.3 [M+H]+ . [0538] Synthesis of compound (±)-trans-60.5. Compound (±)-60.5 was prepared from compound (±)-60.4 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 316.6 [M+H]+. [0539] Synthesis of compound (±)-trans-60.6. To a solution of (±)-trans-60.5 (0.23 g, 0.729 mmol, 1.0 equiv), camphor sulphonic acid (0.203 g, 0.876 mmol, 1.2 equiv) and tetra- butylammonium bromide (0.282 g, 0.876 mmol, 1.2 equiv) in acetonitrile (10 mL) tert-butyl nitrile (0.105 g, 1.46 mmol, 2.0 equiv) dropwise followed by copper(II)bromide (0.031 g, 0.219 mmol, 0.3 equiv). The reaction mixture was stirred at room temperature for 15 min. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 33% ethyl acetate in hexane) to afford (±)-trans-60.6 (0.19 g, 69%). MS(ES): m/z 379.3 [M+H]+ and 381.2 [M+H]+ . [0540] Synthesis of compound (±)-trans-60.7. Compound (±)-trans-60.7 was prepared from compound (±)-trans-60.7, following the procedure described in the synthesis of compound 6.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 427.1 [M+H]+. [0541] Synthesis of compound (±)-trans-60.8. To a solution of (±)-trans-60.7 (0.14 g, 0.328 mmol, 1.0 equiv) in acetonitrile (10 mL) and water (2 mL) was added 3.1 (0.332 g, 0.361 mmol, 1.1 equiv), potassium carbonate (0.135 g, 0.984 mmol, 3.0 equiv). The reaction mixture was degassed by bubbling though a stream of argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex (0.027 g, 0.03 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 1.5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.9% methanol in DCM) to afford (±)-trans-60.8 (0.060 g, 36%). MS(ES): m/z 510.3 [M+H]+ and 512.2 [M+H]+. [0542] Synthesis of compound (±)-I-60. Compound (±)-I-59 was prepared from compound (±)-59.8 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM). MS(ES): m/z 515.3 [M+H]+. [0543] I-60-a and I-60-b. The racemate was separated by column CHIRALPAK IC (250 x 21 mm,5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in MeOH: MeCN (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-60-a) and second eluting fraction (I-60-a). *The absolute configuration of the chiral center is not determined. I-60-a: MS(ES): m/z: 515.26 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 8.99 (s, 1H), 8.35-8.32 (d, J = 13.2 Hz, 2H), 8.00 (s, 1H), 7.75-7.73 (d, J = 7.6 Hz, 1H), 7.41-7.39 (d, J = 7.6 Hz, 1H), 7.28-7.25 (m, 1H), 4.87-4.82 (m, 1H), 3.78-3.59 (m, 8H), 3.27 (s, 3H), 2.32-2.27 (m, 2H), 2.06-1.98 (m, 2H), 1.75-1.67 (m, 2H), 0.77-0.75 (m, 4H). I-60-b: MS(ES): m/z: 515.29 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 8.99 (s, 1H), 8.35-8.32 (d, J = 13.2 Hz, 2H), 8.00 (s, 1H), 7.75-7.73 (d, J = 7.6 Hz, 1H), 7.41-7.39 (d, J = 7.6 Hz, 1H), 7.28-7.25 (m, 1H), 4.87-4.82 (m, 1H), 3.78-3.59 (m, 8H), 3.27 (s, 3H), 2.32-2.27 (m, 2H), 2.06-1.98 (m, 2H), 1.75-1.67 (m, 2H), 0.77-0.75 (m, 4H). Example I-61-a and I-61-b: (R)-N-(3-(2-methoxy-3-(5-(methylsulfonyl)-6,7-dihydro-5H,9H- imidazo[2,1-c][1,4]oxazepin-2-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and (S)-N-(3-(2-methoxy-3-(5-(methylsulfonyl)-6,7-dihydro- 5H,9H-imidazo[2,1-c][1,4]oxazepin-2-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000195_0001
Figure imgf000196_0001
[0544] Synthesis of compound 61.1. A mixture of ethyl 4-bromo-1H-imidazole-2- carboxylate (13.0 g, 59.36 mmol, 1.0 equiv), cesium carbonate (38.58 g, 118.72 mmol, 2 equiv) and (chloromethyl)(methyl)sulfane (8.547 g, 89.04 mmol, 1.5 equiv) in DMF (130 mL) was stirred at 80 °C for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 61.1 (8 g, 48%). MS(ES): m/z 279.2 and 281.2 [M+H]+. [0545] Synthesis of compound 61.2. To a solution of 61.1 (8.0 g, 28.67 mmol, 1.0 equiv) in THF (50 mL) at 0 °C was added lithium borohydride (2 M in THF, 0.937 g, 43.20 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 61.2 (4.5 g, 66%). MS(ES): m/z 237.1 and 239.1 [M+H]+. [0546] Synthesis of compound 61.3. To a solution of 61.2 (4.5 g, 18.98 mmol, 1.0 equiv) in DCM was added silver oxide (21.92 g, 94.93 mmol, 5.0 equiv) and 1-chloro-2-iodoethane (46.88 g, 246.74 mmol, 13 equiv) at room temperature. The reaction mixture was stirred at room temperature for 48 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 61.3 (1.2 g, 21%). MS(ES): m/z 299.10 and 301.1 [M+H]+. [0547] Synthesis of compound 61.4. To a solution of 61.3 (1.2g 4.0133 mmol, 1.0 equiv) in DCM at 0 °C was added m-chloroperbenzoic acid (2.5 g, 16.05 mmol, 4.0 equiv) in portions. The reaction mixture was stirred at same temperature for 1 h. It was transferred into saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 61.4 (0.670 g, 51%). MS(ES): m/z 331.1 and 334.9 [M+H]+. [0548] Synthesis of compound (±)-61.5. To a solution of 61.4 (0.670g 2.02 mmol, 1.0 equiv) in DMF (15 mL) at 0 °C was added sodium hydride (60% in mineral oil, 0.50 g, 8.09 mmol, 4.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)-61.5 (0.60 g, 95%). MS(ES): m/z 295.2 and 297.1[M+H]+. [0549] Synthesis of compound (±)-61.6. Compound (±)-61.6 was prepared from compound (±)-61.5 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of compound (±)-11.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 338.31 [M+H]+. [0550] Synthesis of compound (±)-61.7. To a solution of (±)-61.6 (0.30 g, 0.89 mmol, 1.0 equiv) in acetonitrile (10 mL) was added camphosulfonic Acid (0.247 g, 1.068 mmol, 1.2 equiv), tetra-butylammonium bromide (0.573 g, 1.78 mmol, 1.2 equiv) and copper bromide (0.059 g, 0.26 mmol, 0.3 equiv). The reaction mixture was stirred at room temperature followed by dropwise addition of t-butyl nitrite (0.11 g, 1.068 mmol, 1.2 equiv). The reaction mixture was stirred at same temperature for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford (±)-61.7 (0.29 g, 81%). MS(ES): m/z 400.9 and 402.9 [M+H]+. [0551] Synthesis of compound (±)-61.8. Compound (±)-61.8 was prepared from compound (±)-61.7, following the procedure described in the synthesis of compound 6.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 449.31 [M+H]+. [0552] Synthesis of compound (±)-61.9. A mixture of (±)-61.8 (0.19 g, 0.42 mmol, 1.0 equiv) and 3.1 (0.157 g, 0.46 mmol, 1.1 equiv) in acetonitrile (5 mL), water(1.5 mL) mixture was degassed by bubbling though a stream of argon for 10 min. Sodium carbonate (0.133 g, 1.27 mmol, 3.0 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (0.034 g, 0.04 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h. It was cooled to room temperature and transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford (±)-61.9 (0.120 g, 53%). MS(ES): m/z 532.31 and 534.1 [M+H]+. [0553] Synthesis of compound (±)-I-61. Compound (±)-I-61 was prepared from compound (±)-61.9 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 537.2 [M+H]+. [0554] I-61-a and I-61-b. The racemate was separated by chiral SFC (column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phase: (A) Liquid CO2, (B) 0.1% diethylamine in propane-2-ol: methanol (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (I-61-a) and second eluting fraction (I-61-b). *The absolute configuration of the chiral center is not determined. I-61-a: MS(ES): m/z 537.23 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 9.00 (s, 1H), 8.32 (s, 1H), 8.16-8.14 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.43-7.42 (d, J = 6.0 Hz, 1H), 7.31- 7.29 (m, 1H), 4.88-4.81(m, 1H), 4.23 (s, 3H), 4.16-4.13 (m, 2H), 3.09 (s, 6H), 2.78-2.63 (m, 3H), 2.03-1.91 (m, 2H), 0.76-0.74 (m, 4H). I-61-b: MS(ES): m/z 537.21 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 9.00 (s, 1H), 8.32 (s, 1H), 8.16-8.14 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.50-7.42 (m, 1H), 7.31-7.29 (m, 1H), 4.92-4.81 (m, 2H), 4.22 (s, 6H), 4.13 (m, 1H), 3.08 (s, 3H), 2.78-2.63 (m, 3H), 2.03-1.91 (m, 2H), 0.76-0.74 (m, 4H). Example I-62-a and I-62-b: (R)-N-(3-(4-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)- 3-methoxypyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and (S)-N-(3-(4-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000199_0001
[0555] Synthesis of compound (±)-62.1. To a solution of cyclopentanone (200.0 g, 238.09 mmol, 1.0 equiv) in DCM (1.4 L) was added p-toluenesulphonic acid (24.57 g, 14.28 mmol, 0.06 equiv) and NBS (508.5 g, 285.70 mmol, 1.2 equiv) in portions at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was direct filter . The combined organic layers were washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-62.1 (192 g, 51%). [0556] Synthesis of compound (±)-62.2. A mixture of (±)-62.1 (192.0 g, 117.79 mmol, 1.0 equiv) and potassium carbonate (650.0 g, 471.16 mmol, 4.0 equiv) in acetonitrile (1.9L) was added a solution of 4-bromo-1H-pyrazole (865.7 g, 235.58 mmol, 2.0 equiv) in acetonitrile dropwise at 0 °C for 1.5 h. The reaction mixture was stirred at room temperature for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-62.2 (36.4 g, 13.5%). MS(ES): m/z 229.07 and 231.07 [M+H]+. [0557] Synthesis of compound (±)-62.3. To a solution of (±)-62.2 (36.0 g, 157.20 mmol, 1.0 equiv) in benzene (380 mL) was added boron trifluroide etherate (11.16 g, 78.60 mmol, 0.5 equiv) and ethylene glycol (9.74 g, 157.20 mmol, 1 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-62.3 (19.0 g, 45%). MS(ES): m/z 273.1 and 275.1 [M+H]+. [0558] Synthesis of compound (±)-62.4. Compound (±)-62.4 was prepared from compound (±)-62.3, following the procedure described in the synthesis of compound 6.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 321.12 [M+H]+. [0559] Synthesis of compound (±)-62.5. Compound (±)-62.5 was prepared from compound (±)-62.4 and 1-bromo-2-methoxy-3-nitrobenzene, following the procedure described in the synthesis of compound (±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 347.31 [M+H]+. [0560] Synthesis of compound (±)-62.6. A mixture of (±)-62.5 (2.8 g, 1.53 mmol, 1.0 equiv) and 10% palladium on charcoal (1.6 g) in methanol (30 mL) was ad stirred under hydrogen (1 atm) at room temperature for 2 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford (±)-62.6 (1.9 g, 79%). MS(ES): m/z 317.21 [M+H]+ . [0561] Synthesis of compound (±)-62.7. A solution of (±)-62.6 (1.9 g, 0.89 mmol, 1.0 equiv) in DCM (20 mL) at 0 °C was added isopentyl nitrile (0.573 g, 1.78 mmol, 1.2 equiv) and copper bromide (0.059 g, 0.26 mmol, 0.3 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford (±)-62.7 (0.70 g, 81%). MS(ES): m/z 380.1 and 382.1 [M+H]+. [0562] Synthesis of compound (±)-62.8. Compound (±)-62.8 was prepared from compound (±)-62.7 and 3.1, following the procedure described in the synthesis of compound (±)-9.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 511.05 and 513.01 [M+H]+. [0563] Synthesis of compound (±)-I-62. Compound (±)-I-62 was prepared from compound (±)-62.8 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 516.27 [M+H]+. [0564] I-62-a and I-62-b. The racemate was separated by chiral HPLC (column: CHIRALPAK AD-H (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1%diethylamine in isopropanol: MeCN (70: 30); flow rate = 20 mL/min) to afford first eluting fraction (I-62-a) and second eluting fraction (I-62-b). *The absolute configuration of the chiral center is not determined. I-62-a: MS(ES): m/z 516.26 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.02 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.74 (m, 1H), 4.68-4.65 (m, 1H), 4.27 (s, 3H), 3.83- 3.77 (m, 3H), 3.62 (s, 3H), 2.34-2.27 (m, 2H), 2.03-1.88 (m, 5H), 1.78-1.74 (m, 2H), 0.79-0.77 (m, 4H). I-62-b: MS(ES): m/z 516.50 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.76 (s, 1H), 9.00 (s, 1H), 8.77 (s, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 7.72-7.71 (d, J = 4.8 Hz, 1H), 4.66-4.62 (m, 1H), 4.25 (s, 3H), 3.83-3.75 (m, 3H), 3.60 (s, 3H), 2.32-2.30 (m, 2H), 2.01-1.89 (m, 5H), 1.78-1.72 (m, 2H), 0.79-0.77 (m, 4H). Example I-63-a and I-63-b: N-(3-(3-methoxy-4-(1-((2R,3R)-2-(methoxymethyl)tetrahydro-2H- pyran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide and N-(3-(3-methoxy-4-(1-((2S,3S)-2-(methoxymethyl)tetrahydro- 2H-pyran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)cyclopropanecarboxamide
Figure imgf000202_0001
[0565] Synthesis of compound (±)-63.1. To a solution of (±)-38.7 (20.0 g, 62.08 mmol, 1.0 equiv) in dimethyl sulfoxide (200 mL) was added bis(pinacolato)diborane (22.07 g, 86.91 mmol, 1.4 equiv) and potassium acetate (24.33 g, 248.32 mmol, 4.0 equiv). The reaction mixture was degassed by bubbling though a stream of argon for 10 min, bis(triphenylphosphine)palladium(II) dichloride (2.27 g,3.10 mmol, 0.05 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 120 °C for 2 h. It was cooled to room temperature, and transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (±)-63.1 (17.0 g). MS(ES): m/z 323.62 [M+H]+. [0566] Synthesis of compound (±)-63.2. Compound (±)-63.2 was prepared from compound (±)-63.1 and 4-bromo-3-methoxy-2-nitropyridine, following the procedure described in the synthesis of compound (±)-10.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 31% ethyl acetate in hexane). MS(ES): m/z 349.62 [M+H]+. [0567] Synthesis of compound (±)-63.3. A mixture of compound (±)-63.2 (10.2 g, 29.31 mmol, 1.0 equiv) and 10% palladium on carbon (5.0 g) in methanol (120 mL) was stirred under hydrogen (1 atm) for 3 h. The mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-63.3 (6.1 g, 65%). MS(ES): m/z 319.23 [M+H]+. [0568] Synthesis of compound (±)-63.4. To a solution of (±)-63.3 (6.1 g, 19.18 mmol, 1.0 equiv) in DCM (70 mL) was added tert-butyl nitrite (7.87 g, 76.72 mmol, 4.0 equiv), then copper(II) bromide (17.11 g, 76.72 mmol, 4.0 equiv) was added. reaction mixture was stirred at rt for 1 h. It was added into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM) to afford (±)-63.4 (3.0 g, 41%). MS(ES): m/z 382.1 and 384.1 [M+H]+. [0569] Synthesis of compound 63.5. To a solution of 3.1 (5.0 g, 14.79 mmol, 1.0 equiv) in 1,4-dioxane (50 mL) was added hexamethylditin (9.67 g, 29.59 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium (0) (1.70 g, 1.47 mmol, 0.1 equiv). The reaction mixture was stirred at 110 °C for 1.5 h in microwave reactor. It was cooled to room temperature, diluted with ethyl acetate and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 28% ethyl acetate in hexane) to afford 63.5 (3.5 g, 63%). MS(ES): m/z 374.5 and 376.5 [M+H]+. [0570] Synthesis of compound (±)-63.6. To a solution of 63.5 (0.6 g, 1.57 mmol, 1.0 equiv) in 1,4-dioxane (13 mL) was added (±)-63.4 (0.822 g, 2.19 mmol, 1.4 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.181 g, 0.15 mmol, 0.1 equiv). The reaction mixture was degassed for 15 min and stirred at 100 °C for 14 h. It was cooled to room temperature, diluted with ethyl acetate, and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.7% methanol in Dichloromethane) to afford (±)-63.6 (0.09 g, 11%). MS(ES): m/z 513.2 and 515.2 [M+H]+. [0571] Synthesis of compound (±)-I-63. Compound (±)-I-63 was prepared from compound (±)-63.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.9% methanol in DCM). MS(ES): m/z 518.17 [M+H]+. [0572] I-63-a and I-63-b. The racemate was separated by chiral HPLC (column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in hexane, (B) 0.1% diethylamine in propane-2-ol: methanol (50: 50); flow rate: 20 mL/min) to afford first eluting fraction (I-63-a) and second eluting fraction (I-63-b). *The absolute configuration of the chiral center is not determined. I-63-a: MS(ES): m/z: 518.17 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.02 (s, 1H), 8.78 (s, 1H), 8.47-8.44 (t, J = 4.4 Hz, 2H), 8.20 (s, 1H), 7.72-7.71 (d, J = 5.2 Hz, 1H), 4.32 (m, 1H), 4.27 (s, 2H), 3.95-3.93 (m, 1H), 3.80-3.78 (m, 1H), 3.62 (s, 3H), 3.49-3.43 (m, 2H), 3.14 (s, 3H), 3.06-3.03 (m, 2H), 2.19-2.18 (m, 2H), 2.03 (m, 1H), 1.76 (m, 1H), 1.24 (s, 1H), 0.86-0.78 (m, 3H). I-63-b: MS(ES): m/z: 518.50 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.78 (s, 1H), 9.01 (s, 1H), 8.77 (s, 1H), 8.45-8.43 (t, J = 5.6 Hz, 2H), 8.19 (s, 1H), 7.70-7.69 (d, J = 4.8 Hz, 1H), 4.31 (m, 1H), 4.25 (s, 3H), 3.93 (m, 1H), 3.77 (m, 1H), 3.60 (s, 3H), 3.48-3.46 (m, 2H), 3.12 (s, 3H), 3.07-3.04 (m, 2H), 2.17-2.15 (m, 2H), 2.01 (m, 1H), 1.74 (m, 1H), 1.22 (m, 1H), 0.84-0.75 (m, 3H). Example I-64-a and I-64-b: N-(3-(4-(1-((5R,9S)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4- yl)-3-methoxypyridin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide and N-(3-(4-(1-((5S,9R)-1,7-dioxaspiro[4.4]nonan-9-yl)-1H-pyrazol-4-yl)-3-methoxypyridin-2- yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxamide
Figure imgf000205_0001
[0573] Synthesis of compound (±)-64.1. To a solution of (±)-47.4 (1.6 g, 5.90 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) was added bis(pinacolato)diboron (2.24 g, 8.85 mmol, 1.5 equiv) and potassium acetate (1.74 g, 17.70 mmol, 3.0 equiv). The reaction mixture was degassed by bubbling through a stream of argon for 10 min. (1,1'-Bis(diphenylphosphino)ferrocene) palladium(II) dichloride (0.431 g, 0.590 mmol, 0.1 equiv) was added and again degassed for 5 min. The reaction mixture was stirred at 120 °C for 12 h. It was cooled to rt, added water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-64.1 (1.6 g, 85%). MS(ES): m/z 319.20 [M+H]+. [0574] Synthesis of compound (±)-64.2. Compound (±)-64.2 was prepared from compound (±)-64.1 and 4-bromo-3-methoxy-2-nitropyridine, following the procedure described in the synthesis of compound (±)-10.3. The product material was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane). MS(ES): m/z 345.19 [M+H]+. [0575] Synthesis of compound (±)-64.3. A mixture of (±)-64.2 (0.76 g, 2.21 mmol, 1.0 equiv) and 10% palladium on carbon (0.30 g) in methanol was stirred at room temperature under hydrogen atmosphere for 2 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue material was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford (±)-64.3 (0.460 g, 66%). MS(ES): m/z 317.33 [M+H]+. [0576] Synthesis of compound (±)-64.4. To a solution of (±)-64.3 (0.460g 1.45 mmol, 1.0 equiv) in hydrobromic acid (47%, 6 mL) was added sodium nitrite (0.101 g, 1.45 mmol, 1.0 equiv) and bromine (0.465 g, 2.91 mmol, 2.0 equiv) was added at -5 °C. The reaction mixture was stirred at 60 °C for 30 min. It was transferred into ice-water, neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane) to afford (±)-64.4 (0.18 g, 33%), MS(ES): m/z 380.04 and 382.04 [M+H]+. [0577] Synthesis of compound (±)-64.5. To a solution of (±)-64.4 (0.18 g, 0.473 mmol, 1.0 equiv), compound 63.5 (0.178 g, 0.946 mmol, 2.0 equiv) in 1,4-dioxane (5 mL) was degassed by bubbling through a stream of argon for 10 min. Tetrakis(triphenylphosphine)palladium (0) (0.055 g, 0.047 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 16 h. It was concentrated under reduced pressure. The residue material was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM) to afford (±)- 64.5 (0.068 g, 28%). MS(ES): m/z 511.13 and 513.13 [M+H]+. [0578] Synthesis of compound (±)-I-64. Compound (±)-I-64 was prepared from compound (±)-64.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of compound 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 516.26 [M+H]+. [0579] I-64-a and I-64-b. The racemate was separated by chiral SFC (column: CHIRALPAK IH (250 x 21 mm, 5 μm); mobile phase: (A) CO2, (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to isolate first eluting fraction (I-64-a) and second eluting fraction (I-64-b). *The absolute configuration of the chiral center is not determined. I-64-a: MS(ES): m/z: 516.17 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 9.00 (s, 1H), 8.77 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 4.87 (m, 1H), 4.31-4.20 (m, 2H), 4.25 (s, 3H), 3.90 (m, 2H), 3.82-3.80 (m, 2H), 3.60 (s, 3H ), 2.07-2.01 (m, 2H), 1.80 (m, 2H), 1.50 (m, 1H), 0.84-0.79 (m, 4H). I-64-b: MS(ES): m/z: 516.16 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 9.00 (s, 1H), 8.77 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 4.87 (m, 1H), 4.31-4.20 (m, 2H), 4.25 (s, 3H), 3.90 (m, 2H), 3.82-3.80 (m, 2H), 3.60 (s, 3H ), 2.07-2.01 (m, 2H), 1.80 (m, 2H), 1.50 (m, 1H), 0.84-0.79 (m, 4H). JAK2 JH2 Domain Binding Assay [0580] JAK2 (JH2domain-pseudokinase, NP_004963.1, partial length construct with AA start/stop at R513/N824) was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non- specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111x stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plate. Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. [0581] Results of the JAK2 JH2 Domain Binding Assay described above are presented in Table 2. Compounds denoted as “A” had a Kd < 10 nM; compounds denoted as “B” had a Kd ≥ 10 nM and < 50 nM; compounds denoted as “C” had a Kd ≥ 50 nM and < 1 µM; compounds denoted as “D” had a Kd ≥ 1 µM and < 5 µM; and compounds denoted as “E” had a Kd ≥ 5 µM. Table 2.
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
JAK Family Selectivity Assays [0582] Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (Kd) in the above JAK2 Binding Assay with their binding affinity (Kd) for one or more other kinases. Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 111X stocks in 100% DMSO. Kds are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non- contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384- well plate. Each has a final volume of 0.02 ml. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non- biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates is measured by qPCR. Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds. In some embodiments, provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2. SET2-pSTAT5 Cellular Assay [0583] This assay measures inhibition of JAK2-mediated pSTAT5 signaling in constitutively active essential thrombocytopenia cells carrying the V617F mutation. Cells are harvested from a flask into cell culture medium, and the number of cells is counted. The cells are diluted with culture medium and 100 µL of cell suspension (50000/well) is added into each well of a 96-well cell culture plate. A solution of test compound is added to the assay plate. The plates are covered with a lid and placed in a 37 °C 5% CO2 incubator for 4 hours. After 4 hours, the cells are spun, and the cell pellets are re-suspended with 100 µL cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 µL lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pellet. The cell lysate is shaken at 4 °C for 20 min to fully lyse the cells. The cell lysate is spun at 4 °C and 4000 rpm for 15 min, and then the supernatant is transferred into a new plate and stored at -80 °C. Meso-scale discovery (MSD) is used to analyze plates as follows: a standard MSD plate is coated with capture antibody in PBS (40 µL/well) and is incubated at 4 °C overnight with shaking. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (Tris-buffered saline with 0.1% Tween® 20 detergent, TBST). The MSD plates are then blocked with 150 µL of blocking buffer (5% BSA in TBST) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates (25 µL/well) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). Detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). A secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). MSD reading buffer (1x) is added to the plates (150 µL/well), and they are diluted from 4x with water. The plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions. Caco2 Permeability Assay [0584] Preparation of Caco-2 Cells: 50 μL and 25 mL of cell culture medium are added to each well of a Transwell® insert and reservoir, respectively. Then, the HTS Transwell® plates are incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. Caco-2 cell cells are diluted to 6.86х105 cells/mL with culture medium, and 50 μL of cell suspension are dispensed into the filter well of the 96-well HTS Transwell® plate. Cells are cultivated for 14-18 days in a cell culture incubator at 37 °C, 5% CO2, 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating. [0585] Preparation of Stock Solutions: 10 mM stock solutions of test compounds are prepared in DMSO. The stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM. Digoxin and propranolol are used as control compounds in this assay. [0586] Assessment of Cell Monolayer Integrity: Medium is removed from the reservoir and each Transwell® insert and is replaced with prewarmed fresh cuture medium. Transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA). The Plate is returned to the incubator once the measurement is done. The TEER value isss calucated according to the following equation: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm•cm2). A TEER value greater than 230 ohm•cm2 indicates a well-qualified Caco-2 monolayer. [0587] Assay Procedure: The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 μM working solutions. The stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 μM working solutions. The final concentration of DMSO in the incubation system is 0.5%. To determine the rate of drug transport in the apical to basolateral direction. 75 μL of 5 μM working solutions of test compounds are added to the Transwell® insert (apical compartment) and the wells in the receiver plate (basolateral compartment) are filled with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine the rate of drug transport in the basolateral to apical direction, 235 μL of 5 μM working solutions of test compounds are added to the receiver plate wells (basolateral compartment) and then the Transwell® inserts (apical compartment) are filled with 75 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Time 0 samples are prepared by transferring 50 μL of 5 μM working solution to wells of the 96-deepwell plate, followed by the addition of 200 μL cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. At the end of the incubation, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) are transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS). Samples are vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant is mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis. To determine the Lucifer Yellow leakage after 2 hour transport period, stock solution of Lucifer yellow is prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM.100 μL of the Lucifer yellow solution is added to each Transwell® insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37 °C for 30 minutes.80 μL samples are removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal is measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission. Cytotoxicity Assay [0588] HEK293T cells are harvested from flask into cell culture medium, and then the cells are counted. The cells are diluted with culture medium to the desired density, and 40 μL of cell suspension is added into each well of a 384-well cell culture plate. The plates are covered with a lid and spun at room temperature at 1,000 RPM for 1 minute and then transferred into 37 °C 5% CO2 incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution.45 μL of stock solution is then transferred to a 384 PP-plate. A 3-fold, 10-point dilution is performed via transferring 15 μL compound into 30 μL DMSO by using TECAN (EVO200) liquid handler. The plates are spun at room temperature at 1,000 RPM for 1 minute and shaken on a plate shaker for 2 minutes. 40 nL of diluted compound is transferred from compound source plate into the cell plate by using liquid handler Echo550. After compound treatment for 48 hours, CTG detection is performed for compound treatment plates: the plates are removed from incubators and equilibrated at room temperature for 15 minutes.30 μL of CellTiter-Glo reagent is added into each well to be detected. The plates are then placed at room temperature for 30 min followed by reading on EnVision. Inhibition activity is calculated with the following formula: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC), wherein HC is reading obtained from cells treated with 0.1% DMSO only and LC is reading from cells treated with 10 μL staurosporine. IC50 values are calculated using XLFit (equation 201). Hepatocyte Stability Assay [0589] 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 μM by combining 198 μL of 50% acetonitrile/50% water and 2 μL of 10 mM stock solution. Verapamil is used as positive control in the assay. Vials of cryopreserved hepatocytes are thawed in a 37 °C water bath with gently shaking. The contents are poured into the 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature. Thawing medium is aspirated and hepatocytes are re-suspended with serum- free incubation medium to yield ~1.5 × 106 cells/mL. Cell viability and density are counted using a Trypan Blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5×106 viable cells/mL. A portion of the hepatocytes at 0.5×106 viable cells/mL are boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed. Aliquots of 198 μL hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes. Aliquots of 2 μL of the 100 μM test compound and 2 μL positive control are added into respective wells of a non-coated 96-well plate to start the reaction. The final concentration of test compound is 1 μM. This assay is performed in duplicate. The plate is incubated in the incubator for the designed time points. 25 μL of contents are transferred and mixed with 6 volumes (150 μL) of cold acetonitrile with internal standard (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 200 nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samples are centrifuged for 25 minutes at 3,220 g and aliquots of 150 μL of the supernatants are used for LC-MS/MS analysis. Kinetic Solubility Assay [0590] Stock solutions of test compounds are prepared in DMSO at the concentration of 10 mM, and a stock solution of control compound is prepared in DMSO at the concentration of 30 mM. Diclofenac is used as positive control in the assay. 30 µL stock solution of each compound is placed into their a 96-well rack, followed by adding 970 µL of PBS at pH 4.0 and pH 7.4 into each vial of the cap-less solubility sample plate. This study is performed in duplicate. One stir stick is added to each vial and then vials are sealed using a molded PTDE/SIL 96-Well Plate Cover. The solubility sample plate is transferred to the Thermomixer comfort plate shaker and incubated at RT for 2 hours with shaking at 1100 rpm. After 2 hours incubation, stir sticks are removed using a big magnet and all samples from the solubility sample plate are transferred into the filter plate. All the samples are filtered by vacuum manifold. The filtered samples are diluted with methanol. Samples are analyzed by LC-MS/MS and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard:
Figure imgf000215_0001
Plasma Protein Binding Assay [0591] Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 μM, and then the working solutions are spiked into plasma. The final concentration of compound is 1 μM. The final concentration of DMSO is 0.5%. Ketoconazole is used as positive control in the assay. Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. The dialysis set up is assembled according to the manufacturer’s instruction. Each Cell is with 150 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay is performed in duplicate. The dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate. 50 μL of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample.400 μL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoplofen) is added to precipitate protein and release compounds. Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 µL of the supernatant is diluted by 150 µL acetonitrile containing internal standards : ultra- pure H2O = 1 : 1, and the mixture is used for LC-MS/MS analysis. [0592] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of Formula I’:
Figure imgf000217_0001
or a pharmaceutically acceptable salt thereof, wherein: X is CRx or N; Y is CRy or N; Rx and Ry are each independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; L1 is a bond or is optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; L2 is a bond or is optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; Ring A is absent or is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1 is hydrogen or optionally substituted C1-6 aliphatic; each Ra is independently -L3-Cy1, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; L3 is a bond or optionally substituted C1-6 aliphatic, wherein each methylene is optionally and independently replaced with -N(R)-, -O-, or -S-; each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rc is independently Cy2, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rd is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; m is 0, 1, 2, 3, 4, or 5, as valency permits; n is 0, 1, 2, 3, 4, or 5, as valency permits; each p is independently 0, 1, 2, 3, 4, or 5, as valency permits; each q is independently 0, 1, 2, 3, 4, or 5, as valency permits; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R, when attached to the same nitrogen atom, are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently an optionally substituted group selected from C1-6 aliphatic and 3- to 7- membered monocyclic cycloaliphatic.
2. The compound of claim 1, wherein L1 is a bond.
3. The compound of claim 1, wherein L1 is optionally substituted C1-C6 aliphatic and wherein one or more methylene groups are optionally and independently replaced with -C(O)N(R)- or - N(R)C(O)-.
4. The compound of claim 1, wherein L1 is wherein x is 0, 1, 2, 3, or 4.
Figure imgf000219_0001
5. The compound of claim 1, wherein L1 is
Figure imgf000220_0002
.
6. The compound of claim 1, wherein L1 is
Figure imgf000220_0003
, wherein x is 0, 1, 2, 3, or 4 and R is hydrogen or optionally substituted C1-6 aliphatic.
7. The compound of claim 1, wherein L1 is
Figure imgf000220_0004
wherein R is hydrogen or optionally substituted C1-6 aliphatic.
8. The compound of any one of claims 4-7, wherein L1 is
Figure imgf000220_0001
and * represents a point of attachment to Ring A.
9. The compound of claim 1, wherein the compound has a structure of Formula I’-A:
Figure imgf000220_0005
or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.
10. The compound of claim 1, wherein the compound has a structure of Formula I’-A-1:
Figure imgf000220_0006
or a pharmaceutically acceptable salt thereof, wherein x is 0, 1, 2, 3, or 4.
11. The compound of claim 1, wherein the compound has a structure of Formula I’-A-2:
Figure imgf000221_0005
or a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 1-11, wherein Ring A is absent.
13. The compound of any one of claims 1-12, wherein L2 is -N(R)-.
14. The compound of any one of claims 1-12, wherein L2 is -N(R)- and R is hydrogen or optionally substituted C1-6 aliphatic.
15. The compound of any one of claims 1-12, wherein L2 is -NH-.
16. The compound of any one of claims 1-12, wherein L2 is optionally substituted C1-C6 aliphatic and one or more methylene groups are optionally and independently replaced with - C(O)N(R)- or -N(R)C(O)-.
17. The compound of any one of claims 1-12, wherein L2 is
Figure imgf000221_0001
wherein y is 0, 1, 2, 3, or 4
18. The compound of any one of claims 1-12, wherein L2 is
Figure imgf000221_0002
19. The compound of any one of claims 1-12, wherein L2 is
Figure imgf000221_0003
wherein y is 0, 1, 2, 3, or 4 and R is hydrogen or optionally substituted C1-6 aliphatic.
20. The compound of any one of claims 1-12, wherein L2 is
Figure imgf000221_0004
and R is hydrogen or optionally substituted C1-6 aliphatic.
21. The compound of any one of claims 17-20, wherein L2 is
Figure imgf000222_0005
and * represents a point of attachment to Ring B.
22. The compound of any one of claims 17-20, wherein L2 is
Figure imgf000222_0006
and * represents a point of attachment to Ring B.
23. The compound of any one of claims 1-11, wherein the compound has a structure of Formula I’-B:
Figure imgf000222_0004
or a pharmaceutically acceptable salt thereof.
24. The compound of any one of claims 1-23, wherein L3 is a bond.
25. The compound of any one of claims 1-23, wherein L3 is optionally substituted C1-C6 aliphatic and one or more methylene groups are optionally and independently replaced with - C(O)N(R)- or -N(R)C(O)-.
26. The compound of any one of claims 1-23, wherein L3 is.
Figure imgf000222_0001
, wherein z is 0, 1, 2, 3, 4, or 5.
27. The compound of any one of claims 1-23, wherein L3 is
Figure imgf000222_0002
28. The compound of any one of claims 26-27, wherein L3 is
Figure imgf000222_0003
and *represents a point of attachment to Ring A.
29. The compound of any one of claims 1-23, wherein the compound has a structure of Formula I’-C:
Figure imgf000223_0001
or a pharmaceutically acceptable salt thereof.
30. A compound of Formula I:
Figure imgf000223_0002
or a pharmaceutically acceptable salt thereof, wherein: X is CRx or N; Y is CRy or N; Rx and Ry are each independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; Ring A is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1 is hydrogen or optionally substituted C1-6 aliphatic; each Ra is independently Cy1, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rc is independently Cy2, halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, - C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; each Cy2 is independently substituted with q Rd groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, 4- to 10-membered bicyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rd is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic; m is 0, 1, 2, 3, 4, or 5, as valency permits; n is 0, 1, 2, 3, 4, or 5, as valency permits; each p is independently 0, 1, 2, 3, 4, or 5, as valency permits; each q is independently 0, 1, 2, 3, 4, or 5, as valency permits; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R, when attached to the same nitrogen atom, are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently an optionally substituted group selected from C1-6 aliphatic and 3- to 7- membered monocyclic cycloaliphatic.
31. The compound of any one of claims 1-30, wherein the compound is not:
Figure imgf000225_0001
32. The compound of any one of claims 1-31, wherein Ring B is 3- to 7-membered monocyclic cycloaliphatic or 4- to 10-membered bicyclic cycloaliphatic.
33. The compound of claim 32, wherein Ring B is 3- to 5-membered monocyclic cycloalkyl.
34. The compound of claim 32, wherein Ring B is 5- to 8-membered bicyclic cycloalkyl.
35. The compound of any one of claim 1-34, wherein each Rb is independently halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -S(O)2OR’, or optionally substituted C1-6 aliphatic.
36. The compound of claim 35, wherein each Rb is independently halogen, -CN, or optionally substituted C1-6 aliphatic.
37. The compound of any one of claims 1-11 and 13-33, wherein Ring A is phenyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
38. The compound of claim 34, wherein Ring A is phenyl.
39. The compound of any one of claims 1-11, 13-24 and 30-38, wherein each Ra is independently Cy1, -OR, or optionally substituted C1-6 aliphatic.
40. The compound of any one of claims 1-39, wherein no more than one Ra is Cy1.
41. The compound of any one of claims 1-40, wherein each Cy1 is independently substituted with p Rc groups and is independently selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic cycloaliphatic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
42. The compound of claim 41, wherein each Cy1 is independently substituted with p Rc groups and is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
43. The compound of claim 41, wherein each Cy1 is independently substituted with p Rc groups and is a 3- to 7-membered monocyclic cycloaliphatic.
44. The compound of claim 41, wherein each Cy1 is independently substituted with p Rc groups and is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
45. The compound of any one of claims 1-40, wherein each Cy1 is independently substituted with p instances of Rc groups and wherein Cy1 is a 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
46. The compound of any one of claims 1-45, wherein each Rc is independently Cy2, -CN, - C(O)OR, -C(O)N(R)2, -SO2R’, or optionally substituted C1-6 aliphatic.
47. The compound of any one of claims 1-46, wherein no more than one Rc is Cy2.
48. The compound of any one of claims 1-47, wherein each Cy2 is independently substituted with q Rd groups and is independently selected from 3- to 7-membered monocyclic cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
49. The compound of claim 48, wherein each Cy2 is independently substituted with q Rd groups and is a 3- to 7-membered monocyclic cycloaliphatic.
50. The compound of claim 48, wherein each Cy2 is independently substituted with q Rd groups and is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
51. The compound of claim 48, wherein each Cy2 is independently substituted with q Rd groups and is a 4- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
52. The compound of claim 51, wherein each Cy2 is independently substituted with q Rd groups and is a 7- to 10-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
53. The compound of any one of claims 1-52, wherein each Rd is independently halogen, -CN, -OR, or optionally substituted C1-6 aliphatic.
54. The compound of any one of claims 1-46, wherein each Rc is independently optionally substituted C1-6 aliphatic.
55. The compound of any one of claims 1-11, 13-24 and 30-54, wherein Ring A substituted with m Ra groups is:
Figure imgf000227_0001
; and m is 0, 1, 2, 3, or 4.
56. The compound of claim 55, wherein Ring A substituted with m Ra groups is:
Figure imgf000228_0001
.
57. The compound of any one of claims 1-11, 13-24 and 30-56, wherein Ring A substituted with m Ra groups is:
Figure imgf000228_0003
m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.
58. The compound of claim 55, wherein Ring A substituted with m Ra groups is:
Figure imgf000228_0002
.
59. The compound of any one of claims 1-58, wherein m is 0, 1, or 2.
60. The compound of any one of claims 1-59, wherein n is 0 or 1.
61. The compound of any one of claims 1-60, wherein each p is independently 0, 1, or 2.
62. The compound of any one of claims 1-61, wherein each q is independently 0 or 1.
63. The compound of any one of claims 1-62, wherein X is N.
64. The compound of any one of claims 1-62, wherein X is CRx.
65. The compound of claim 64, wherein Rx is hydrogen.
66. The compound of any one of claims 1-65, wherein Y is N.
67. The compound of any one of claims 1-65, wherein Y is CRy.
68. The compound of claim 67, wherein Ry is hydrogen.
69. The compound of any one of claims 1-68, wherein R1 is hydrogen.
70. The compound of any one of claims 1-68, wherein R1 is optionally substituted C1-6 aliphatic.
71. The compound of claim 70, wherein R1 is C1-3 alkyl.
72. The compound of any one of claims 1-71, wherein each R is independently hydrogen or optionally substituted C1-6 aliphatic.
73. The compound of any one of claims 1-72, wherein each R’ is independently optionally substituted C1-6 aliphatic.
74. The compound of any one of claims 1-2 and 15-73, wherein the compound is a compound of Formula I-A:
Figure imgf000229_0001
or a pharmaceutically acceptable salt thereof.
75. The compound of any one of claims 1-2 and 15-73, wherein the compound is a compound of Formula I-B:
Figure imgf000229_0002
or a pharmaceutically acceptable salt thereof.
76. The compound of any one of claims 1-2 and 15-73, wherein the compound is a compound of Formula I-C:
Figure imgf000229_0003
or a pharmaceutically acceptable salt thereof.
77. The compound of any one of claims 1-2, 15-24 and 30-76, wherein the compound is a compound of Formula II:
Figure imgf000230_0001
or a pharmaceutically acceptable salt thereof.
78. The compound of any one of claims 1-2, 15-24 and 30-77, wherein the compound is a compound of Formula II-A:
Figure imgf000230_0002
or a pharmaceutically acceptable salt thereof.
79. The compound of any one of claims 1-2, 15-24 and 30-78, wherein the compound is a compound of Formula II-B:
Figure imgf000230_0003
or a pharmaceutically acceptable salt thereof.
80. The compound of any one of claims 1-2, 15-24 and 30-79, wherein the compound is a compound of Formula III:
Figure imgf000231_0003
or a pharmaceutically acceptable salt thereof.
81. The compound of any one of claims 1-2, 15-24 and 30-80, wherein the compound is a compound of Formula III-A:
Figure imgf000231_0002
or a pharmaceutically acceptable salt thereof.
82. The compound of any one of claims 1-2, 15-24 and 30-81, wherein the compound is a compound of Formula III-B:
Figure imgf000231_0001
or a pharmaceutically acceptable salt thereof.
83. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
84. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
85. A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of claims 1-83 or the composition of claim 84.
86. A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of claims 1-83 or the composition of claim 84.
87. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-83 or the composition of claim 84.
88. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of claims 1-83 or the composition of claim 84.
89. The method of claim 88, wherein the hematological malignancy is leukemia or lymphoma.
90. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of claims 1-83 or the composition of claim 84.
91. The method of claim 90, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.
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