Indazolyl compounds as inhibitors of the STAT6 pathway

Abstract

Compounds having formula (I), and enantiomers, and diastereomers, stereoisomers, pharmaceutically˗acceptable salts thereof, (I) and wherein R1 is (II) are useful as kinase modulators, including STAT6 modulation. All the variables are as defined herein.

Description

[0001] INDAZOLYL COMPOUNDS AS INHIBITORS OF THE STAT6 PATHWAY

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the priority benefit of U. S. Provisional Application No.

[0003] 63 / 752,919, filed February 3, 2025, U. S. Provisional Application No. 63 / 760,731, filed February 20, 2025 and U. S. Provisional Application No. 63 / 894,178, filed October 6, 2025 and their content of which is herein incorporated by reference in their entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to novel compounds that inhibit transcription factors and methods of making and using the same. Specifically, the present invention relates to indazolyl compounds as STAT6 pathway inhibitors.

[0006] BACKGROUND OF THE INVENTION STAT6 (Signal Transducer and Activator of Transcription 6) is a member of the STAT family of transcription factors that plays a critical role in Type 2 inflammatory response. It is predominantly activated downstream of interleukin-4 (IL-4) and interleukin- 13 (IL-13)1(1. Bernstein ZJ, Shenoy A, Chen A, Heller NM, Spangler JB. Engineering the IL-4 / IL-13 axis for targeted immune modulation. Immunol Rev. 2023 Nov;320(1):29-57. doi: 10.1111 / imr.13230. Epub 2023 Jun 7. PMID: 37283511), which are key drivers of pathology in allergic and atopic diseases, such as atopic dermatitis (AtD), eosinophilic esophagitis (EoE), prurigo nodularis (PN), asthma, allergic rhinitis and others23.

[0007] IL-4 and IL- 13 signal through two types of receptors. IL-4 receptor Type I is a heterodimer composed of interleukin-4 receptor alpha chain (IL-4Ra) and common gamma chain (yc)4; it exclusively binds IL-4. IL-4 receptor type II is a heterodimer of IL-4Ra and interleukin- 13 receptor alpha 1 chain (IL-13Ral); it can interact with both IL-4 and IL-134. Binding of the cytokines to the receptors activates receptor-associated Janus kinases (JAKs) 1, 2 or 3, which phosphorylate the receptors and create docking site for STAT65. STAT6 is phosphorylated by JAKs and forms head-to-head dimers, which translocate into the nucleus and activate transcription of target genes5.The critical role of IL-4 / IL-13 in allergic and atopic diseases has been demonstrated by clinical success of IL-4Ra blocking antibody Dupilumab in AtD, asthma, EoE, chronic sinusitis with nasal polyps, eosinophilic chronic obstructive pulmonary disease (COPD) and others67. Additionally, IL- 13 blocking antibodies Cendakimab, Tralokinumab and Lebrikizumab demonstrated clinical efficacy in AtD and EoE89. Thus, blocking IL-4 / IL- 13 -driven pathways is expected to be efficacious in treatment of these diseases. JAK inhibitors have also proven efficacious in treatment of atopic dermatitis but carry increased risks due to their broad effect on multiple signaling pathways10.

[0008] STAT6 is tightly linked to IL-4 / IL-13 signaling and associated pathology. Mice with STAT6 knockout are resistant to allergen-induced airway hyperresponsiveness11. Rare hyperactive mutations in STAT6 protein result in severe allergic disease, AtD, asthma, further stressing direct contribution of STAT6 to activation of pathological type 2 inflammation12. Administration of topical STAT6 decoy oligonucleotide to the affected skin of AtD patients decreased facial erythema, pruritis and clinical score in a small openlabel study13. It is thus expected that inhibition of STAT6 function will result in suppression of pathological Type 2 inflammation and lead to efficacious treatments for AtD, PN, EoE, eosinophilic COPD, asthma and other diseases sharing this mechanism of action.

[0009] References:

[0010] 1. Bernstein ZJ, Shenoy A, Chen A, Heller NM, Spangler JB. Engineering the IL-4 / IL-13 axis for targeted immune modulation. Immunol Rev. 2023 Nov;320(1):29-57. doi: 10.1111 / imr.13230. Epub 2023 Jun 7. PMID: 37283511.

[0011] 2. Dubin C, Del Duca E, Guttman- Yassky E. The IL-4, IL-13 and IL-31 pathways in atopic dermatitis. Expert Rev Clin Immunol. 2021 Aug;17(8):835-852. doi:

[0012] 10.1080 / 1744666X.2021.1940962. Epub 2021 Jul 21. PMID: 34106037.

[0013] 3. Maspero J, Adir Y, Al-Ahmad M, Celis-Preciado CA, Colodenco FD, Giavina-Bianchi P, Lababidi H, Ledanois O, Mahoub B, Perng DW, Vazquez JC, Yorgancioglu A. Type 2 inflammation in asthma and other airway diseases. ERJ Open Res. 2022 Aug l;8(3):00576-2021. doi: 10.1183 / 23120541.00576-2021. PMID: 35923421; PMCID: PMC9339769.4. Junttila IS. Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes. Front Immunol. 2018 Jun 7;9:888. doi:

[0014] 10.3389 / fimmu.2018.00888. PMID: 29930549; PMCID: PMC6001902.

[0015] 5. Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK / STAT pathway. Protein Sci. 2018 Dec;27(12): 1984-2009. doi:

[0016] 10.1002 / pro.3519. PMID: 30267440; PMCID: PMC6237706.

[0017] 6. Harb H, Chatila TA. Mechanisms of Dupilumab. Clin Exp Allergy. 2020 Jan;50(1):5-14. doi: 10.1111 / cea.13491. Epub 2019 Sep 30. PMID: 31505066; PMCID: PMC6930967.

[0018] 7. Bhatt SP, Rabe KF, Hanania NA, Vogelmeier CF, Bafadhel M, Christenson SA, Papi A, Singh D, Laws E, Patel N, Yancopoulos GD, Akinlade B, Maloney J, Lu X, Bauer D, Bansal A, Abdulai RM, Robinson LB; NOTUS Study Investigators. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med. 2024 Jun 27;390(24):2274-2283. doi: 10.1056 / NEJMoa2401304. Epub 2024 May 20. PMID: 38767614.

[0019] 8. Lytvyn Y, Gooderham M. Targeting Interleukin 13 for the Treatment of Atopic Dermatitis. Pharmaceutics. 2023 Feb 8;15(2):568. doi: 10.3390 / pharmaceutics15020568. PMID: 36839890; PMCID: PMC9966769.

[0020] 9. Ridolo E, Barone A, Ottoni M, Peveri S, Montagni M, Nicoletta F. The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs. Int J Mol Sci. 2024 Jan 30;25(3):1702. doi: 10.3390 / ijms25031702. PMID: 38338983;

[0021] PMCID: PMC10855546.

[0022] 10. Mikhaylov D, Ungar B, Renert-Yuval Y, Guttman- Yassky E. Oral Janus kinase inhibitors for atopic dermatitis. Ann Allergy Asthma Immunol. 2023 May;130(5):577-592. doi: 10.1016 / j.anai.2023.01.020. Epub 2023 Feb 1. PMID: 36736457.

[0023] 11. Kuperman D, Schofield B, Wills-Karp M, Grusby MJ. Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J Exp Med. 1998 Mar 16;187(6):939-48. doi: 10.1084 / jem.187.6.939. PMID: 9500796; PMCID: PMC2212182.

[0024] 12. Sharma M, Leung D, Momenilandi M, Jones LCW, Pacillo L, James AE, Murrell JR, Delafontaine S, Maimaris J, Vaseghi-Shanjani M, Del Bel KL, Lu HY, Chua GT, Di Cesare S, Fornes O, Liu Z, Di Matteo G, Fu MP, Amodio D, Tam IYS, Chan GSW,Sharma AA, Dalmann J, van der Lee R, Blanchard-Rohner G, Lin S, Philippot Q, Richmond PA, Lee JJ, Matthews A, Seear M, Turvey AK, Philips RL, Brown-Whitehorn TF, Gray CJ, Izumi K, Treat JR, Wood KH, Lack J, Khleborodova A, Niemela JE, Yang X, Liang R, Kui L, Wong CSM, Poon GWK, Hoischen A, van der Made CI, Yang J, Chan KW, Rosa Duque JSD, Lee PPW, Ho MHK, Chung BHY, Le HTM, Yang W, Rohani P, Fouladvand A, Rokni-Zadeh H, Changi-Ashtiani M, Miryounesi M, Puel A, Shahrooei M, Finocchi A, Rossi P, Rivalta B, Cifaldi C, Novelli A, Passarelli C, Arasi S, Bullens D, Sauer K, Claeys T, Biggs CM, Morris EC, Rosenzweig SD, O'Shea JJ, Wasserman WW, Bedford HM, van Karnebeek CDM, Palma P, Burns SO, Meyts I, Casanova JL, Lyons JJ, Parvaneh N, Nguyen ATV, Cancrini C, Heimall J, Ahmed H, McKinnon ML, Lau YL, Beziat V, Turvey SE. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J Exp Med. 2023 May l;220(5):e20221755. doi: 10.1084 / jem.20221755. Epub 2023 Mar 8. PMID: 36884218; PMCID: PMC10037107.

[0025] 13. Igawa K, Satoh T, Yokozeki H. A therapeutic effect of STAT6 decoy oligodeoxynucleotide ointment in atopic dermatitis: a pilot study in adults. Br J Dermatol.

[0026] 2009 May; 160(5): 1124-6. doi: 10.1111 / j.1365-2133.2009.09070.x. Epub 2009 Mar 9. PMID: 19292714.

[0027] SUMMARY OF THE INVENTION

[0028] The present invention provides novel indazole compounds including stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof, which are useful as inhibitors of STAT6.

[0029] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0030] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof.

[0031] The compounds of the invention may be used in the treatment and / or prophylaxis of conditions associated with STAT6 inhibition.

[0032] The compounds of the present invention may be used in therapy.The compounds of the present invention may be used for the manufacture of a medicament for the treatment and / or prophylaxis of a condition associated with STAT6 inhibition.

[0033] In another aspect, the present invention is directed to a method of treating diseases mediated at least partially by STAT6 including inflammatory diseases, hematological diseases and cancers, which method comprises administering to a patient in need of such treatment, a compound of the present invention as described above.

[0034] The compounds of the invention can be used alone, and in combination with other compounds of the present invention, or in combination with one or more, or with one to two other agent(s).

[0035] These and other features of the invention will be set forth in expanded form as the disclosure continues.

[0036] DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0037] In one aspect, the present invention provides, inter alia, compounds of Formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0038]

[0039] wherein, independently for each occurrence:

[0040] R1is

[0041]

[0042] Rlais H, D, OH, halo, C1-3 alkyl, or C1-3 alkoxy substituted with 0-1 -OH, OCH3, or halo;or 2 Rlaon the same or adjacent carbon atoms may join to form a 3-5 membered cycloalkyl substituted with 0-1 of -OH, halo, or -OCH3;

[0043] one of R2and R5is phenyl or a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, the phenyl or the heterocycle being substituted with R7and are further substituted with 0-2 R11and 0-1 R10;

[0044] the other of R2and R5is H, F, Cl, CH3, OCH3, CHF2or CF3;

[0045] R3is -H, Cl, F, C1-3alkyl, C1-3alkoxy, -CN, -CF3, -CHF2, or cyclopropyl;

[0046] R4is -H, -CH3, -OCH3, -F, -Cl, or -CHF2;

[0047] R6is -H or -F;

[0048] R7is -H, halo, -NH2, -CHF2, -C1-6 alkyl substituted with 0-3 R7d, cyclopropyl substituted with 0-2 R7d, -S(O)-Ci-6 alkyl, -S(O)2-C1-6alkyl, -NHC(O)C1-3alkyl, -NHS(O)2CI-3alkyl, -CON(R7b)(R7c), or -S(O)2-azetidinyl;

[0049] or R7is a 4-6 membered heterocycle having 1-4 heteroatoms selected from N, O, and S, wherein the heterocycle is substituted with 0-3 R7a;

[0050] R7ais H, halo, -OH, =0, C1-3alkyl, C1-3deuteroalkyl, C1-5alkoxy C3-6cycloalkyl, -CH2OH, -CH2OCH3, -CHF2, -CF3, -OCH3, -NHCH3, -N(CH3)2, -NH2, or -C(O)NH2 or a 3-6 membered heterocycle having 1-2 heteroatoms selected from N, O, or S;

[0051] R7band R7care independently H, C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 alkoxyalkyl, or C1-5 deuteroalkyl;

[0052] alternatively, R7band R7c, together with the N to which they are are attached, join to form a 3-6 membered ring substituted with 0-1 substituents selected from H, F, -OH, or -CH3;

[0053] R7dis F, OH, or C1-3alkoxy;

[0054] R9is phenyl, or a 5 or 10 membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, any of which are substituted with 0-4 R9a;

[0055] R9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)P-NR12R12, -(CH2)P-NR12R17, -COOH, Ci-3 alkyl, Ci-3 alkoxy, Ci-3

[0056] hydroxyalkyl, -(CH2)P-NR12COOR12, -(CH2)p-NR12CONR17R12,

[0057] -(CH2)P-OCONR17R12, -(CH2)P-NR12(CO)-R12, -(CH2)P-SO2NH2,

[0058] -(CH2)p-C(O)N(R12)(R17), -(CH2)P-C(O)R14, -(CH2)P-S(O2)N(R12)(R17), -(CH2)P-S(O)(NH)-R12, -(CH2)P-SO2CI-3 alkyl, or a 5-6 membered heterocycle orheteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein alkyl, heterocycle or heteroaryl are substituted with 0-2R7a;

[0059] R10is -H or

[0060] R

[0061]

[0062] 11is -H, -CH3, -F, -Cl, -CN, -OCH3, or

[0063] R12is H, C1-3 alkyl, C1-3 dueteroalkyl, C1-3 haloalkyl or alkoxyalkyl;

[0064] R14is H, -C1-6 alkyl, C1-3 deuteroalkyl, -NRaRa, methyl-piperazinyl, morpholinyl, pyrrolidinyl, or piperidinyl;

[0065] R17is -H, C1-6 alkyl, -(CH2)-C(O)N(R12)(R12), -(CH2)P-C3-6 cycloalkyl, -(CH2)P-phenyl, or a -(CH2)P-4 to 10 membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, the alkyl, cycloalkyl, phenyl, or heterocycle are substituted with 0-3 R17a;

[0066] or R12and R17, together with the N to which they are attached, join to form a 4-10 membered heterocycle or bicyclic heterocycle having an additional 0-2 heteroatoms selected from N, O, or S, substituted with 0-3 R17a;

[0067] R17ais H, D, halo, -OH, C1-4 alkyl substituted with 0-3 Re, C1-6 hydroxyalkyl, C1-6 alkoxy, =0, C1-3 fluoroalkyl, or C3-6 cycloalkyl substituted with 0-3 Re, -(CH2)n-CO2-C1-3alkyl, -(CH2)n-N(R7b)(R7c), -(CH2)n-C(O)N(R7b)(R7c), -(CH2)n-N(R7b)C(O)-R7b, -(CH2)n-NR7bC(O)N(R7b)(R7c), -(CH2)n-OC(O)N(R7b)(R7c),

[0068] -(CH2)n-OC(O)N(R7b)(R7c), -(CH2)n-NR7bC(O)O(R7b), -(CH2)n-pyridyl, -(CH2)n-piperazinyl, or -(CH2)n-cyclopropyl;

[0069] R19is -H, -NH2, or -OH;

[0070] Rais H, or C1-6 alkyl;

[0071] Reis H, F, Cl, -OH, -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamine, C1-6 dialkylamine, morpholino, pyrrolidino, S(O)2Ci-6 alkyl, or C3-6 cycloalkyl;

[0072] n is 0, 1 or 2;m is 0, 1, 2, 3 or 4;

[0073] p is 0 or 1; and

[0074] q is 1, 2, or 3.

[0075] In another aspect, the present invention provides compounds of Formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0076]

[0077] wherein, independently for each occurrence:

[0078] R1is

[0079]

[0080] Rlais H, OH, halo, C1-3alkyl, or C1-3alkoxy substituted with 0-1 -OH, OCH3, or halo; or 2 R1aon the same or adjacent carbon atoms may join to form a 3-5 membered cycloalkyl substituted with 0-1 of -OH, halo, or -OCH3;

[0081] one of R2and R5is phenyl or a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, the phenyl or the heterocycle being substituted with R7and are further substituted with 0-2 R11and 0-1 R10;

[0082] the other of R2and R5is H, F, Cl, CH3, OCH3, CHF2or CF3;

[0083] R3is -H, Cl, F, C1-3 alkyl, C1-3 alkoxy, -CN, -CF3, -CHF2, or cyclopropyl;

[0084] R4is -H, -CH3, -OCH3, -F, -Cl, or -CHF2;

[0085] R6is -H or -F;R7is -H, halo, -NH2, -CHF2, -C1-6 alkyl substituted with 0-3 R7d, cyclopropyl substituted with 0-2 R7d, -S(O)-Ci-6 alkyl, -S(O)2-C1-6alkyl, -NHC(O)C1-3alkyl, -NHS(O)2C 1-3 alkyl, -CON(R7b)(R7c), or -S(O)2-azetidinyl;

[0086] or R7is a 4-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, wherein the heterocycle is substituted with 0-2 R7a;

[0087] R7ais H, halo, -OH, =0, C1-3 alkyl, cyclopropyl, halo, -CH2OH, -CH2OCH3, -CHF2, -OCH3, -NHCH3, -N(CH3)2, -NH2, or -C(0)NH2;

[0088] R7band R7care independently H, C1-5 alkyl, C1-5 hydroxyalkyl, or C1-5 deuteroalkyl; alternatively, R7band R7c, together with the N to which they are are attached, join to form a a 3-6 membered ring substituted with 0-1 substituents selected from H, F, -OH, or -CH3;

[0089] R7dis F, OH, or C1-3 alkoxy;

[0090] R9is phenyl, or a 5 or 10 membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, any of which are substituted with 0-3 R9a;

[0091] R9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)P-NR12R12, -COOH, C1-3 alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, -(CH2)p-SO2NH2, -(CH2)P- C(O)N(R12)(R17), -(CH2)P-NR12CONR17R12, or a 5 membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S;

[0092] R10is -H or

[0093]

[0094] R11is -H, -CH3, -F, -Cl, -CN, or -OCH3;

[0095] R12is H, C1-3 alkyl, C1-3 dueteroalkyl, or C1-3 haloalkyl;

[0096] Reis H, F, Cl, -OH, -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamine, C1-6 dialkylamine, morpholino, pyrrolidino, S(O)2Ci-6 alkyl, or C3-6 cycloalkyl;

[0097] R17is -H, C1-3 alkyl, C3-6 cycloalkyl, or a 4 to 10 membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl or heterocycle are substituted with 0-2 R17a;R17ais H, halo, -OH, C1-3 alkyl substituted with 0-3 Re, C1-6 hydroxyalkyl, C1-6 alkoxy, =0, C1-3 fluoroalkyl, or C4-6 cycloalkyl substituted with 0-3 Re, -(CH2)n-CO2-Ci-3 alkyl, -(CH2)n-N(R7b)(R7c), -(CH2)n-C(O)N(R7b)(R7c), -(CH2)n-N(R7b)C(O)-R7b, -(CH2)n-NR7bC(O)N(R7b)(R7c), -(CH2)n-OC(O)N(R7b)(R7c), -(CH2)n- C(O)N(R7b)(R7c), -(CH2)n-OC(O)N(R7b)(R7c), -(CH2)n-pyridyl, or-(CH2)n- cyclopropyl;

[0098] R19is -H, -NH2, or -OH;

[0099] n is 0, 1 or 2;

[0100] m is 0, 1 or 2;

[0101] p is 0 or 1; and

[0102] q is 1, 2, or 3.

[0103] In another aspect, the present invention provides compounds of Formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0104]

[0105] wherein, independently for each occurrence:

[0106] R1is

[0107]

[0108] Rlais H, OH, halo, C1-3alkyl, or C1-3alkoxy substituted with 0-1 -OH, OCH3, or halo; or 2 R1aon the same or adjacent carbon atoms may join to form a 3-5 membered cycloalkyl substituted with 0-1 of -OH, halo, or -OCH3;one of R2and R5is phenyl or a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, the phenyl or the heterocycle being substituted with R7and are further substituted with 0-2 R11and 0-1 R10;

[0109] the other of R2and R5is H, F, Cl, CH3, OCH3, CHF2or CF3;

[0110] R3is -H, Cl, F, C1-3alkyl, C1-3alkoxy, -CN, -CF3, -CHF2, or cyclopropyl;

[0111] R4is -H, -CH3, -OCH3, -F, -Cl, or -CHF2;

[0112] R6is -H or -F;

[0113] R7is -H, halo, -NH2, -CHF2, -C1-6 alkyl substituted with 0-3 R7d, cyclopropyl substituted with 0-2 R7d, -S(O)-Ci-6 alkyl, -S(O)2-C1-6alkyl, -NHC(O)C1-3alkyl, -NHS(O)2C1-3alkyl, -CON(R7b)(R7c), or -S(O)2-azetidinyl;

[0114] or R7is a 4-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, wherein the heterocycle is substituted with 0-2 R7a;

[0115] R7ais H, halo, -OH, =0, C1-3alkyl, C1-3deuteroalkyl, C1-5alkoxy C3-6cycloalkyl, -CH2OH, -CH2OCH3, -CHF2, -CF3, -OCH3, -NHCH3, -N(CH3)2, -NH2, or -C(O)NH2 or a 3-6 membered heterocycle having 1-2 heteroatoms selected from N, O, or S; R7band R7care independently H, C1-5 alkyl, C1-5 hydroxyalkyl, or C1-5 deuteroalkyl;

[0116] alternatively, R7band R7c, together with the N to which they are are attached, join to form a a 3-6 membered ring substituted with 0-1 substituents selected from H, F, -OH, or -CH3;

[0117] R7dis F, OH, or C1-3alkoxy;

[0118] R9is phenyl, or a 5 or 10 membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, any of which are substituted with 0-3 R9a;

[0119] R9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)P-NR12R12, -(CH2)P-NR12R17, -COOH, Ci-3 alkyl, Ci-3 alkoxy, Ci-3

[0120] hydroxyalkyl, -(CH2)P-NR12COOR12, -(CH2)p-NR12CONR17R12,

[0121] -(CH2)P-OCONR17R12, -(CH2)P-NR12(CO)-R12, -(CH2)P-SO2NH2,

[0122] -(CH2)p-C(O)N(R12)(R17), -(CH2)P-C(O)R14, -(CH2)P-S(O2)N(R12)(R17), -(CH2)p-S(O)(NH)-R12, or a 5-6 membered heterocycle or heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein alkyl, heterocycle or heteraryl are substituted with 0-2R7a;

[0123] R10is -H or

[0124]

[0125] R11is -H, -CH3, -F, -Cl, -CN, or -OCH3;

[0126] R12is H, C1-3 alkyl, C1-3 dueteroalkyl, C1-3 haloalkyl or alkoxyalkyl;

[0127] R14is H, -C1-6 alkyl, C1-3 deuteroalkyl, -NRaRa, methyl-piperazinyl, morpholinyl, pyrrolidinyl, or piperidinyl;

[0128] R17is -H, C1-6 alkyl, -(CH2)-C(O)N(R12)(R12), -(CH2)P-C3-6 cycloalkyl, -(CH2)P-phenyl, or a -(CH2)P-4 to 10 membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, the alkyl, cycloalkyl, phenyl, or heterocycle are substituted with 0-3 R17a;

[0129] or R12and R17, together with the N to which they are attached, join to form a 4-10 membered heterocycle or bicyclic heterocycle having an additional 0-2 heteroatoms selected from N, O, or S, substituted with 0-3 R17a;

[0130] R17ais H, halo, -OH, C1-3 alkyl substituted with 0-3 Re, C1-6 hydroxyalkyl, C1-6 alkoxy, =0, C1-3 fluoroalkyl, or C3-6 cycloalkyl substituted with 0-3 Re, -(CH2)n-CO2-C1-3alkyl, -(CH2)n-N(R7b)(R7c), -(CH2)n-C(O)N(R7b)(R7c), -(CH2)n-N(R7b)C(O)-R7b, -(CH2)n-NR7bC(O)N(R7b)(R7c), -(CH2)n-OC(O)N(R7b)(R7c),

[0131] -

[0132]

[0133] (CH2)n-OC(O)N(R7b)(R7c), -(CH2)n-NR7bC(O)O(R7b), -(CH2)n-pyridyl, -(CH2)n-piperazinyl, or -(CH2)n-cyclopropyl;

[0134] R19is -H, -NH2, or -OH;

[0135] Rais H, or C1-6 alkyl;

[0136] Reis H, F, Cl, -OH, -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamine, C1-6 dialkylamine, morpholino, pyrrolidino, S(O)2Ci-6 alkyl, or C3-6 cycloalkyl;

[0137] n is 0, 1 or 2;

[0138] m is 0, 1 or 2;

[0139] p is 0 or 1; and

[0140] q is 1, 2, or 3.Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0141] R2is phenyl or a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, the phenyl or the heterocycle being substituted with R7and are further substituted with 0-2 R11and 0-1 R10; and

[0142] R5is H, F, Cl, CH3, OCH3, CHF2or CF3.

[0143] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0144] R1is

[0145]

[0146] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0147]

[0148] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0149] R2is

[0150]

[0151] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0152]

[0153] R7is -H, halo, -NH2, -CHF2, -S(O)-Ci-6 alkyl, -CON(CH3)2, NHS(O)2CH3, -CON(R7b)(R7c), or -NHS(O)2CH3;

[0154] or R7is H, cyclopropyl, oxazolyl, oxetanyl, oxadiazolyl, thiazolyl, imidazolyl, triazolyl, oxoimidazolidinyl, tetrazolyl, 2-oxo-2,3-dihydro-1H-imidazol-l-yl, piperidinyl, pyrrolidinyl, morpholinyl, oxomorpholinyl, dioxoimidazolidinyl, piperazinyl, oxopiperazinyl, pyrazolyl, or oxopyrrolidinyl, any of which are substituted with 0-2 R7a;

[0155] or R7is

[0156]

[0157] R7ais H, C1-3alkyl, =O, -NH2, or -OH;

[0158] R7band R7care independently H, C1-5 alkyl, C1-5 alkoxy, C1-5 hydroxyalkyl, or C1-5 deuteroalkyl;

[0159] R8is H, C1-3alkyl, or cyclopropyl;

[0160] R8ais H, halo, C1-3alkyl, CH2OH, or CHF2; and

[0161] R19is H, OH, NH2, OMe, NHCH3, N(CH3)2, CH2OH, CH2OCH3, or CH3.Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0162]

[0163] R7is -H, halo, -NH2, -CHF2, -S(O)-Ci-6 alkyl, -CON(CH3)2, NHS(O)2CH3, -CON(R7b)(R7c), or -NHS(O)2CH3;

[0164] or R7is H, cyclopropyl, oxazolyl, oxetanyl, oxadiazolyl, thiazolyl, imidazolyl, triazolyl, oxoimidazolidinyl, tetrazolyl, 2-oxo-2,3-dihydro-1H-imidazol-l-yl, piperidinyl, pyrrolidinyl, morpholinyl, oxomorpholinyl, dioxoimidazolidinyl, piperazinyl, oxopiperazinyl, pyrazolyl, or oxopyrrolidinyl, oxopyridinyl, or oxopyridazinyl, any of which are substituted with 0-2 R7a;

[0165] or R7is

[0166]

[0167] R7ais H, C1-3alkyl, =O, -NH2, or -OH;

[0168] R7band R7care independently H, C1-5 alkyl, C1-5 alkoxy, C1-5 hydroxyalkyl, or C1-5 deuteroalkyl;

[0169] R8is H, C1-3 alkyl, or cyclopropyl;

[0170] R8ais H, halo, C1-3 alkyl, CH2OH, or CHF2, or CF3; and

[0171] R19is H, OH, NH2, OMe, NHCH3, N(CH3)2, CH2OH, CH2OCH3, or CH3.

[0172] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0173]

[0174] R9is phenyl, thiazolyl, pyrazinyl, pyridazinyl, dihydropyridinyl, pyrimidinyl, pyridinyl, dihydroisoquinolinyl, indolyl, pyrazolyl, or isoindolinyl, any of which are substituted with 0-3 R9a; and

[0175] R9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)p-NR12R12, -COOH, -(CH2)P-CONHCH3, -(CH2)p-C(O)NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, -(CH2)p-SO2NH2, -(CH2)p-C(O)NH-R17, or -(CH2)p-C(O)N(R12)(R17).

[0176] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0177] R1is

[0178]

[0179] R9is phenyl, thiazolyl, pyrazinyl, pyridazinyl, dihydropyridinyl, pyrimidinyl, pyridinyl, dihydroisoquinolinyl, indolyl, pyrazolyl, or isoindolinyl, any of which are substituted with 0-3 R9a; and

[0180] R9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)p-NR12R12, -COOH, -(CH2)P-CONHCH3, -(CH2)p-C(O)NH2, C1-3alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, -(CH2)p-SO2NH2, -(CH2)p-C(O)NH-R17, -(CH2)p-NR12CONR17R12, or -(CH2)p-C(O)N(R12)(R17). Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0181] R9is phenyl or pyridinyl substituted with 0-3 R9a.

[0182] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0183] R17is -H, methyl, ethyl, cyclopropylmethyl, oxanyl, pyrazolyl, l-methyl-2-oxo-l,2- dihy dropyri din-3 -yl,

[0184] O

[0185]

[0186]

[0187] any of of which are substituted with 0-2 R17a

[0188] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0189] R

[0190]

[0191] 9is0; and

[0192] R9bis H, orF.

[0193] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0194]

[0195] R9bis H, orF.

[0196] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0197] R17is -H, methyl, ethyl, cyclopropylmethyl, oxanyl, pyrazolyl, l-methyl-2-oxo-l,2- dihy dropyri din-3 -yl, any of which are substituted with 0-1 R17a,orR17is

[0198]

[0199] R31is -H, -F, -Me, -OH, -CH2OH, -CO2-C1-3 alkyl, -CONH2, or -CF3; and

[0200] R32is -H, C1-3 alkyl substituted with 0-3 Re, C1-3 fluoroalkyl, C4-6 cycloalkyl substituted with 0-3 Re, -(CH2)q-C(O)N(R7b)(R7c), -(CH2)n-pyridyl, or -(CH2)n-cyclopropyl.

[0201] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is

[0202]

[0203] R9bis H, CH3, OCH3orF.

[0204] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is

[0205] R17

[0206]

[0207] and

[0208] R9bis H, CH3, OCH3or F.

[0209] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is

[0210]

[0211] R9bis H, CH3, OCH3or F.Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is

[0212]

[0213] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is

[0214]

[0215] R9bis H, CH3, OCH3or F.

[0216] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0217]

[0218] R8is H, C1-3 alkyl, or cyclopropyl; and

[0219] R8ais H, halo, C1-3 alkyl, CH2OH, or CHF2.Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0220] R9is

[0221]

[0222] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0223]

[0224] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0225] R7is

[0226]

[0227]

[0228] R7ais H, C1-3alkyl, =O, -NH2, or -OH;

[0229] R8is H, C1-3alkyl, or cyclopropyl; and

[0230] R8ais H, halo, C1-3 alkyl, CH2OH, or CHF2.

[0231] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein

[0232] R9ais -(CH2)p-C(O)NH-R17

[0233] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0234] R9is

[0235]

[0236] R9bis H orF.

[0237] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0238] R9is

[0239]

[0240] R9bis H or F.

[0241] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0242] R9ais H, -NH2, - NR12R17-NR12(CO)-R12, -C(O)N(R12)(R17), -(CH2)P-C(O)R14, -NR12CONR17R12, or -(CH2)P-S(O)(NH)-R12;

[0243] R12is H, C1-3alkyl, or C1-3deuteroalkyl; and

[0244] R14is H or C1-3 alkyl, -NRaRa, -ORa, or methyl-piperizinyl,R17is -H, C1-3alkyl, -(CH2)-C(O)N(R12)(R12), -C3-6cycloalkyl, or a -(CH2)p-4 to 10 membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, the alkyl, cycloalkyl, phenyl, or heterocycle are substituted with 0-2 R17a; wherein the heterocycle is selected from pyrrolidinyl, pyrazolyl tetrahydrofuranyl, tetrazolyl, pyridinonyl, pyrrolidinonyl;

[0245] or R12and R17, together with the N to which they are attached, join to form a 4-7 membered heterocycle have an additional 0-2 heteroatoms selected from N, O, or S, substituted with 0-3 R17a; and

[0246] R17ais H, C1-3 alkyl, =0, or pyrimidinyl.

[0247] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0248] R2is

[0249]

[0250] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:R7is

[0251]

[0252]

[0253] any of which are substituted with 0-3 R7a; and

[0254] R7ais H, =O, C1-3alkyl, CF3, CHF2, or CD3.

[0255] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0256] R9ais

[0257] N

[0258] ^ R12

[0259] □ 17 <

[0260] K

[0261]

[0262] ; andR12is H, C1-3alkyl, or C1-3deuteroalkyl; and

[0263]

[0264] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0265] R9is phenyl or pyridinyl, either of which are substituted with 0-3 R9a.

[0266] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0267] R9is phenyl substituted with 0-3 R9a.

[0268] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects,salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0269] R9ais -H, -NH2, -NR12R17, -NR12(CO)-R12, -(CH2)P-C(O)R14, -NR12CONR17R12, or -(CH2)P-S(O)(NH)-R12,

[0270]

[0271] which may be substituted with 0-3 -OH, =0, C1-3 alkyl, or C1-3 alkoxy, N(Ra)2, or -CH2-C(O)N(Ra)2.

[0272] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0273] R9ais -H, -NH2, -NR12R17, -NR12(CO)-R12, -(CH2)P-C(O)R14, -(CH2)P-C(O)NR17R12, or -NR12CONR17R12,

[0274]

[0275] which may be substituted with 0-3 -OH, =0, C1-3 alkyl, or C1-3 alkoxy, N(Ra)2, or -CH2-C(O)N(Ra)2.

[0276] In another aspect of the invention, there are disclosed compounds of Formula (I), or compounds of Formula (I) as described by any of the other embodiments or aspects, salts, enantiomers, diastereomers, tautomers, pharmaceutically-acceptable salts, hydrates, or solvates thereof, wherein:

[0277] R12and R17, together with the nitrogen to which they are attached, join to form

[0278] *

[0279]

[0280]

[0281] , or, (wherein * indicates the point of attachment) any of which may be substituted with 0-2 -OH, =0, C1-3 alkyl, or Ci-3 alkoxy, N(Ra)2, or -CH2-C(O)N(Ra)2.Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is (la)

[0282] R9a

[0283]

[0284] (la), and wherein

[0285] R3is H, F, or C1-3 alkyl;

[0286] R4is H;

[0287] R5is H or F;

[0288] R6is H or F;

[0289] R9bis H or F;

[0290] R7is -CON(R7b)(R7c);

[0291] or R7is

[0292]

[0293] R8is H, C1-3 alkyl, or cyclopropyl;

[0294] R8ais H, halo, C1-3 alkyl, CH2OH, or CHF2;

[0295] R9ais -(CH2)p-NR12CONR17R12, -(CH2)p-C(O)N(R12)(R17), or -(CH2)P-C(O)R14; and

[0296] R9bis H.Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound of Formula (I) is (la)

[0297] R9a

[0298]

[0299] (la), and wherein

[0300] R3is H, F, or C1-3 alkyl;

[0301] R4is H;

[0302] R5is H or F;

[0303] R6is H or F;

[0304] R9bis H or F;

[0305] R7is -CON(R7b)(R7c);

[0306] or R7is

[0307]

[0308] R8is H, C1-3 alkyl, or cyclopropyl;

[0309] R8ais H, halo, C1-3 alkyl, CH2OH, or CHF2;

[0310] R9ais -(CH2)p-NR12CONR17R12, -(CH2)p-C(O)N(R12)(R17), or -(CH2)P-C(O)R14;

[0311] R9bis H;

[0312] R12is H or CH3;R17is -H, C1-3 alkyl, -(CH2)-C(O)N(R12)(R12), -(CH2)P-C3-6 cycloalkyl, -(CH2)P-phenyl, or a -(CH2)P-4 to 10 membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, wherein the heterocycle is selected from oxetanyl, oxolanyl, triazolyl, oxanyl, pyrazolyl, pyrimidinyl, triazolyl, oxazolyl, pyridinyl, imidazolyl, benzothiazolyl, tetrazolyl, thiadiazolyl, pyridinonyl, pyridazinyl, pyrrolidinyl, and wherein the alkyl, cycloalkyl, phenyl, or heterocycle are substituted with 0-3 R17a; and

[0313] R12and R17, together with the nitrogen to which they are attached, join to form azetidinyl.

[0314] Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound is selected from the examples. The present invention is also directed to pharmaceutical compositions useful in treating diseases associated with modulation and / or inhibition of STAT6, comprising compounds of formula (I), or pharmaceutically-acceptable salts thereof, and pharmaceutically-acceptable carriers or diluents.

[0315] The invention further relates to methods of treating diseases associated with the modulation of STAT6, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to formula (I).

[0316] The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0317] The present invention also provides a method for treating and inflammatory diseases, hematological disorders, and cancers, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0318] The present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic eosinophilicpneumonia, allergic bronchopulmonary aspergillosis, atopic dermatitis (AtD), prurigo nodularis (PN), bullous pemphigoid, eosinophilic esophagitis (EoE), allergic eosinophilic gastroenteritis, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), food allergy, hypereosinophilic syndrome, urticaria; hematological disorders such as systemic mastocytosis with eosinophilia; cancers such as breast cancer, colorectal cancer, melanoma, hematological cancers such as B cell lymphomas and others, cancerous solitary fibrous tumors of various organs.

[0319] The present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, atopic dermatitis (AtD), prurigo nodularis (PN), eosinophilic esophagitis (EoE), urticaria; and cancer.

[0320] The present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, atopic dermatitis (AtD), prurigo nodularis (PN), eosinophilic esophagitis (EoE), and urticaria.

[0321] The present invention also provides a method of treating diseases, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with other therapeutic agents.

[0322] The present invention also provides the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.

[0323] In another embodiment, compounds of formula (I), are selected from exemplified examples or combinations of exemplified examples or other embodiments herein.

[0324] The present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of an inflammatory disease, hematological disorder, and cancers.

[0325] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses allcombinations of preferred aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0326] The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.

[0327] Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more.

[0328] When any variable (e.g., R3) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R3, then said group may optionally be substituted with up to two R3groups and R3at each occurrence is selected independently from the definition of R3. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0329] Unless otherwise indicated, any carbon or heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0330] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0331] In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxides) to afford other compounds of thisinvention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N— >0) derivative.

[0332] In accordance with a convention used in the art,

[0333]

[0334] is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0335] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.

[0336] The term “optionally substituted” in reference to a particular moiety of the compound of Formula (I), (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable.

[0337] As used herein, the term “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “(4.10 alkyl” (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Additionally, for example, “Ci-Cg alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0338] When the term “alkyl” is used together with another group, such as in “arylalkyl”, this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, “arylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(Co-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, z.e., aryl(Co)alkyl.The term “heteroarylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.

[0339] “Alkenyl" or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, “C2-6 alkenyl” (or alkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,

[0340] 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0341] " Alkynyl" or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, “C2-6 alkynyl” (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

[0342] When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.

[0343] The term “alkoxy” refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term “alkoxy” includes the group -O-C1-6alkyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,

[0344] 3 -methylpentoxy, and the like. “Lower alkoxy” refers to alkoxy groups having one to four carbons.

[0345] It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the field to provide stable compounds.

[0346] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When a substituent is oxo, or keto, (i.e., =0) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listedas a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0347] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain a N-halo, S(O)2H, or S(O)H group.

[0348] The term “carbocyclyl” or “carbocyclic” refers to a saturated or unsaturated, or partially unsaturated, monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 5 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,

[0349] [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle e.g., [2.2.2]bicyclooctane). Carbocycles, can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term “carbocycle” is used, it is intended to include “aryl”. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0350] The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted. A preferred aryl group is optionally-substituted phenyl.The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. C3-7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like, which optionally may be substituted at any available atoms of the ring(s).

[0351] The terms “heterocycloalkyl”, “heterocyclo”, “heterocycle”, “heterocyclic”, or “heterocyclyl” may be used interchangeably and refer to substituted and unsubstituted aromatic or non-aromatic 3 -to 7-membered monocyclic groups, 7-to 11 -membered bicyclic groups, and 10-to 15-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. The term “heterocycle” includes “heteroaryl” groups. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =0 (oxo).

[0352] Exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl,

[0353] 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro- 1,1 -di oxothienyl and the like, including the exemplary groups listed under “heteroaryl”. Exemplary bicyclic heterocyclo groups include quinuclidinyl.

[0354] The term “heteroaryl” refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to

[0355] 14-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =0 (oxo).

[0356] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

[0357] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrol opyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0358] Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0359] Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl) the reference is intended to include rings having 0 to 3, preferably 0-2, substituents, as appropriate.

[0360] The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

[0361] The term “haloalkyl” means a substituted alkyl having one or more halo substituents. For example, “haloalkyl” includes mono, bi, and trifluorom ethyl.

[0362] The term “haloalkyl” means a substituted alkyl having one or more halo substituents. For example, “haloalkyl” includes mono, bi, and trifluorom ethyl.The term “haloalkoxy” means an alkoxy group having one or more halo substituents. For example, “haloalkoxy” includes OCF3.

[0363] The term “deuteroalkyl” means a substituted alkyl having one or more deuterium atom. For example, the term “deuteroalkyl” includes mono, bi, and trideuteromethyl.

[0364] The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

[0365] When the term “unsaturated” is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

[0366] One skilled in the field will understand that, when the designation “CO2” is used O II

[0367] herein, this is intended to refer to the group C O

[0368] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and / or intermediate compounds useful in making pharmaceutically-acceptable compounds.

[0369] The compounds of formula (I) may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof. The term “salt(s)” denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term “salt(s) may include zwitterions (inner salts), e.g., when a compound of formula (I), contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0370] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates,citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides,

[0371] 2-hydroxy ethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0372] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine,

[0373] N-benzyl-β-phenethylamine, 1 -ephenamine, N, N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. In one embodiment, salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.

[0374] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0375] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limitedto, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0376] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, the disclosure of which is hereby incorporated by reference.

[0377] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. As an example, an alkyl substituent is intended to cover alkyl groups have either hydrogen, deuterium, and / or some combination thereof. Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate

[0378] isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0379] Prodrugs and solvates of the inventive compounds are also contemplated. The term “prodrug” denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula (I), and / or a salt and / or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula (I)) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula (I) compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula (I) include C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6alkanoyloxy-C1-6alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C1-6alkoxycarbonyloxy-C1-6alkyl, e.g. methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,

[0380] (5-methyl-2-oxo-l,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

[0381] Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 112, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

[0382] b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H. Bundgaard, pp. 113-191 (1991); and

[0383] c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38 (1992), each of which is incorporated herein by reference.

[0384] Compounds of the formula (I) and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

[0385] Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. All geometric isomers, tautomers, atropisomers, hydrates, solvates, polymorphs, and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention. Methods of solvation are generally known in the art.

[0386] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.UTILITY

[0387] The compounds of the invention modulate kinase activity, including the inhibition of the STAT6 Pathway. Accordingly, compounds of formula (I) have utility in treating conditions associated with the inhibition of STAT6 pathway, and particularly the selective inhibition of STAT6 activity.

[0388] As used herein, the terms “treating” or “treatment” encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) achieving a full or partial reduction of the symptoms or disease state, and / or alleviating, ameliorating, lessening, or curing the disease or disorder and / or its symptoms.

[0389] In view of their activity as inhibitors of STAT6, compounds of Formula (I) are useful in treating STAT6-associated conditions including, but not limited to, inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, atopic dermatitis (AtD), prurigo nodularis (PN), bullous pemphigoid, eosinophilic esophagitis (EoE), allergic eosinophilic gastroenteritis, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), food allergy, hypereosinophilic syndrome, urticaria; hematological disorders such as systemic mastocytosis with eosinophilia; cancers such as breast cancer, colorectal cancer, melanoma, hematological cancers such as B cell lymphomas and others, cancerous solitary fibrous tumors of various organs.

[0390] When the terms “STAT6-associated condition” or “STAT6 -associated disease or disorder” are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by STAT6 activity and / or inhibition of the STAT6 pathway.

[0391] The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound of Formula (I) or a salt thereof. “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit STAT6.The methods of treating STAT6-associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and / or other suitable therapeutic agents useful in treating such conditions. Accordingly, “therapeutically effective amount” is also intended to include an amount of the combination of compounds claimed that is effective to inhibit STAT6 and / or treat diseases associated with STAT6.

[0392] Exemplary of such other therapeutic agents include corticosteroids such as prednisone or dexamethasone, cytokine-suppressive anti-inflammatory drugs (CSAIDs), salicylates, nitric oxide, calcineurin inhibitors and other immunosuppressants;

[0393] non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; anti-inflammatory antibodies such as vedolizumab, ustekinumab and adalimumab; anti-infammatory kinase inhibitors such as TYK2 and JAK inhibitors; PDE-4 antagonists such as apremilast; P-adrenergic receptor agonists such as albuterol; muscarinic receptor antagonists such as ipratropium; antiviral agents such as abacavir; antibiotics such as azithromycin; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide.

[0394] The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians’ Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating STAT6-associated conditions, as described above.

[0395] The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.Accordingly, the present invention further includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.

[0396] A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.

[0397] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art.

[0398] Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington ’s Pharmaceutical Sciences, 17th ed., 1985, which is incorporated herein by reference in its entirety.

[0399] The compounds of Formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrastemal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release.Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.

[0400] Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0401] Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and / or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymer (e.g., GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

[0402] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0403] Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0404] The therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 1000 mg / kg; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg; 250-1000 mg / kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term “patient” is used herein, this term is intended to include all subjects, most preferably mammalian species, that are affected by mediation of STAT6 activity.

[0405] STAT6 Phosphorylation Assay

[0406] Inhibition of STAT6 phosphorylation was measured in THP-1 cells using a TR-FRET based assay (Bioauxillium). Cells were dispensed into assay plates containing test compounds dissolved in dimethylsulfoxide (DMSO) and evaluated at eleven concentrations. Cells were incubated with compounds for 1 hour at 37°C in 5% CO2. Cell stimulation was performed by addition of IL-4 (R& D Systems) into each well, and plates were incubated for 1 hour at 37°C in 5% CO2. For the TR-FRET assay, cells were lysed using a 5X lysis buffer prepared with a phosphatase inhibitor cocktail. 1μL of the lysis buffer was added to each well, and plates were incubated with shaking for 30 minutes at room temperature. Detection reagents were prepared by diluting Antibody 1 (Eu-labeled phospho-STAT6 (Y641) antibody) and Antibody 2 (Acceptor-labeled phospho-STAT6 (Y641) antibody) in a IX detection buffer. The antibody mixture was further diluted with assay media and dispensed into the plates. Plates were incubated at room temperature,protected from light, for 20-24 hours before reading on an EnVision plate reader (Perkin Elmer) with 665nm / 615nm settings. Dose response curves were generated to determine the concentration required for inhibiting 50% of STAT6 phosphorylation.

[0407] Using these assays, the IC50values of the following compounds were determined. See Table A.

[0408] Table ApSTAT6 pSTAT6 Example # Example #

[0409] IC50(μM) IC50(μM) 1-1 0.244 2-1 0.004 1-2 0.072 2-2 0.148 1-3 1.78 2-3 3.59 1-4 0.190 2-4 0.145 1-5 0.670 2-5 0.071 1-6 0.683 2-6 0.591 1-7 0.022 2-7 0.980 1-8 0.908 2-8 0.579 1-9 0.993 2-9 0.417 1-10 0.063 2-10 0.434 1-11 0.254 2-11 0.108 1-12 0.117 2-12 0.209 1-13 0.192 2-13 0.198 1-14 1.023 2-14 0.500 1-15 0.334 2-15 1.94 1-16 0.183 2-16 0.230 1-17 0.328 2-17 1.50 1-18 0.096 2-18 0.213 1-19 0.960 2-19 0.018 1-20 1.01 2-20 0.163 1-21 0.030 2-21 0.146 1-22 0.070 2-22 0.017 1-23 4.15 2-23 0.017 1-24 1.28 2-24 0.004 1-25 0.100 2-25 0.020 1-26 1.43 3-1 0.000 1-27 0.062 3-2 0.150 1-28 0.108 3-3 0.061 1-29 0.033 3-4 0.006 1-30 0.123 3-5 0.224 1-32 3.3 3-6 0.193 1-33 0.037 3-7 0.003 1-34 0.055 3-8 0.003 1-35 0.044 3-9 0.004 1-36 0.015 3-10 0.071 1-37 0.089 3-11 0.360 1-38 0.177 3-12 0.009 1-39 0.309 3-13 0.018 1-40 0.388 3-14 0.014 1-41 0.144 3-15 0.134

[0410]

[0411] 1-42 0.303

[0412]

[0413] 3-16 0.016pSTAT6 pSTAT6 Example # Example #

[0414] IC50(μM) IC50(μM) 3-17 0.048 4-30 0.002 3-18 0.007 4-31 0.001 3-19 0.008 4-32 0.278 3-20 0.014 4-33 0.122 3-21 0.003 4-34 0.003 3-22 0.003 4-35 0.298 3-23 0.040 4-36 0.223 3-24 0.045 4-37 0.005 3-25 0.039 4-38 0.138 3-27 0.042 4-39 0.013 3-28 0.258 4-40 0.005 3-29 0.347 4-41 0.001 3-30 0.003 5-1 0.303 4-1 0.004 5-2 2.39 4-2 0.002 5-3 1.13 4-3 0.002 5-4 0.443 4-4 0.099 5-5 0.187 4-5 0.007 5-6 0.001 4-6 0.005 5-8 3.40 4-7 0.003 5-9 0.519 4-9 0.001 5-10 0.778 4-10 0.045 5-13 0.712 4-11 0.002 5-14 0.384 4-12 0.013 5-15 0.392 4-13 0.002 5-16 1.69 4-14 0.003 5-17 1.10 4-15 0.010 5-18 0.686 4-16 0.464 5-19 1.28 4-17 0.023 5-20 0.734 4-18 0.123 5-22 1.32 4-19 0.044 5-23 2.87 4-20 1.10 5-24 0.492 4-21 0.002 5-25 0.593 4-22 0.007 5-26 0.024 4-23 0.007 5-27 1.15 4-24 <0.002 5-28 1.67 4-25 0.004 5-29 0.561 4-26 0.008 5-30 0.542 4-27 0.019 5-31 0.017 4-28 0.014 5-32 0.721

[0415]

[0416] 4-29 0.240

[0417]

[0418] 5-33 0.059pSTAT6 pSTAT6 Example # Example #

[0419] IC50(μM) IC50(μM) 5-34 0.053 5-76 0.002 5-35 0.059 5-77 0.269 5-36 0.070 5-78 0.058 5-37 0.057 5-79 0.129 5-38 0.756 5-80 0.671 5-39 0.051 5-81 0.187 5-40 0.187 5-82 0.356 5-41 0.022 5-83 0.003 5-42 0.135 5-84 0.001 5-43 0.024 5-85 0.005 5-45 0.0004 5-86 0.002 5-46 0.273 5-87 0.070 5-47 1.32 5-88 0.418 5-48 0.001 5-89 0.016 5-49 0.010 5-90 0.002 5-50 0.002 5-91 0.086 5-51 0.032 5-92 0.319 5-52 0.333 5-93 0.001 5-53 0.021 5-94 0.066 5-54 0.194 5-95 0.001 5-55 0.092 5-96 0.002 5-56 0.004 5-97 0.004 5-57 1.53 5-98 0.005 5-58 0.002 5-99 0.001 5-59 0.251 5-100 0.022 5-60 0.020 5-101 0.001 5-61 0.021 5-102 0.002 5-62 0.004 5-103 0.017 5-63 0.065 5-104 0.005 5-64 0.007 5-105 0.120 5-65 0.041 5-106 0.206 5-66 0.037 5-107 0.080 5-67 0.040 5-108 0.0004 5-68 0.434 5-109 0.002 5-69 0.177 5-110 0.001 5-70 0.012 5-111 0.003 5-71 0.002 5-112 0.002 5-72 0.002 5-113 0.002 5-73 0.009 5-114 0.011 5-74 0.002 5-115 0.001

[0420]

[0421] 5-75 0.161

[0422]

[0423] 5-116 0.001pSTAT6 pSTAT6 Example # Example #

[0424] IC50(μM) IC50(μM) 5-117 0.003 9-24 0.021 5-118 0.003 9-25 0.004 5-119 0.001 9-26 0.008 5-120 0.017 9-27 0.097 5-121 0.007 9-28 0.019 5-122 0.002 9-29 0.003 5-123 0.005 9-30 0.012 6-1 0.001 9-31 0.0007 6-2 0.006 9-32 0.005 6-3 0.005 9-33 0.005 6-4 0.002 9-34 0.009 6-5 0.002 9-35 0.001 6-6 0.0002 9-36 0.001 6-7 0.008 9-37 0.036 6-8 0.013 9-38 0.023 7-1 0.228 9-39 0.082 8-1 0.002 9-40 0.001 8-2 0.007 9-41 0.001 9-1 0.001 9-42 0.0015 9-2 0.002 9-43 0.019 9-3 0.141 9-44 0.008 9-4 0.893 9-45 0.004 9-5 0.003 9-46 0.003 9-6 0.0005 9-47 0.003 9-7 0.005 9-48 0.014 9-8 0.013 9-49 0.010 9-9 0.0006 9-50 0.004 9-10 0.002 9-51 0.034 9-11 0.009 9-52 0.006 9-12 0.001 9-53 0.002 9-13 0.004 9-54 0.001 9-14 0.004 9-55 0.002 9-15 0.029 9-56 0.002 9-16 0.0008 9-57 0.007 9-17 0.0009 9-58 0.0005 9-18 0.005 9-59 0.004 9-19 0.0009 9-60 0.017 9-20 0.003 9-61 0.0005 9-21 0.016 9-62 0.495 9-22 0.0008 9-63 0.005

[0425]

[0426] 9-23 0.018

[0427]

[0428] 9-64 0.053pSTAT6 Example #

[0429] IC50(μM) 9-65 0.004 9-66 0.207 9-67 0.015 9-68 0.075 9-69 0.001 9-70 0.001 9-71 0.369 9-72 0.007 9-73 0.016 9-74 0.001 9-75 0.002 9-76 0.003 9-77 0.008 9-78 0.003 9-79 0.001 9-80 0.975 9-81 0.191 9-82 0.047 9-83 0.052 9-84 0.585 9-85 0.0007 9-86 0.0015 9-87 <0.0015

[0430]

[0431] 9-88 <0.0015Methods of Preparation

[0432] Compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (I), can be prepared using procedures shown in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.

[0433] Abbreviations as used herein, are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, "° C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, " L" for liter or liters, "mL" for milliliter or milliliters, "pL" for microliter or microliters, " N" for normal, " M" for molar, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, " RT" for room temperature, " ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "sat" or "saturated" for saturated, " CVs" for column volumes, " MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, " MS" or " Mass Spec" for mass spectrometry, “m / z” for mass per unit charge, " ESI" for electrospray ionization mass spectroscopy, " HR" for high resolution, " HRMS" for high resolution mass spectrometry, “APCI” for atmospheric pressure chemical ionization, " LCMS" or “LC / MS” for liquid chromatography mass spectrometry, " HPLC" for high pressure liquid chromatography, " RP HPLC" for reverse phase HPLC, “prep” for preparative, “SFC” for supercritical fluid chromatography, " TLC" or "tic" for thin layer chromatography, “Rf’ for retention factor, “UV” for ultraviolet, " NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy,1H" for proton, "6" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, " MHz" for megahertz, and "a", " ", " R", " S", " E", and " Z" are stereochemical designations familiar to one skilled in the art.

[0434] Me methyl

[0435] Et ethyl

[0436] Pr propyl

[0437] z-Pr isopropylBu butyl

[0438] zz-BuLi n-butyllithium

[0439] z-Bu isobutyl

[0440] / -Bu tert-butyl

[0441] Ph phenyl

[0442] Bn benzyl

[0443] BISPIN bis(pinacolato)diboron

[0444] Boc tert-butyl oxy carb ony 1

[0445] AcOH or HO Ac acetic acid

[0446] BOP benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0447] CBz carbobenzyloxy

[0448] DCE 1,2 di chloroethane

[0449] DCM dichloromethane

[0450] DIEA / DIPEA / Hunig’s Base diisopropylethylamine

[0451] DMAP 4-dimethylaminopyridine

[0452] DME 1,2-dimethoxy ethane

[0453] DMF dimethyl formamide

[0454] DMSO dimethyl sulfoxide

[0455] EDC / EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide Et3N or TEA triethylamine

[0456] EtOAc ethyl acetate

[0457] Et2O diethyl ether

[0458] EtOH ethanol

[0459] HC1 hydrochloric acid

[0460] HATU O-(7-azabenzotriazol- 1 -yl)-A, A, N', N'- tetramethyluronium hexafluorophosphate

[0461] Hex hexane

[0462] HOBt or HOBT 1 -hydroxybenzotri azole

[0463] z-PrOH or IPA isopropanol

[0464] KOAc potassium acetate

[0465] LAH lithium aluminum hydride

[0466] LDA lithium diisopropylamideLG leaving group

[0467] MeCN or ACN acetonitrile

[0468] MeOH methanol

[0469] Mel iodomethane

[0470] MgSO4magnesium sulfate

[0471] Na2SO4sodium sulfate

[0472] NH4OAc ammonium acetate

[0473] OTf triflate or trifluoromethanesulfonate

[0474] Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2palladium(II) acetate

[0475] Pd / C palladium on carbon

[0476] PdCh(dtbpf) [1,1 ’-Bis(di -tert- butylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2[ 1, L -bi s(diphenylphosphino)- ferrocene]dichloropalladium(II)

[0477] PG protecting group

[0478] RuPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l, 1 biphenyl) [2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) RuPhos-Pd-G3 methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i- propoxy- 1, 1 '-biphenyl)(2'-amino- 1, 1 '-biphenyl-2- yl)palladium(II)

[0479] Selectfluor 1 -chloromethyl-4-fluoro- 1,4-diazoniabicyclooctane bis(tetrafluoroborate)

[0480] SEM (2-(trimethylsilyl)ethoxy)methyl

[0481] SiO2silica oxide or silica gel

[0482] S-Phos or SPhos dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2- yl)phosphine

[0483] TBAI tetra- / 7-butylammonium iodide

[0484] TFA trifluoroacetic acid

[0485] THF tetrahydrofuran

[0486] X-Phos or XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenylXPhos Pd G2 2nd generation XPhos precatalyst, chloro(2- dicy clohexylphosphino-2 ',4 ', 6 ' -trii sopropyl -1,1'- biphenyl) [2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) XPhos Pd G3 (2-di cy clohexylphosphino-2', 4', 6'-triisopropyl- 1,1'- biphenyl) [2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate

[0487] GENERAL SYNTHESIS INCLUDING SCHEMES

[0488] The compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, J. P. et al., Heterocycles, 16(1):35-37 (1981)). General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. The “R” groups used within the schemes may differ from those used in the claims and are not meant to limit the claims. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence to give the desired compound or compounds.

[0489] Examples of compounds of the present invention prepared by methods described in the general schemes are given in the intermediates and examples section set out hereinafter. Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functionalities into racemic intermediates which serve to control the diastereoselectivity of transformations, providing enantio-enriched products upon cleavage of the chiral auxiliary.

[0490] The compounds of the present invention can be prepared in many ways known to one skilled in organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled inthe art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

[0491] It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0492] The “R” groups used in the following Schemes do not necessarily correspond with the “R” groups used in the claims or elsewhere in the description of the embodiments.

[0493] Scheme 1.

[0494] N-NH LG C-N bond formation C-C bond formation Ar-B(OR)2

[0495]

[0496] X = Br, Cl, I, etc LG = leaving group

[0497] n = 1, 2

[0498]

[0499] Scheme 1 depicts the synthesis of generic pyrrolidine derived compounds Id.

[0500] Substituted pyrrolidine lb can react with N2 of indazole derivative la, under the appropriate C-N bond formation conditions, such as the analogous Mitsunobu reaction condition, or other relevant alkylation conditions, to provide 1c. Further transformation with desired aryl derivatives under appropriate C-C bond formation conditions, such as Suzuki reaction, provides target structure Id.Scheme 2.

[0501] PG_ C-N bond formation C-C bond formation

[0502] 2a

[0503]

[0504] X = Br, Cl, I, etc

[0505] LG = leaving group

[0506]

[0507] PG = protecting group n = 1, 2 Alternatively, Id may be synthesized according to Scheme 2 by following a different synthesis sequence from Scheme 1. N-protected pyrrolidine 2a reacts with la via C-N bond formation to provide 2b. Transformation of 2b with the desired aryl derivatives under the appropriate C-C bond formation conditions, such as Suzuki coupling reaction, provides intermediate 2c. Removal of the protecting group from pyrrolidine under the appropriate conditions gives amine 2d. N- substitution reactions, such as Buckwald C-N coupling, Chan-Lam, or S\Ar substitution, etc., provide generic structure Id.

[0508] Scheme 3.

[0509]

[0510] 3d, n = 1, 2Alternatively, N2-substituted indazole derivatives with generic structure 3d may be synthesized by following the general synthesis as shown in Scheme 3. 2-Azidobenzaldehyde 3a reacts with amine 3b to provide indazole 3c. Further reactions with desired aryl derivatives under appropriate C-C bond formation conditions, such as Suzuki coupling reaction, afford generic structure 3d.

[0511] Details of the synthesis of the specific examples are described below. The purification of the intermediates and final products was conducted via normal or reverse phase chromatography. Normal phase chromatography was carried out using prepacked SiO2cartridges or alumina cartridges eluting with gradients of solvent pairs of hexanes / EtO Ac, DCM / MeOH or DCM / EtOAc, unless otherwise indicated. Reverse phase preparative HPLC was carried out using XBridge C18 columns eluting with gradients of solvent A - 0.05% TFA in MeCN: H2O (5:95) and solvent B - 0.05% TFA in MeCN: H2O (95:5); or solvent A - 10 mM NH4OAC in MeCN: H2O (5:95) and solvent B - 10 mM NFUOAc in MeCN: H2O (95:5). Other similar appropriate purification conditions are also utilized. Chiral resolutions of racemate or diastereomer mixtures were conducted using appropriate SFC conditions.

[0512] Unless otherwise stated, analysis of final products was carried out by reverse phase analytical HPLC. The analytical HPLC purity is > 95% except stated otherwise.

[0513] ANALYTICAL LC / MS METHODS:

[0514] Method A:

[0515] Start % B = 0, final % B = 100 over 1 min gradient

[0516] Flow Rate = 1.0 mL / min

[0517] Wavelength = 254 nm

[0518] Solvent A = 0.05% TFA in MeCN: H2O (5:95)

[0519] Solvent B = 0.05% TFA in MeCN: H2O (95:5)

[0520] Column = Acquity BEH C18 1.7 pm particles; 2.1 x 50 mm

[0521] Temperature = 50 °C

[0522] Method B:

[0523] Start % B = 0, final % B = 100 over 1 min gradient

[0524] Flow Rate = 1.0 ml / min

[0525] Wavelength = 220 nm

[0526] Solvent A = 10 mM NH4OAc in MeCN: H2O (5:95)

[0527] Solvent B = 10 mM NH4OAc in MeCN: H2O (95:5)Column = Acquity BEH C18 1.7 pm particles; 2.1 x 50 mm Temperature = 50 °C

[0528] Method C:

[0529] Start % B = 0, final % B = 100 over 3 min gradient Flow Rate = 1.0 mL / min

[0530] Wavelength = 254 nm

[0531] Solvent A = 0.05% TFA in MeCN: H2O (5:95)

[0532] Solvent B = 0.05% TFA in MeCN: H2O (95:5)

[0533] Column = Acquity BEH C18 1.7 pm particles; 2.1 x 50 mm Temperature = 50 °C

[0534] Method D:

[0535] Start % B = 0, final % B = 100 over 3 min gradient Flow Rate = 1.0 ml / min

[0536] Wavelength = 254 nm

[0537] Solvent A = 10 mM NH4OAc in MeCN: H2O (5:95) Solvent B = 10 mM NH4OAc in MeCN: H2O (95:5) Column = Acquity BEH C18 1.7 pm particles; 2.1 x 50 mm Temperature = 50 °C

[0538] Method E:

[0539] Start % B = 0, final % B = 100 over 3 min gradient Flow Rate = 1.0 mL / min

[0540] Wavelength = 254 nm

[0541] Solvent A = 0.05% TFA in MeCN: H2O (5:95)

[0542] Solvent B = 0.05% TFA in MeCN: H2O (95:5)

[0543] Column = XBridge C18 1.7 pm particles; 2.1 x 50 mm Temperature = 50 °C

[0544] Method F:

[0545] Start % B = 0, final % B = 100 over 3 min gradient Flow Rate = 1.0 ml / min

[0546] Wavelength = 254 nmSolvent A = 10 mM NH4OAc in MeCN: H2O (5:95)

[0547] Solvent B = 10 mM NH4OAc in MeCN: H2O (95:5)

[0548] Column = XBridge C18 1.7 m particles; 2.1 x 50 mm

[0549] Temperature = 50 °C

[0550] Method G:

[0551] Start % B = 20, final % B = 100 over 4 min gradient

[0552] Flow Rate = 1.0 ml / min

[0553] Wavelength = 220 nm

[0554] Solvent A = 5 mM ammonium formate in FBChMeCN: (98:2)

[0555] Solvent B = 5 mM ammonium formate in FBO eCN (2:98)

[0556] Column = Kinetex XBridge C182.6 pm particles; 3 x 75 mm

[0557] Temperature = 25 °C

[0558] SYNTHESIS OF INTERMEDIATES

[0559] Intermediate 1: (5)-l-(pyridin-2-yl)pyrrolidin-3-ol

[0560]

[0561] To a solution of (5)-3-pyrrolidinol (1.0 g, 11.48 mmol) in 2-propanol (5 mL) was added TEA (3.20 mL, 22.96 mmol) followed by the addition of 2-fluoropyridine (1.67 g, 17.2 mmol) at rt. The reaction was stirred under N2 at 90 °C overnight. The solvent was removed. The crude product was purified by normal phase chromatography to provide Intermediate 1 as a pale solid (1.75 g, 93%). MS (ESI) m / z 165.1 (M+H)+. 'H NMR (400 MHz, CDCh) 6 8.13 (ddd, J=5.0, 1.9, 0.8 Hz, 1H), 7.43 (ddd, J=8.6, 7.0, 2.0 Hz, 1H), 6.57 - 6.49 (m, 1H), 6.36 (d, J=8.5 Hz, 1H), 4.58 (tt, J=4.6, 2.5 Hz, 1H), 3.66 - 3.45 (m, 4H), 2.53 (br s, 1H), 2.19 - 2.01 (m, 2H).

[0562] Intermediate 2: tert-butyl (A)-3-(5-bromo-2H-indazol-2-yl)pyrrolidine-l -carboxylate

[0563] Nz

[0564] 'N

[0565]

[0566] H

[0567] A vial was charged with 5-bromo-lH-indazole (1.00 g, 5.08 mmol), (5)-l-Boc-3-hydroxypyrrolidine (1.43 g, 7.61 mmol) and 2-(tributylphosphoranylidene)acetonitrile (10.15 mL, 10.15 mmol) (1 M solution in toluene) at rt under N2. The reaction was heated at 80 °Covernight. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 2 (0.70 g, 38%). MS (ESI) m / z 365.8 / 367.8 (M+H)+. 'HNMR (400 MHz, CDCh) 67.92 (s, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.60 (d,. / =9,2 Hz, 1H), 7.36 (dd, J=9.1, 1.8 Hz, 1H), 5.18 (quin, J=5.9 Hz, 1H), 4.04 - 3.53 (m, 4H), 2.63 - 2.45 (m, 2H), 1.50 (br s, 9H).

[0568] Intermediate 3: (A)-5-bromo-2-( 1 -(pyridin-2-yl)pyrrolidin-3 -yl)-2H-indazole

[0569]

[0570] To a solution of Intermediate 2 (250 mg, 0.68 mmol) in DCM (3 mL), TFA (1.0 mL, 13.0 mol) was added at rt. The reaction was stirred under N2 at rt for 30 min. The solvent was removed. The obtained product was dissolved in DMF (3 mL), Then, K2CO3 (283 mg, 2.05 mmol) and 2-fluoropyridine (99 mg, 1.02 mmol) were added. The reaction was stirred at 90 °C overnight. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SC>4, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Intermediate 3 (81 mg, 35%). MS (ESI) m / z 342.8 / 344.8 (M+H)+. 'HNMR (500 MHz, CDCh) 68.25 - 8.20 (m, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.80 (dd, J=1.8, 0.7 Hz, 1H), 7.60 (dt, J=9.2, 0.8 Hz, 1H), 7.54 (ddd, J=8.5, 7.1, 1.8 Hz, 1H), 7.35 (dd, J=9.2, 1.8 Hz, 1H), 6.71 - 6.63 (m, 1H), 6.48 (d, J=8.5 Hz, 1H), 5.43 - 5.32 (m, 1H), 4.19 - 4.09 (m, 2H), 3.86 - 3.69 (m, 2H), 2.69 (td, J=7.0, 5.8 Hz, 2H).

[0571] Intermediate 4: (R)-5-bromo-7-methyl-2-(l-(pyridin-2-yl)pyrrolidin-3-yl)-2H-indazole

[0572]

[0573] To a vial containing 5-bromo-7-methyl-1H-indazole (100 mg, 0.47 mmol) and Intermediate 1 (117 mg, 0.71 mmol), was added 2-(tributylphosphoranylidene)acetonitrile (0.93 ml, 0.93 mmol) (1 M solution in toluene). The reaction was stirred under N2 at 80 °C overnight. The solvent was removed. The crude product was purified by normal phase chromatography to give Intermediate 4 (135 mg, 80%). MS (ESI) m / z 356.8 / 358.7 (M+H)+. 'HNMR (500 MHz, CDCh) 68.26 - 8.18 (m, 1H), 7.88 (s, 1H), 7.61 (dd, J=1.7, 0.6 Hz, 1H), 7.54.7.48 (m, 1H), 7.13 (dd, J=1.8, 1.1 Hz, 1H), 6.65 (ddd, J=7.1, 5.1, 0.8 Hz, 1H), 6.45 (d,, / =8.5 Hz, 1H), 5.44 - 5.33 (m, 1H), 4.17 - 4.04 (m, 2H), 3.81 - 3.65 (m, 2H), 2.70 - 2.63 (m, 2H), 2.61 - 2.57 (m, 3H).

[0574] Intermediate 5: (5)-3-(3-hydroxypyrrolidin-l-yl)benzonitrile

[0575] CN

[0576]

[0577] A reaction vessel charged with 3 -bromobenzonitrile (6.00 g, 33.0 mmol), (S)-3-hydroxypyrrolidine (3.45 g, 39.6 mmol), Cs2CO3 (23.63 g, 72.5 mmol) and RuPhos-Pd-G3 (1.38 g, 1.65 mmol) was sparged with N2 before adding dioxane (14 ml). The reaction was stirred at 100 °C for 3 h. The crude material was filtered, concentrated, and was purified by normal phase chromatography to give Intermediate 5 (4.32 g, 70%). MS (ESI) m / z 189.1 (M+H)+. 'HNMR (400 MHz, CDCh) 67.33 - 7.30 (m, 1H), 6.99 (dt, J=7.5, 1.1 Hz, 1H), 6.84 - 6.79 (m, 2H), 4.68 (tt, J=4.6, 2.3 Hz, 1H), 3.60 - 3.50 (m, 2H), 3.44 - 3.38 (m, 1H), 3.30 (dt, J=10.6, 1.5 Hz, 1H), 2.29 - 2.19 (m, 1H), 2.18 - 2.10 (m, 1H).

[0578] Intermediate 6: tert-butyl (A)-3-(5-bromo-7-methyl-2H-indazol-2-yl)pyrrolidine-l-carb oxy late

[0579]

[0580] To a vial containing 5-bromo-7-methyl-1H-indazole (2.50 g, 11.8 mmol) and S)-l-Boc-3 -hydroxypyrrolidine (2.66 g, 14.2 mmol), was added 2-(tributylphosphoranylidene) acetonitrile (23.7 mL, 23.7 mmol) (1 M solution in toluene). The reaction was stirred under N2 at 80 °C overnight. The crude product was purified by normal phase chromatography to provide Intermediate 6 as a light brown solid (3.49 g, 77 % yield). MS (ESI) m / z 379.9 / 381.9 (M+H)+. 'HNMR (500 MHz, CDCh) 67.88 (s, 1H), 7.64 (s, 1H), 7.14 (s, 1H), 5.25 - 5.14 (m, 1H), 4.01 - 3.81 (m, 2H), 3.78 - 3.52 (m, 2H), 2.60 (s, 3H), 2.56 - 2.46 (m, 2H), 1.50 (br s, 9H).

[0581] Intermediate 7: (7?)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrile

[0582]

[0583] A solution of 2-(tributylphosphoranylidene)acetonitrile (1 M in toluene, 17.43 ml, 17.43 mmol) was added to 5-bromo-7-methyl-1H-indazole (1.84 g, 8.71 mmol) and Intermediate 5 (1.64 g, 8.71 mmol) at rt. The reaction was stirred under N2 at 80 °C overnight. The crude product was purified by normal phase chromatography to give Intermediate 7 (2.04 g, 62%). MS (ESI) m / z 380.9 / 382.9 (M+H)+. 'HNMR (500 MHz, CDCh) 67.89 (s, 1H), 7.63 (d, J=0.7 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.04 (d,, / =7.5 Hz, 1H), 6.87 - 6.81 (m, 2H), 5.49 - 5.38 (m, 1H), 4.00 - 3.93 (m, 1H), 3.92 - 3.85 (m, 1H), 3.77 - 3.65 (m, 1H), 3.56 (dt, J=9.3, 6.7 Hz, 1H), 2.78 - 2.67 (m, 2H), 2.60 (s, 3H).

[0584] Intermediate 8: (A)-7-methyl-2-(l-(pyridin-2-yl)pyrrolidin-3-yl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2H-indazole

[0585]

[0586] To a solution of Intermediate 4 (220 mg, 0.62 mmol) in acetonitrile (5 mL), was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (188 mg, 0.74 mmol) followed by the addition of potassium acetate (121 mg, 1.23 mmol) and PdC12(dppf) (45 mg, 0.062 mmol). The reaction was stirred under N2 at 90 °C for 2 h. The reaction was filtered through a plug of silica gel eluting with EtOAc. The solvent was removed to give Intermediate 8 in quantitative yield. MS (ESI) m / z 404.9 (M+H)+.

[0587] Intermediate 9: (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)pyrrolidin-l-yl)benzamide

[0588]

[0589] To a solution of Intermediate 7 (1.00 g, 2.62 mmol) in DMSO (10 mL), was added K2CO3 (1.45 g, 10.49 mmol) followed by the addition of hydrogen peroxide (30% solution,2.68 mL, 26.2 mmol) dropwise at 0 °C. The reaction was stirred under N2 at rt for 2 h. The reaction was diluted with H2O. The white solid formed was collected by filtration and dried under vacuum to give Intermediate 9 (1.05 g, 100% yield). MS (ESI) m / z 398.9 / 400.8 (M+H)+. 'HNMR (500 MHz, CDCh) 67.92 (s, 1H), 7.64 (dd, J=1.7, 0.7 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.23 - 7.18 (m, 2H), 7.04 - 6.98 (m, 1H), 5.55 - 5.49 (m, 1H), 4.08 (dd, J=10.8, 6.6 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.86 - 3.78 (m, 1H), 3.68 (td, J=8.9, 4.4 Hz, 1H), 2.83 - 2.74 (m, 1H), 2.70 - 2.65 (m, 1H), 2.64 (s, 3H).

[0590] Intermediate 10: (A)-3-(3-(7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrile

[0591]

[0592] To a solution of Intermediate 7 (1.05 g, 2.75 mmol) in acetonitrile (15 mL), was added bis(pinacolato)diboron (0.84 g, 3.30 mmol) followed by addition of KOAc (0.54 g, 5.51 mmol) and PdC12(dppf) (0.20 g, 0.28 mmol). The reaction was stirred under N2 at 90 °C for 4 h. The reaction was cooled to rt, then was diluted with EtOAc. The solution was passed through a short column of silica gel. The solvent was removed to afford Intermediate 10 (1.15 g, 97%), as a light tan solid. MS (ESI) m / z 429.1 (M+H)+. ‘HNMR (500 MHz, CDCh) 8 8.07 (s, 1H), 7.96 (s, 1H), 7.44 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.86 -6.81 (m, 2H), 5.44 (quin, J=5.6 Hz, 1H), 3.99 - 3.87 (m, 2H), 3.70 (dt, J=9.2, 7.3 Hz, 1H), 3.56 (ddd, J=9.3, 8.1, 5.7 Hz, 1H), 2.78 - 2.67 (m, 2H), 2.62 (s, 3H), 1.38 (s, 12H).

[0593] Intermediate 11: ((A)-3-(3-(7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzamide

[0594]

[0595] To a stirred solution of Intermediate 9 (450 mg, 1.13 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (429 mg, 1.69 mmol) in 1,4 dioxane (15 mL), was added KOAc (332 mg, 3.38 mmol) followed by the addition of PdC12(dppf) (92 mg, 0.11 mmol). The reaction was heated at 100 °C for 16 h. After cooling, the reaction mass wasfiltered through celite washing with EtOAc. The solvent was removed to provide Intermediate 11 (700 mg, quanititative), as a yellow solid. MS (ESI) m / z 447.4 (M+H)+.

[0596] Intermediate 12: 2-azido-5-bromo-3-fluorobenzaldehyde

[0597]

[0598] To a solution of 5-bromo-2,3-difluorobenzaldehyde (5.0 g, 22.6 mmol) in DMSO (20 mL) at rt, was added sodium azide (2.94 g, 45.2 mmol). The reaction was stirred under N2 at 50 °C for 4 h. H2O was added to form a precipitate, which was collected by filtration. The solid was further washed with H2O and dried under vacuum to give Intermediate 12, as an off-white solid (5.47 g, 99%). 'HNMR (500 MHz, CDCh) 6 10.29 (s, 1H), 7.81 (dd, J=2.2, 1.5 Hz, 1H), 7.52 (dd, J=10.5, 2.3 Hz, 1H).

[0599] Intermediate 13: 2-azido-5-bromo-3-methylbenzaldehyde

[0600]

[0601] To a solution of 5-bromo-3-fluoro-2-methylbenzaldehyde (3.0 g, 13.8 mmol) in DMSO (40 mL), was added sodium azide (1.35 g, 20.7 mmol). The reaction was heated at 50 °C for 16 h. The reaction was poured into ice water to form a precipitate, which was collected by filtration. The solid was further washed with H2O and dried under vacuum to provide a white solid (3.0 g, 90 %).1HNMR(500 MHz, CDCh) 6 10.10 (s, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 2.39 (s, 3H).

[0602] Intermediate 14: tert-butyl (A)-(l-(3-cyanophenyl)pyrrolidin-3-yl)carbamate

[0603] 'tlHBoc

[0604]

[0605] A vial charged with 3 -bromobenzonitrile (1.0 g, 5.49 mmol), (R)-(+)-3-(Boc-amino)pyrrolidine (1.13 g, 6.04 mmol) and Cs2CO3 (3.94 g, 12.1 mmol) was degassed before dioxane (10 mL) was added. Then RuPhos-Pd-G3, 0.23 g, 0.28 mmol) was added at rt. The reaction wash heated at 100 °C overnight. The reaction mixture was purified by normal phasechromatography to afford Intermediate 14 (1.57 g, 99%). MS (ESI) m / z 288.1 (M+H)+. 'H NMR (500 MHz, CDCh) 67.33 - 7.27 (m, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.79 - 6.73 (m, 2H), 4.76 (br s, 1H), 4.40 (br s, 1H), 3.60 (dd, J=9.8, 6.1 Hz, 1H), 3.49 - 3.41 (m, 1H), 3.35 (td, J=8.8, 5.5 Hz, 1H), 3.19 (br dd, J=9.6, 3.7 Hz, 1H), 2.41 - 2.28 (m, 1H), 2.05 - 1.95 (m, 1H), 1.48 (s, 9H).

[0606] Intermediate 15: tert-butyl (A)-(l-(3-cyanophenyl)pyrrolidin-3-yl)carbamate, TFA salt

[0607]

[0608] To a solution of Intermediate 14 (3.2 g, 11.14 mmol) in DCM (15 mL), was added TFA (8.0 mL, 104 mmol). The reaction was stirred under N2 at rt for 1 h. The solvent was removed to give Intermediate 15 in quantitative yield. MS (ESI) m / z 188.1 (M+H)+.

[0609] Intermediate 16: (A)-3-(3-(5-bromo-7-fluoro-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrile

[0610]

[0611] Intermediate 15 (3.2 g, 10.6 mmol) was dissolved in DCM. The solution was washed with saturated NaHCO3 solution twice. The organic phase was dried over Na2SC>4, filtered, and the solvent was removed to give a light tan oil (2.04 g). The obtained amine (free base) was dissolved in DCM (30 mL), then Intermediate 12 (2.59 g, 10.62 mmol) and molecular sieves (4 A, 5 g) were added. The reaction was stirred at rt for 4 h. The reaction was filtered through celite. The solvent was removed. The obtained intermediate was dissolved in toluene (20 mL), then heated at 110 °C for 3 h. The solvent was removed. The crude product was purified by normal phase chromatography to provide Intermediate 16 (3.57 g, 87%). MS (ESI) m / z 384.9 / 386.8 (M+H)+. 'H NMR (500 MHz, CDCh) 67.98 (d, J=2.6 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.08 (dd, J=10.4, 1.4 Hz, 1H), 7.03 (dt, J=7.6, 1.1 Hz, 1H), 6.87 - 6.80 (m, 2H), 5.47 - 5.37 (m, 1H), 4.00 - 3.93 (m, 1H), 3.93 - 3.87 (m, 1H), 3.71 (dt, J=9.3, 7.3 Hz, 1H), 3.57 (ddd, J=9.3, 8.0, 5.7 Hz, 1H), 2.81 - 2.67 (m, 2H).

[0612] Intermediate 17: (A)-3-(3-(5-bromo-7-fluoro-2H-indazol-2-yl)pyrrolidin-l-yl)benzamide

[0613]

[0614] To a solution of Intermediate 16 (200 mg, 0.52 mmol) in DMSO (4 mL) was added K2CO3 (287 mg, 2.09 mmol), followed by the addition of hydrogen peroxide (30%, 0.53 mL, 5.19 mmol). The reaction was stirred at rt overnight. H2O was added to form a precipitate, which was collected by filtration, then dried under vacuum to give Intermediate 17 (205 mg, 98%), as a tan solid. MS (ESI) m / z 402.9 / 404.8 (M+H)+.

[0615] Intermediate 18: tert-butyl (A)-(l-(3-cyano-2-fluorophenyl)pyrrolidin-3-yl)carbamate

[0616]

[0617] IM HBoc

[0618] To a solution of 3-bromo-2-fluorobenzonitrile (1.5 g, 7.50 mmol) in DMSO (10 mL), was added (A)-(+)-3-(Boc-amino)pyrrolidine (2.10 g, 11.3 mmol) followed by addition of l,4-diazabicyclo[2.2.2]octane (3.07 g, 27.4 mmol), nickel(II) chloride hexahydrate (0.45 g, 1.88 mmol) and tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate (0.15 g, 0.17 mmol). The reaction was purged with N2 for 10 min, then was stirred under blue LED irradiation at rt overnight. The reaction was diluted with EtOAc, washed with 1 M HC1, 1 M K2HPO4 and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Intermediate 18 (1.61 g, 70%), as a white solid. MS (ESI) m / z 306.0 (M+H)+.1H NMR (500 MHz, CDCh) 67.10 -7.04 (m, 1H), 6.94 (ddd, J=7.6, 5.0, 1.5 Hz, 1H), 6.86 (td, J=8.5, 1.0 Hz, 1H), 4.78 (br s, 1H), 4.36 (br s, 1H), 3.72 - 3.58 (m, 2H), 3.52 - 3.42 (m, 1H), 3.33 (dt, J=10.1, 3.1 Hz, 1H), 2.28 (dq, J=14.2, 6.6 Hz, 1H), 2.01 - 1.90 (m, 1H), 1.48 (s, 9H). Alternatively, Intermediate 18 was synthesized by following a similar procedure to that described in Intermediate 14 in good yield.

[0619] Intermediate 19: (A)-3-(3-aminopyrrolidin-l-yl)-2-fluorobenzonitrile

[0620]

[0621] '"hl HBoc

[0622] To a solution of Intermediate 18 (1.15 g, 3.77 mmol) in DCM (5 mL), was added TFA (3.0 mL, 38.9 mmol) at rt. The reaction was stirred under N2 at rt for 1 h. The solvent was removed. The reaction mixture was diluted with DCM, washed with sat NaHCO3. The organic phase was dried over Na2SC>4, filtered and concentrated to provide Intermediate 19 (0.74 g, 96%) as a tan solid. MS (ESI) m / z 206.1.

[0623] Intermediate 20: (R)-3 -(3 -(5 -bromo-7 -fluoro-2H-indazol-2-yl)pyrrolidin- 1 -yl)-2-fluorobenzonitrile

[0624]

[0625] To a solution of Intermediate 19 (0.74 g, 3.61 mmol) in DCM (15 mL), was added Intermediate 12 (0.88 g, 3.61 mmol) and molecular sieves (4 A, 1.5 g). The reaction was stirred under N2 at rt for 4 h. The reaction mass was filtered through a plug of celite, and the solvent was removed. The obtained intermediate was dissolved in toluene (15 mL). The solution was heated at reflux for 1.5 h, and then at 100 °C overnight. The solvent was removed. The crude product was purified by normal phase chromatography providing Intermediate 20 (1.08 g, 74%). MS (ESI) m / z 402.8 / 404.9 (M+H)+. 'H NMR (500 MHz, CDCh) 68.05 (d, J=2.6 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.09 (dd, J=10.4, 1.5 Hz, 1H), 7.02 (ddd, J=7.7, 5.1, 1.6 Hz, 1H), 6.95 (td, J=8.5, 1.5 Hz, 1H), 5.38 (qd, J=6.1, 4.4 Hz, 1H), 4.10 - 4.05 (m, 1H), 4.04 - 4.00 (m, 1H), 3.86 (dtd, J=9.7, 7.4, 2.4 Hz, 1H), 3.67 (dtd, J=9.4, 7.0, 2.2 Hz, 1H), 2.72 - 2.65 (m, 2H).

[0626] Intermediate 21: ( / ?)-2-fluoro-3-(3-(7-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrileCN

[0627]

[0628] To a solution of Intermediate 20 (1.00 g, 2.48 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (945 mg, 3.72 mmol) in 1,4-dioxane (15.0 mL), was added KO Ac (730 mg, 7.44 mmol) followed by the addition of PdC12(dppf) (203 mg, 0.25 mmol). The reaction was heated at 90 °C for 16 h. Reaction mixture was filter through celite washing with ethyl acetate. Removal of the solvent provided Intermediate 21 (1.5 g, 79%). MS (ESI) m / z 451.1 (M+H)+.

[0629] Intermediate 22: (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)pyrrolidin-l-yl)-2-fluorobenzonitrile

[0630]

[0631] A suspension of Intermediate 13 (1.80 g, 7.50 mmol), Intermediate 19 (1.54 g, 7.50 mmol) and CU2O (0.11 g, 0.75 mmol) in DCE (20 mL) was heated at 80 °C for 16 h The reaction mixture was filtered through celite and was further washed with EtOAc. The solvent was removed. Purification by normal phase chromatography provided Intermediate 22 (1.17 g, 38%) as a brown solid. MS (ESI) m / z 399.2 / 401.2 (M+H)+.

[0632] Intermediate 23: (A)-2-fluoro-3-(3-(7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrile

[0633]

[0634] A mixture of Intermediate 22 (560 mg, 1.40 mmol), bispin (427 mg, 1.68 mmol) and KOAc (275 mg, 2.81 mmol) in 1,4-dioxane (10 mL) was purged with argon before adding Pd(dppf)C12 (103 mg, 0.14 mmol). The reaction was heated at 90 °C for 16 h. To the reactionmixture was added ice water (5 mL). It was then extracted with ethyl acetate. The organic phase was over Na2SC>4, filtered, and concentrated. Purification by normal phase chromatography provided Intermediate 23 (610 mg, 80%). MS (ESI) m / z 447.5 (M+H)+.

[0635] Intermediate 24: tert-butyl (A)-3-(5-bromo-7-fluoro-2H-indazol-2-yl)pyrrolidine-l-carboxylate

[0636]

[0637] (A)-l-Boc-3-aminopyrrolidine (1.76 g, 9.43 mmol) was dissolved in DCM (30 mL), then Intermediate 12 (2.3 g, 9.43 mmol) and molecular sieves (4, 5 g) were added. The reaction was stirred at rt. After 4 h, the reaction was filtered through celite. The solvent was removed.

[0638] The obtained intermediate was dissolved in toluene (20 mL), then was heated at 110 °C for 3 h. The solvent was removed. The crude product was purified by normal phase chromatography to provide Intermediate 24 (2.44 g, 67%). MS (ESI) m / z 405.9 / 407.9 (M+Na)+ 1H NMR (500 MHz, CHLOROFORM-d) 67.97 (d,. / =2,6 Hz, 1H), 7.62 (d, J=1.4 Hz, 1H), 7.09 (dd, J=10.3, 1.5 Hz, 1H), 5.21 (quin, J=5.8 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.94 (br s, 1H), 3.76 - 3.54 (m, 2H), 2.62 - 2.49 (m, 2H), 1.50 (s, 9H).

[0639] Intermediate 25: (R)-6-(3-(5-bromo-7-fluoro-2H-indazol-2-yl)pyrrolidin-l-yl)picolinonitrile

[0640] CN

[0641]

[0642] To a solution of Intermediate 24 (100 mg, 0.26 mmol) in DCM (1 mL), was added TFA (0.5 mL, 6.49 mmol). The reaction was stirred under N2 at rt for 30 min The solvent was removed. The obtained intermediate was dissolved in DMF (1 mL), then K2CO3 (108 mg, 0.781 mmol) and 2-cyano-6-fluoropyridine (38 mg, 0.31 mmol) were added. The reaction was heated at 90 °C for 1 h. The solvent was removed. The crude product was purified by normal phase chromatography to provide Intermediate 25 (92 mg, 92%). MS (ESI) m / z 385.8 / 387.8 (M+H)+. lHNMR(500 MHz, CDC13) 87.99 (d, J=2.6 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.57 (dd, J=8.7, 7.2 Hz, 1H), 7.09 (dd, J=10.4, 1.5 Hz, 1H), 7.03 (dd, J=7.2, 0.6 Hz,1H), 6.65 (dd, J=8.7, 0.6 Hz, 1H), 5.42 - 5.36 (m, 1H), 4.20 - 4.11 (m, 2H), 3.85 (dt, J=10.3, 7.5 Hz, 1H), 3.73 (ddd, J=10.4, 8.4, 5.1 Hz, 1H), 2.83 - 2.66 (m, 2H).

[0643] Intermediate 26: methyl (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)pyrrolidin-l-yl)benzoate

[0644]

[0645] To a solution of Intermediate 6 (3.49 g, 9.18 mmol) in DCM (15 mL) was added TFA (5 mL, 64.9 mmol). The reaction was stirred under N2 at rt for 1 h The solvent was removed. The obtained product was dissolved in DCM. The solution was carefully neutralized with saturated NaHCO3 solution. The organic phase was separated, and the solvent was removed. MS (ESI) m / z 279.8 / 281.8 (M+H)+.

[0646] To a solution of the above intermediate (2.3 g, 8.21 mmol) in DCM (30 mL) was added 3-methoxycarbonylphenylboronic acid (2.95 g, 16.4 mmol), followed by the addition of molecular sieves (5 g), copper(II) acetate (2.98 g, 16.4 mmol) and pyridine (2.0 mL, 24.6 mmol). The reaction was stirred under air at rt for 2 days. The reaction was filtered through celite, and the solvent was removed. The crude product was purified by normal phase chromatography to give Intermediate 26 (1.09 g, 32%). MS (ESI) m / z 413.9 / 415.9 (M+H)+. 'H NMR (500 MHz, CDCh) 67.88 (s, 1H), 7.60 (dd, J=1.8, 0.7 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.38 - 7.32 (m, 2H), 7.14 (dd, J=1.8, 1.1 Hz, 1H), 6.88 (dd, J=8.2, 2.1 Hz, 1H), 5.43 (tt, J=6.5, 4.4 Hz, 1H), 4.02 - 3.96 (m, 1H), 3.92 (s, 3H), 3.94 - 3.89 (m, 1H), 3.78 - 3.68 (m, 1H), 3.63 - 3.56 (m, 1H), 2.76 - 2.62 (m, 2H), 2.60 (s, 3H).

[0647] Intermediate 27: tert-butyl 3-(5-bromo-7-methyl-2H-indazol-2-yl)-3-methylpyrrolidine-l-carb oxy late

[0648] Me

[0649]

[0650] A suspension of Intermediate 13 (1.5 g, 6.25 mmol), tert-butyl 3-amino-3-methylpyrrolidine-1 -carboxylate (1.38 g, 6.87 mmol) and CU2O (0.089 g, 0.63 mmol) in DCE (20 mL) was heated at 80 °C for 16 h. The reaction mixture was filtered through celite andwashed with EtOAc. The filtrate was concentrated. Purification by normal phase chromatography provided Intermediate 27 (2.1 g, 83%). MS (ESI) m / z 394.2 / 396.2 (M+H)+.

[0651] Intermediate 28: 5-bromo-7-methyl-2-(3-methylpyrrolidin-3-yl)-2H-indazole

[0652]

[0653] To a cooled (0 °C) suspension of Intermediate 27 (2.1 g, 5.33 mmol) in DCM (10 mL), was added HC1 solution in dioxane (4 M, 4 mL). The reaction was stirred at 0 °C for 2 h. The solvent was removed. The product was dissolved in DCM and washed with saturated NaHCO3 solution. The solvent was removed to provided Intermediate 28 (1.4 g, 89%). MS (ESI) m / z 294.2 / 296.1 (M+H)+.

[0654] Intermediate 29: 5-bromo-7-methyl-2-(3-methyl- l-(pyri din-2 -yl)pyrrolidin-3-yl)-2H-indazole

[0655]

[0656] Me

[0657] To a solution of the above obtained Intermediate 28 (500 mg, 1.16 mmol) in DMF (8 mL), were added 2-fluoropyridine (224 mg, 2.31 mmol) and K2CO3 (640 mg, 4.62 mmol). The reaction was stirred at 100 °C for 16 h. After cooled to rt, ice water was added to form a precipitate, which was collected by filtration. Normal phase chromatography purification afforded Intermediate 29 (350 mg, 80%). MS (ESI) m / z 371.2 / 373.2 (M+H)+.

[0658] Intermediate 30: 6-(3-(5-bromo-7-methyl-2H-indazol-2-yl)-3-methylpyrrolidin-l-yl)picolinonitrile

[0659]

[0660] Following the same procedure as the synthesis of Intermediate 29 using 6-fluoropicolinonitrile, Intermediate 30 was obtained in 63% yield. MS (ESI) m / z 396.0 / 398.0 (M+H)+.Intermediate 31: 3 -(3 -(5 -bromo-7-methyl-2H-indazol-2-yl)-3 -methylpyrrolidin- 1 -yl)benzonitrile

[0661] B(OH)2

[0662]

[0663] To a suspension of Intermediate 28 (700 mg, 1.62 mmol), (3-cyanophenyl)boronic acid (475 mg, 3.24 mmol) and Cu(OAc)2 (320 mg, 1.62 mmol) in DCM (20 mL), were added pyridine (0.13 mL, 1.62 mmol) and molecular sieves. The reaction vessel was purged with oxygen and kept under oxygen atmosphere white stirring at rt for 16 h. The reaction was filtered through celite rinsing with EtOAc. The solvent was removed. Normal phase chromatography purification afforded Intermediate 31 (330 mg, 31%). MS (ESI) m / z 396.0 (M+H)+.

[0664] Intermediate 32: (5)-3-(3-hydroxypiperidin-l-yl)benzonitrile

[0665]

[0666] To a stirred solution of (5)-piperi din-3 -ol (0.61 g, 6.04 mmol) and 3-bromobenzonitrile (1.0 g, 5.49 mmol) in 1,4-dioxane (15 mL), was added Cs2CO3 (3.58 g, 11.0 mmol). After purging with N2, Ruphos-Pd-G2 (0.64 g, 0.82 mmol) was added. The reaction was heated at 100 °C for 16 h. The reaction mass was filter through celite washing with EtOAc (100 mL). The solvent was removed. Purification by normal phase chromatography afforded Intermediate 32 (400 mg, 36%). MS (ESI) m / z 203.1.0 (M+H)+.

[0667] Intermediate 33: (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)piperidin-l-yl)benzonitrile

[0668]

[0669] To a stirred solution of Intermediate 32 (552 mg, 2.73 mmol), 5-bromo-7-methyl-2H-indazole (320 mg, 1.52 mmol) in toluene (5.0 mL), was added 2-(tributylphosphoranylidene) acetonitrile (1.69 mL, 4.55 mmol). The reaction was heated at 80 °C for 16 h. The solvent was removed. Normal phase chromatography afforded Intermediate 33 (140 mg, 20%). MS (ESI) m / z 395.0 (M+H)+.

[0670] Intermediate 34: rac-tert-butyl (3S,4S)-3-(5-bromo-7-methyl-2H-indazol-2-yl)-4- hydroxypyrrolidine- 1 -carboxylate

[0671] BocN

[0672]

[0673] To a solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (290 mg, 1.56 mmol) in DMF (3 mL), was added 5-bromo-7-methyl-1H-indazole (300 mg, 1.42 mmol), followed by the addition of K2CO3 (196 mg, 1.42 mmol). The reaction was stirred under N2 at 80 °C for 5 h. The reaction was filtered, and the solvent was removed. The crude product was purified by normal phase chromatography to provide Intermediate 34 (422 mg, 75%). MS (ESI) m / z 395.9 / 397.9 (M+H)+. 'H NMR (500 MHz, CDCI3) 67.87 (br d, J=3.5 Hz, 1H), 7.65 (s, 1H), 7.19 - 7.14 (m, 1H), 4.89 (br dd, J=10.3, 5.8 Hz, 1H), 4.79 (q, J=6.0 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.01 - 3.81 (m, 2H), 3.46 (br s, 1H), 2.58 (s, 3H), 1.52 (s, 9H).

[0674] Intermediate 35: Rac-(3S,4S)-4-(5-bromo-7-methyl-2H-indazol-2-yl)-l-(pyridin-2-

[0675]

[0676] To a solution of Intermediate 34 (100 mg, 0.25 mmol) in DCM (1.5 mL), was added TFA (0.5 mL, 6.49 mmol). The reaction was stirred at rt for 30 min. The solvent was removed. The intermediate was dissolved in DMF (2 mL), and then K2CO3 (105 mg, 0.76 mmol) was added followed by the addition of 2-fluoropyridine (73.5 mg, 0.76 mmol) at rt. The reaction was stirred under N2 at 90 °C overnight. The crude product was purified by reverse phase chromatography to afford Intermediate 34 (48 mg, 51%). MS (ESI) m / z 372.9 / 374.9(M+H)+.

[0677] Intermediate 36: 4-(4-bromophenyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0678]

[0679] To a suspension of 4-(4-bromophenyl)-lH-l,2,4-triazol-5(4H)-one (1.0 g, 4.17 mmol) in DMF (4 mL), was added iodomethane (0.31 mL, 5.0 mmol), followed by the addition of K2CO3 (1.15 g, 8.33 mmol) at rt. The reaction was stirred at 50 °C for 2 h. The suspension was diluted with NH4Cl solution. Solid was collected by filtration rinsing with H2O to give Intermediate 36 as a white solid (1.06 g, 100%). MS (ESI) m / z 253.9 / 255.9 (M+H)+. 'H NMR (500 MHz, CDCh) 67.69 (s, 1H), 7.65 - 7.60 (m, 2H), 7.50 - 7.46 (m, 2H), 3.56 (s, 3H).

[0680] Intermediate 37: 2-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H- 1,2,4-triazol-3 -one

[0681]

[0682] To a solution of Intermediate 36 (1.06 g, 4.17 mmol) in acetonitrile (20 mL), was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (1.27 g, 5.01 mmol) followed by addition of potassium acetate (0.82 g, 8.34 mmol) and PdCl₂(dppf) (0.31 g, 0.42 mmol). The reaction was stirred under N2 at 90 °C for 4 h. The reaction was cooled to rt. It was filtered through celite and a plug of silica gel washing with EtOAc. Intermediate 37 was obtained in quantitative yield as a light grey solid. Analytically pure product was obtained by normal phase chromatography as a white solid. MS (ESI) m / z 301.9 (M+H)+.1H NMR (500 MHz, CDCl3) δ 7.95 - 7.90 (m, 2H), 7.74 (s, 1H), 7.63 - 7.59 (m, 2H), 3.56 (s, 3H), 1.38 (s, 12H).

[0683] Intermediate 38: l-(4-bromophenyl)-5-methyl-1H-l,2,4-triazole

[0684] HN^ NH2>

[0685] HCI

[0686]

[0687] To a solution of formamidine hydrochloride (1.19 g, 14.8 mmol) in DMF (10 mL) at 0 °C, was added acetyl chloride (1.05 mL, 14.8 mmol), followed by the addition of DIEA (9.38 mL, 53.7 mmol). The reaction was stirred under N2 at rt for 8 h. Then, (4-bromophenyl)hydrazine hydrochloride (3.00 g, 13.42 mmol) and AcOH (60 mL) were addedcarefully. Upon addition, the reaction was heated at 80 °C overnight. Most AcOH was removed. The reaction was diluted with EtOAc, washed with saturated NaHCO3 and brine. The organic phase was dried over Na2SC>4, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Intermediate 38 (1.94 g, 61%). MS (ESI) m / z 237.9 / 239.9(M+H)+. ¹H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.70 - 7.65 (m, 2H), 7.39 - 7.35 (m, 2H), 2.57 (s, 3H).

[0688] Intermediate 39: 5-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH- 1,2,4-triazole

[0689]

[0690] To a solution of Intermediate 38 (1.76 g, 7.39 mmol) in acetonitrile (30 mL), was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (2.06 g, 8.13 mmol), followed by addition of potassium acetate (1.45 g, 14.78 mmol) and PdC12(dppf) (0.27 g, 0.37 mmol). The reaction was stirred under N2 at 90 °C for 4.5 h. The reaction was cooled to rt and was diluted with EtOAc. The crude solution was passed through a celite and silica gel pad rinsing with EtOAc. After removal of the solvents, Intermediate 39 was obtained in quantitative yield as a grey solid, which was used without further purification. MS (ESI) m / z 286.0 (M+H)+.

[0691] Intermediate 40: 2-chloro-5-(5-methyl-1H-l,2,4-triazol-l-yl)pyridine

[0692]

[0693] To a solution of formamidine hydrochloride (0.93 g, 11.5 mmol) in DMF (10 mL) at 0 °C, was added acetyl chloride (0.82 mL, 11.5 mmol) followed by the addition of DIEA (5.5 mL, 31.3 mmol). The reaction was stirred under N2 at rt for 4.5 h. Then 2-chloro-5-hydrazinopyridine (1.5 g, 10.5 mmol) and AcOH (40 mL) were added very carefully. Upon addition, the reaction was heated at 80 °C overnight. Most AcOH was removed. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Intermediate 40 (1.18 g, 58%), as light tan solid. MS (ESI) m / z195.0 (M+H)+. ¹H NMR (500 MHz, CDCl3) δ 8.58 (dd, J=2.8, 0.7 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J=8.5, 2.8 Hz, 1H), 7.54 (dd, J=8.5, 0.6 Hz, 1H), 2.61 (s, 3H).

[0694] Intermediate 41: l-(4-bromophenyl)-5-methyl-1H-pyrazole

[0695]

[0696] To a solution of 3-butyn-2-one (0.91 g, 13.4 mmol) in MeOH (10 mL) at rt, was added (4-bromophenyl)hydrazine hydrochloride (3.0 g, 13.4 mmol) followed by the addition of HC1 (0.2 mL, 2.44 mmol). The reaction was heated with microwave at 120 °C for 30 min. The solvent was removed. The reaction mixture was diluted with EtOAc, washed with 1 M K2HPO4 and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Intermediate 41 (785 mg, 25%). MS (ESI) m / z 236.9 / 238.9 (M+H)+. ¹H NMR (500 MHz, CDCl3) δ 7.66 - 7.58 (m, 3H), 7.39 - 7.34 (m, 2H), 6.24 (s, 1H), 2.38 (s, 3H).

[0697] Intermediate 42: 5-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-pyrazole

[0698]

[0699] To a solution of Intermediate 41 (1.57 g, 6.62 mmol) in acetonitrile (20 mL), was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.02 g, 7.95 mmol) followed by the addition of potassium acetate (1.30 g, 13.24 mmol) and PdC12(dppf) (0.49 g, 0.66 mmol). The reaction was stirred under N2 at 90 °C for 2 h. The reaction was diluted with EtOAc. The solution was filtered through a pad of silica gel. The solvent was removed to provide crude Intermediate 42 as a solid (2.8 g), which was used without further purification. MS (ESI) m / z 284.8 (M+H)+.

[0700] Intermediate 43: 4-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H- 1,2,4-triazol-3 -one

[0701]

[0702] To a mixture of 4-(4-bromophenyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1.23 g, 4.84 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.84 g, 7.26mmol) and potassium acetate (1.43 g, 14.5 mmol) in dioxane (10 mL) in a pressure vial, was added Xphos-Pd-G2 (0.38 g, 0.48 mmol). The reaction mixture was heated at 100 °C overnight. The mixture was purified by normal phase chromatography to give Intermediate 43 (1.42 g, 97%). MS (ESI) m / z 301.7 (M+H)+.

[0703] Intermediate 44: 5-(4-bromophenyl)-l-methyl-1H-l,2,4-triazole

[0704] MeNHNH

[0705] OMe >

[0706]

[0707] A mixture of 4-bromobenzamide (3.0 g, 15.0 mmol) and 1,1 -dimethoxy -N, N-dimethylmethanamine (19.9 mL, 150 mmol) was heated under argon at 120 °C for 1.5 h. The methanol formed during the reaction was collected through a distillation head. The reaction mixture was allowed to cool, and the excess of DMF-DMA was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (75 ml) and hexane (50 ml) to give 4-bromo-N-((dimethylamino)methylene)benzamide as white crystals. The intermediate was dissolved in AcOH (15 mL), which was treated with methylhydrazine (1.75 mL, 33.0 mmol). The solution was heated at 90 °C for 4 h. The solvent was removed. The residual oil was diluted with ethyl acetate. The organic solution was washed with saturated NaHCO3, brine, dried over MgSC>4, filtered and concentrated. Purification by normal phase chromatography provided Intermediate 44 (1.57 g, 44%). MS (ESI) m / z 238 / 240 (M+H)+.

[0708] Intermediate 45: 4-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H- 1,2,4-triazol-3 -one

[0709] J \

[0710] .6

[0711]

[0712] A mixture of Intermediate 44 (1.57 g, 6.59 mmol), bispin (2.01 g, 7.91 mmol) and KOAc (1.29 g, 13.2 mmol) in 1,4-dioxane (30 mL) was purged with argon. Then PdC12(dppf) (0.48 g, 0.66 mmol) was added. The reaction was heated at 90 °C for 16 h. Ice water (5 mL) was added, followed by dilution of the reaction mixture with EtOAc. The organic layer was separated and dried over Na2SC>4, filtered, and the filtrate was concentrated. Purification by normal phase chromatography provided Intermediate 45 (1.8 g, 95%). MS (ESI) m / z 286.1 (M+H)+. 'H-NMR (400 MHz, DMSO-d6): 88.02 (s, 1H), 7.79-7.84 (m, 4H), 3.99 (s, 3H), 1.33 (s, 12H).Intermediate 46: 4-(4-bromophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0713] NH2

[0714]

[0715] A pressure vessel was charged with 4-bromoaniline (2.0 g, 11.6 mmol), methyl hydrazinocarboxylate (1.26 g, 14.0 mmol), triethyl orthoacetate (2.26 g, 14.0 mmol), and pTsOH (0.2 g, 1.05 mmol) and n-butanol (29 ml). The reaction was heated at 120 °C overnight.

[0716] The reaction mixture was cooled to rt and concentrated. The resultant residue was partitioned with ethyl acetate and cold water. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. Normal phase chromatography provided Intermediate 46 (1.28 g, 43%). MS (ESI) m / z 253.7 / 255.7 (M+H)+.

[0717] Intermediate 47: 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0718]

[0719] To a mixture of Intermediate 46 (2.0 g, 7.87 mmol) in DMF (10 mL) at 0 °C, was added NaH (60%, 0.47 g, 11.8 mmol). After stirring for 30 min, iodomethane (1.48 mL, 23.6 mmol) was added. The reaction was stirred at rt for 18 h. It was carefully added to ice-water. It was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. Normal phase chromatography afforded Intermediate 47 (2.1 g, 99%). MS (ESI) m / z 268.0 / 270.0 (M+H)+.

[0720] Intermediate 48: 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 2,4-dihydro-3H- 1,2,4-triazol-3 -one

[0721]

[0722] To a mixture of Intermediate 47 (360 mg, 1.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (546 mg, 2.15 mmol) and potassium acetate (395 mg, 4.03 mmol) in dioxane (6 mL), was added PdC12(dppf) (196 mg, 0.27 mmol). Thereaction was heated to 90 °C for 2 h. Purification by normal phase chromatography Intermediate 48 (315 mg, 74%) as a light brown solid. MS (ESI) m / z 315.8 (M+H)+.

[0723] Intermediate 49: tert-butyl (5)-(2-oxo-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)carbamate

[0724]

[0725] Step a: tert-butyl (S)-(l-((4-bromophenyl)amino)-4-hydroxy-l-oxobutan-2-yl)carbamate A solution of 4-bromoaniline (1.0 g, 5.81 mmol) in DCM (30 mL) at 0 °C was treated with AlMes (2 M in toluene, 3.49 mL, 6.98 mmol) dropwise under N2. The mixture was stirred for 30 min before adding dropwise a solution of tert-butyl (S)-(2-oxotetrahydrofuran-3-yl)carbamate (1.40 g, 6.98 mmol) in anhydrous DCM (35 ml). The reaction was allowed to warm up to rt and stirred for 18 h. The organic layer was dried over MgSC>4, filtered, and concentrated. Normal phase chromatography provided 49a (1.1 g, 41%). MS (ESI) m / z 317 (M-55)+. ‘HNMR (400 MHz, DMSO-d6) 6 10.04 (s, 1H), 7.61-7.57 (m, 2H), 7.50-7.46 (m, 2H), 4.56 (d, J = 4.8 Hz, 1H), 4.33-4.11 (m, 2H), 3.48-3.44 (m, 2H), 1.82-1.70 (m, 2H), 1.39 (s, 9H).

[0726] Step b: tert-butyl (5)-(l-(4-bromophenyl)-2-oxopyrrolidin-3-yl)carbamate

[0727] To a stirred solution of 49a (100 mg, 0.27 mmol) in toluene (4 mL), 2-(tributylphosphoranylidene)-acetonitrile (0.1 mL, 0.35 mmol) was added. The reaction was heated at 80 °C for 16 h. The solvent was removed. Purification by normal phase chromatography afforded 49b (70 mg, 63%). MS (ESI) m / z 299 (M-55)+. ¹H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.8 Hz, 2H), 7.59-7.55 (m, 2H), 7.27-7.25 (bs, 1H), 4.82-4.70 (m, 1H), 3.74-3.70 (m, 2H), 2.36-2.31 (m, 1H), 1.99-1.91 (m, 1H), 1.41 (s, 9H).

[0728] Step c: tert-butyl (5)-(2-oxo-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)carbamateTo a stirred solution of 49b (530 mg, 1.49 mmol) in 1,4-dioxane (10 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (568 mg, 2.24 mmol) and KOAc (439 mg, 4.48 mmol) were added. The reaction mixture was degassed for 5 min with N2 and Xphos-Pd-G2 (58.7 mg, 0.075 mmol) was added. The reaction was heated at 100 °C for 16 h. It was concentrated under reduced pressure. The crude product was purified by normal phase chromatography to give Intermediate 49 (572 mg, 35%). MS (ESI) m / z 347 (M-55)+.

[0729] Intermediate 50: tert-butyl (A)-(2-oxo-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)carbamate

[0730] NHBoc

[0731]

[0732] Intermediate 50 was prepared in a similar procedure to that described in Intermediate 49.

[0733] Intermediate 51: (5)-3-((tert-butyldiphenylsilyl)oxy)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

[0734] O O

[0735] 51a

[0736]

[0737] Step a: (5)-3-((tert-butyldiphenylsilyl)oxy)dihydrofuran-2(3H)-one

[0738] A flask was charged with (5)-3-hydroxydihydrofuran-2(3H)-one (500 mg, 4.90 mmol)), imidazole (834 mg, 12.2 mmol)) and anhydrous DCM (10 mL). Then tertbutylchlorodiphenylsilane (1.54 mL, 5.88 mmol) was added. The reaction was stirred at rt for 16 h. The reaction was quenched by adding ice cold water (20 mL), and then diluted with EtOAc The organic layer was separated and dried over Na2SC>4, filtered, and the solvent was removed. Normal phase chromatography provided 51a (1.6 g, 96%).

[0739] Step b: (5)-N-(4-bromophenyl)-2-((tert-butyldiphenylsilyl)oxy)-4-hydroxybutanamideTo a solution of 4-bromoaniline (0.97 g, 5.64 mmol) in DCM (20 mL) at 0 °C was added MesAl (2 M in toluene, 3.52 mL, 7.05 mmol) dropwise. After stirred at rt for 30 min, a solution of 51a (1.6 g, 4.70 mmol) dissolved in DCM (10 ml) was added. The reaction was stirred at rt for 16 h. It was quenched with saturated NH4Cl solution (10 mL) and further diluted with H2O (10 mL). After extraction with ethyl acetate, the combined organic phase was washed with brine and dried over Na2SC>4, filtered and concentrated. Normal phase chromatography provided 51b (2.05 g, 64%). MS (ESI) m / z 512.4 / 514.5 (M+H)+.

[0740] Step c: (5)-l-(4-bromophenyl)-3-((ter / -butyldiphenylsilyl)oxy)pyrrolidin-2-one

[0741] To a solution of di-tert-butyl (E)-azodicarboxylate (3.59 g, 15.6 mmol) in THF (50 mL) was added Bu3P (3.90 mL, 15.6 mmol) dropwise at 0 °C. After stirring at rt for 30 min, a solution of 51b (2.0 g, 3.9 mmol) dissolved in THF (10 mL) was added. The reaction was stirred at rt for 1 h. Ice-cold water was added to quench the reaction. It was extracted with EtOAc. The organic layer was separated and dried over Na2SC>4, filtered and the solvent was removed. Normal phase chromatography purification afforded 51c (1.9 g, 94%). MS (ESI) m / z 416 (M-77)+.

[0742] Step d: (5)-3-((ter / -butyldiphenylsilyl)oxy)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

[0743] To a solution of 51c (1.9 g, 3.84 mmol) in acetonitrile (40 mL) was added bispin (1.27 g, 4.99 mmol) followed by the addition of KOAc (0.75 g, 7.68 mmol) and PdCl2(dppf) (0.28 g, 0.38 mmol). The reaction was stirred at 90 °C for 16 h. To the reaction mixture was partitioned between H2O and EtOAc. The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed. Purification by normal phase chromatography provide Intermediate 51 (2.05 g, 99%). MS (ESI) m / z 541.3 (M+H)+and 464.2 (M-77)+.

[0744] Intermediate 52: (R)-3 -((tert-butyl diphenyl silyl)oxy)- 1 -(4-(4,4, 5, 5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

[0745] o p^Bpin

[0746] TBDPSO-^JNX^^

[0747]

[0748] 62

[0749] Intermediate 52 was prepared in a similar procedure as that described in Intermediate 51.

[0750] Intermediate 53: 2-chloro-5-(5-methyl-1H-pyrazol-l-yl)pyridine

[0751]

[0752] To a solution of 2-chloro-5-iodopyridine (1.0 g, 4.18 mmol) in NMP (8 mL), was added 5-methyl-1h-pyrazole (0.41 g, 5.01 mmol) followed by the addition of Cs2CO3 (2.72 g, 8.35 mmol), cuprous iodide (0.16 g, 0.84 mmol) and L-proline (0.048 g, 0.42 mmol). The reaction was stirred under N2 at 100 °C for 4 h. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SC>4, filtered and concentrated. Normal phase chromatography afforded Intermediate 53 (117 mg, 15%). MS (ESI) m / z 194.0 (M+H)+. ¹H NMR (500 MHz, CDCl3) δ 8.57 (dd, J=2.8, 0.6 Hz, 1H), 7.85 (dd, J=8.6, 2.8 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.48 (dd, J=8.5, 0.7 Hz, 1H), 6.27 (dd, J=1.8, 0.8 Hz, 1H), 2.42 (s, 3H).

[0753] Intermediate 54: 3-(4-bromophenyl)-4-methyl-4H-l,2,4-triazole

[0754]

[0755] A microwave vial containing 4-bromobenzoic hydrazide (1.1 g, 5.3 mmol), DMF-DMA (0.81 mL, 6.4 mmol), and DMF (1.3 mL) was sealed and heated to 130 °C under microwave irradiation for 2 h. The microwave vial was opened, and methylamine HC1 (1.4 g, 21 mmol), and acetic acid (1.8 mL, 32 mmol) were added. The vial was sealed and heated to 130 °C under microwave irradiation for 2 h. The mixture was quenched with IM NaOH (50 mL) and extracted with DCM (2 x 50 mL). Combined organic layers were washed with 10% LiCl (2 x 50 mL) and the organic layer was evaporated under reduced pressure to afford Intermediate 54 (990 mg, 78%) as a tan solid. MS (ESI) m / z 269.6 / 271.7 (M+H)+. ¹H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.98 - 7.90 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 3.77 (s, 3H), 1.37 (s, 12H).

[0756] Intermediate 55: 4-methyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4H- 1,2,4-triazole

[0757]

[0758] A vial containing Intermediate 54 (990 mg, 4.2 mmol), XPhos Pd G2 (330 mg, 0.42 mmol), B2pin2 (1.6 g, 6.2 mmol), KO Ac (1.2 g, 12 mmol), and dioxane (8 mL) was sparged with N2 for 5 minutes, sealed with a septum cap, and heated to 90 °C for 45 min. The crude product was purified by flash chromatography to give Intermediate 55 (550 mg, 47%) as a tan solid. MS (ESI) m / z 285.7 (M+H)+. ¹H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.98 - 7.90 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 3.77 (s, 3H), 1.37 (s, 12H).

[0759] Intermediate 56: 4-(4-bromophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0760]

[0761] To a vial containing 4-(4-bromophenyl)-lH-l,2,4-triazol-5(4H)-one (230 mg, 0.95 mmol), (2-(chloromethoxy)ethyl)trimethylsilane (0.20 mL, 1.1 mmol), and DMF (1.9 mL), was added IM LiHMDS in THF (1.4 mL, 1.4 mmol). The reaction mixture was stirred for 30 min at rt. It was quenched with 100 mL water and 100 mL EtOAc. The organic layer was separated and further washed with brine. The organic layer was concentrated to afford Intermediate 56 (350 mg, 100%). MS (ESI) m / z 341.8 / 343.7 (M+H)+. 'H NMR (500 MHz, CDCh) 6 7.72 (s, 1H), 7.65 - 7.60 (m, 2H), 7.48 (d, J=8.9 Hz, 2H), 5.23 (s, 2H), 3.76 - 3.69 (m, 2H), 1.01 - 0.97 (m, 2H), 0.02 (s, 9H).

[0762] Intermediate 57: 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0763]

[0764] To a vial was added Intermediate 56 (350 mg, 0.95 mmol), XPhos Pd G2 (74 mg, 0.095 mmol), B2pin2 (360 mg, 1.4 mmol), potassium acetate (280 mg, 2.8 mmol) and dioxane (1.9 mL). The reaction mixture was sparged with N2 for 5 minutes, sealed with a septum cap, and heated at 100 °C for 1.5 h. The mixture was purified by silica gel column chromatography with hexanes / EtOAc as the eluant to afford Intermediate 57 (220 mg, 57%yield over two steps) as a light brown solid.1H NMR (500 MHz, CDCh) 67.91 (d, J=8.5 Hz, 2H), 7.76 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 5.23 (s, 2H), 3.74 - 3.68 (m, 2H), 1.35 (s, 12H), 1.01 - 0.96 (m, 2H), 0.01 - 0.00 (m, 9H).

[0765] Intermediate 58: (5)-3 -hydroxy- l-(4-iodophenyl)pyrrolidin-2-one

[0766]

[0767] To a solution of (5)-3-hydroxypyrrolidin-2-one (400 mg, 3.96 mmol) and 1-bromo-4-iodobenzene (1.23 g, 4.35 mmol) in 1,4-dioxane (4 mL), K3PO4 (1680 mg, 7.91 mmol), Cui (75 mg, 0.40 mmol) and N, N'-dimethyl-l,2-cyclohexanediamine (113 mg, 0.79 mmol) were added. The reaction was stirred at 110 °C for 16 h. Water was added to quench the reaction. It was extracted with EtOAc. The organic layer was separated and dried over Na2SC>4, filtered and concentrated. Purification by normal phase chromatography provided Intermediate 58 (300 mg, 25%). MS (ESI) m / z 304.0 (M+H)+.

[0768] Intermediate 59: (A)-3 -hydroxy- l-(4-iodophenyl)pyrrolidin-2-one

[0769]

[0770] Intermediate 59 was prepared in a similar procedure to that described in Intermediate 58. MS (ESI) m / z 303.9 (M+H)+.

[0771] Intermediate 60: l-(4-iodophenyl)piperazin-2-one

[0772]

[0773] To a solution of piperazin-2-one (1.0 g, 9.99 mmol) and l-bromo-4-iodobenzene (3.11 g, 11.0 mmol) in 1,4-dioxane (10 mL), K3PO4 (4.24 g, 20.0 mmol), Cui (0.19 g, 1.0 mmol) andN, N'-dimethyl-l,2-cyclohexanediamine (0.28 g, 2.0 mmol) were added. The reaction was heated at 110 °C for 16 h. Water was added to the reaction, and it was extracted with EtOAc. The organic layer was separated and dried over Na2SO4, filtered and the solventwas removed. The crude product was triturated and washed with pet ether and diethyl ether to afford Intermediate 60 (2.5 g, 44%). MS (ESI) m / z 302.9 (M+H)+.

[0774] Intermediate 61: l-(4-iodophenyl)-4-methylpiperazin-2-one

[0775] o

[0776] Br— \j—

[0777]

[0778] To a solution of Intermediate 60 (500 mg, 1.66 mmol) in DCM (5 mL), were added formaldehyde (0.46 mL, 4.96 mmol) and NaBH(OAc)3 (526 mg, 2.48 mmol). The reaction was stirred at rt for 3 h. Water was added to the reaction, and it was extracted with EtOAc. The organic layer was dried over Na2SC>4, filtered and concentrated. The crude product was triturated and washed with petroleum ether and diethyl ether to afford Intermediate 61 (510 mg, 100%). MS (ESI) m / z 317.2 (M+H)+.

[0779] Intermediate 62: (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)-3-methylpyrrolidin-l-yl)-2-fluorobenzonitrile

[0780]

[0781] Step 62a: / c / 7-butyl (A)-(l-(3-cyano-2-fluorophenyl)-3-methylpyrrolidin-3-yl)carbamate To a stirred solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and tert-butyl (A)-(3-methylpyrrolidin-3-yl)carbamate, HC1 salt (2.37 g, 10.00 mmol) in 1,4-dioxane (5.0 mL), Cs2CO3 (8.15 g, 25.0 mmol) was added followed by the addition Pd2(dba)3 (0.92 g, 1.00 mmol) and xantphos (1.16 g, 2.00 mmol). The reaction was heated at 85 °C for 16 h. The reaction was filter through celite washing with EtOAc. The solvent was removed. Flash chromatography afforded Intermediate 62a (2.25 g, 69%) as a yellow solid. MS (ESI) m / z 320.0 (M+H)+.

[0782] Step 62b: (R)-3-(3-amino-3-methylpyrrolidin-l-yl)-2-fluorobenzonitrileTo a stirred solution of Intermediate 62a (4.5 g, 14.1 mmol) in DCM (10.0 mL), was added TFA (10.0 mL, 130 mmol) dropwise. The reaction was stirred at rt for 3 h. The solvent and excess TFA were removed. The crude product was dissolved in water (100 mL) and neutralized with saturated NaHCO3 solution. The mixture was then extracted with DCM. The organic phase was dried over Na2SC>4, filtered and concentrated to give Intermediate 62b (3.0 g, 97%) as a brown viscous liquid. MS (ESI) m / z 220.0 (M+H)+.

[0783] Step 62c: (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)-3-methylpyrrolidin-l-yl)-2-fluorobenzonitrile

[0784]

[0785] A mixture of Intermediate 62b (1.2 g, 5.47 mmol), Intermediate 13 (1.31 g, 5.47 mmol) and CU2O (0.078 g, 0.55 mmol) in DCE (25.0 mL) was heated at 80 °C for 16 h. The mixture was filter through celite washing with EtOAc. The organic phase was concentrated. The crude product was purified by normal phase chromatography to give Intermediate 62c (1.0 g, 43%) as abrown solid. MS (ESI) m / z 413.1 / 415.1 (M+H)+. ¹H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 7.74 (dd, J = 0.80, 1.80 Hz, 1H), 7.18-7.16 (m, 1H), 7.13-7.12 (m, 1H), 7.10-7.09 (m, 2H), 4.32 (dd, J = 2.40, 10.40 Hz, 1H), 3.83 (dd, J = 2.40, 10.60 Hz, 1H), 3.62-3.54 (m, 2H), 2.94-2.91 (m, 1H), 2.51 (s, 3H), 2.50-2.43 (m, 1H), 1.79 (s, 3H).

[0786] Step 62d: (A)-3-(3-(5-bromo-7-methyl-2H-indazol-2-yl)-3-methylpyrrolidin-l-yl)-2-fluorobenzamide

[0787]

[0788] To a stirred solution of Intermediate 62c (200 mg, 0.48 mmol) in DMSO (3.0 mL), were added K2CO3 (400 mg, 2.90 mmol) and H2O2 (30% aq. solution, 0.30 mL, 2.90 mmol) at rt. The reaction was stirred at rt for 7 h. Ice cold water was added to form a precipitate,which was collected by filtration to afforded Intermediate 62 (200 mg, 92%) as an off-white solid. MS (ESI) m / z 431.0 / 433.0 (M+H)+.

[0789] Intermediate 63: (R)-3 -(3 -(5 -bromo-7 -fluoro-2H-indazol-2-yl)-3 -methylpyrrolidin- 1 -yl)-2-

[0790] fluorob enzami

[0791]

[0792] de

[0793] Intermediate 63 was prepared by following the same procedure as that described in Intermediate 62 by using Intermediate 12 in Step 62c. MS (ESI) m / z 435.0 / 437.0 (M+H)+.

[0794] Intermediate 64: tert-butyl (A)-3-(7-fluoro-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[0795]

[0796] To a solution of Intermediate 24 (300 mg, 0.781 mmol) in dioxane (5 mL) and H2O (1 mL), 4-(l -Methyl- lh-imidazol-2-yl)phenylboronic acid (173 mg, 0.86 mmol) was added followed by the addition of K3PO4 (414 mg, 1.95 mmol) and XPhos-Pd-G2 (61 mg, 0.078 mmol). The reaction was stirred under N2 at 90 °C for 1 h. The reaction was diluted with EtOAc. The organic phase was separated and filtered through a plug of silica gel and celite. The solvent was removed. The crude product was purified by normal phase chromatography to provide Intermediate 64 (310 mg, 86%). MS (ESI) m / z 462.2 (M+H)+.

[0797] Intermediate 65: (A)-7-fluoro-5-(4-(l -methyl- IH-imidazol -2 -yl)phenyl)-2-(pyrrolidin-3-yl)- 2H-indazole, HC1 salt

[0798]

[0799] To a vial charged with Intermediate 64 (100 mg, 0.22 mmol), 4 M HC1 in dioxane (1.0 mL, 4.00 mmol) was added. The reaction was stirred at 50 °C for 30 min. The solvent was removed to give a solid of Intermediate 65 (94 mg, 100%). MS (ESI) m / z 361.9 (M+H)+.

[0800] Intermediate 66: tert-butyl (7?)-3-(7-fluoro-5-(4-(5-oxo-l,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[0801]

[0802] To a solution of Intermediate 24 (300 mg, 0.781 mmol) in dioxane (5 mL) / H20 (1 mL), was added 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (336 mg, 1.17 mmol), followed by the addition of K3PO4 (414 mg, 1.95 mmol) and XPhos-Pd-G2 (61 mg, 0.078 mmol) at rt. The reaction was stirred under N2 at 90 °C for 1 h. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 66 (285 mg, 79%). MS (ESI) m / z 465.1 (M+H)+.

[0803] Intermediate 67: (R)-4-(4-(7-fluoro-2-(pyrrolidin-3-yl)-2H-indazol-5-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, HC1 salt

[0804] F

[0805]

[0806] To a suspension of Intermediate 66 (100 mg, 0.215 mmol) in dioxane (0.5 mL), was added 4 M HC1 in dioxane (1.0 mL, 4.00 mmol) at rt. The suspension was stirred at 50 °C for 30 min. The solvent was removed to provide a solid of Intermediate 67 (86 mg, 100%) as an off-white solid. MS (ESI) m / z 364.9 (M+H)+.

[0807] Intermediate 68: rac-tert-butyl (3R,4S)-3-(5-bromo-7-methyl-2H-indazol-2-yl)-4-methylpyrrolidine- 1 -carboxylate

[0808]

[0809] cis- racTo a vial containing 5-bromo-7-methyl-1H-indazole (280 mg, 1.33 mmol) and tert-butyl(3.s,4.s)-3-hydroxy-4-methyl-pyrrolidine-l -carboxylate (294 mg, 1.46 mmol), was added 2-(tributylphosphoranylidene)acetonitrile (2.65 mL, 2.65 mmol) (1 M in toluene). The reaction was stirred under N2 at 80 °C for overnight. The crude product was purified by normal phase chromatography to afford Intermediate 68 (150 mg, 29%). MS (ESI) m / z 394.0 / 395.7 (M+H)+.

[0810] Intermediate 69: rac-tert-butyl (3A,45)-3-methyl-4-(7-methyl-5-(4-(1-methyl-5-oxo-l,5-dihydro-4H- 1,2,4-triazol-4-yl)phenyl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[0811]

[0812] To a solution of Intermediate 68 (150 mg, 0.380 mmol) in dioxane (3 mL),was added Intermediate 43 (137 mg, 0.46 mmol), followed by the addition of K3PO4 (2 M aq. solution, 0.48 mL, 0.96 mmol) and PdC12(dppf) (28 mg, 0.038 mmol). The reaction was stirred under N2 at 90 °C for 1 h. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 69 (41 mg, 22%). MS (ESI) m / z 489.2 (M+H)+.

[0813] Intermediate 70: rac-2-methyl-4-(4-(7-methyl-2-((3R,4S)-4-methylpyrrolidin-3-yl)-2H-indazol-5-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, TFA salt

[0814]

[0815] To a solution of Intermediate 69 (41 mg, 0.084 mmol) in DCM (0.5 mL), was added TFA (0.2 mL, 2.60 mmol). The reaction was stirred under N2 at rt for 1 h. The solvent was removed to provide Intermediate 70 (42 mg, 100%). MS (ESI) m / z 389.1 (M+H)+.

[0816] Intermediate 71: tert-butyl (A)-3-(7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[0817]

[0818] To a solution of Intermediate 6 (1.05 g, 2.76 mmol) in acetonitrile (10 mL), was added bis(pinacolato)diboron (0.84 g, 3.31 mmol), followed by the addition of KOAc (0.54 g, 5.52 mmol) and PdC12(dppf) (0.10 g, 0.14 mmol) at rt. The reaction was stirred under N2 at 90 °C for 4 h. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 71 (1.12 g, 95%). MS (ESI) m / z 428.1 (M+H)+. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (s, 1H), 7.97 (s, 1H), 7.46 (s, 1H), 5.33 - 5.27 (m, 1H), 4.01 -3.83 (m, 2H), 3.73 - 3.54 (m, 2H), 2.64 (s, 3H), 2.58 - 2.52 (m, 2H), 1.51 (br s, 9H), 1.38 (s, 12H).

[0819] Intermediate 72: tert-butyl (A)-3-(7-methyl-5-(5-(5-methyl-1H-l,2,4-triazol-l-yl)pyridin-2-yl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[0820]

[0821] To a solution of Intermediate 71 (110 mg, 0.257 mmol) in dioxane (2 mL), was added Intermediate 40 (50 mg, 0.26 mmol) followed by the addition of K3PO4 (0.32 mL, 0.64 mmol) and XPhos-Pd-G2 (20.2 mg, 0.026 mmol). The reaction was stirred under N2 at 90 °C for 2 h. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 72 (46 mg, 39%). MS (ESI) m / z 460.2 (M+H)+.

[0822] Intermediate 73: (A)-7-methyl-5-(5-(5-methyl-1H-l,2,4-triazol-l-yl)pyridin-2-yl)-2- (pyrrolidin-3-yl)-2H-indazole, TFA salt

[0823]

[0824] To a solution of Intermediate 72 (46 mg, 0.10 mmol) in DCM (0.5 mL), was added TFA (0.25 mL, 3.24 mmol). The reaction was stirred under N2 at rt for 30 min. The solvent was removed. The crude product was purified by reverse phase chromatography to afford Intermediate 73 (59 mg, 100%). MS (ESI) m / z 360.1 (M+H)+.Intermediate 74: tert-butyl (3S,4S)-3-(5-bromo-7-methyl-2H-indazol-2-yl)-4-methoxypyrrolidine- 1 -carboxylate

[0825]

[0826] To a stirred solution of Intermediate 68 (1.15 g, 2.90 mmol) in THF (3 mL), NaH (60%, 0.14 g, 3.48 mmol) and methyl iodide (0.36 mL, 5.80 mmol) were added. The reaction was stirred at rt for 2 h. The reaction was quenched carefully with water. It was extracted with EtOAc. The organic phase was concentrated. Normal phase chromatography provided Intermediate 74 (1.30 g, 100%) as a solid. MS (ESI) m / z 410.0 / 412.0 (M+H)+.

[0827] Intermediate 75: 5-bromo-2-((3S,4S)-4-methoxypyrrolidin-3-yl)-7-methyl-2H-indazole

[0828]

[0829] To a stirred solution of Intermediate 74 (1.3 g, 3.17 mmol) in DCM (10 mL), TFA (0.244 mL, 3.17 mmol) was added. The reaction mixture stirred at rt for 16 h. The solvent and excess of TFA were removed to afford Intermediate 75 in quantitative yield. MS (ESI) m / z 310.0 / 312.0 (M+H)+.

[0830] Intermediate 76: 3-((3S,4S)-3-(5-bromo-7-methyl-2H-indazol-2-yl)-4-methoxypyrrolidin-l-yl)benzonitrile

[0831]

[0832] To a stirred solution of Intermediate 75 (730 mg, 2.353 mmol) in NMP (3 mL), 3-iodobenzonitrile (808 mg, 3.53 mmol) and Cs2CO3 (1.92 g, 5.88 mmol) were added. The reaction mixture was degassed for 10 min with N2, then L-proline (325 mg, 2.82 mmol) and Cui (90 mg, 0.471 mmol) were added. The reaction was heated at 100 °C for 16 h. The reaction was diluted with EtOAc, washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated. Normal phase chromatography afforded Intermediate 76 (120 mg, 11%). (ESI) m / z 411.0 / 413.0 (M+H)+.Intermediate 77: (A)-7-methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2-(pyrrolidin- 3-yl)-2H-indazole, TFA salt

[0833]

[0834] Step 77a: / c / 7-butyl (A)-3-(7-methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[0835] To a solution of Intermediate 6 (250 mg, 0.66 mmol) in dioxane (5 mL), was added Intermediate 55 (225 mg, 0.79 mmol) followed by the addition of K3PO4 (1.0 mL, 2.0 mmol) and PdC12(dppf) (48 mg, 0.066 mmol). The reaction was stirred under N2 at 90 °C for 1 h. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 77a (285 mg, 95%). MS (ESI) m / z 459.2 (M+H)+.

[0836] Step 77b: (A)-7-methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2-(pyrrolidin-3-yl)-2H-indazole, TFA salt

[0837] To a solution of Intermediate 77a (285 mg, 0.622 mmol) in DCM (2 mL), was added TFA (1 mL, 13 mmol). The reaction was stirred under N2 at rt for 1 h. The solvent was removed. After drying under vacuum, Intermediate 77 was obtained in quantitative yield. MS (ESI) m / z 359.1 (M+H)+.

[0838] Intermediate 78: (A)-3-(3-(7-methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzoic acid

[0839]

[0840] Step 78a: methyl (R)-3-(3-(7- methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzoate

[0841] To a solution of Intermediate 77 (300 mg, 0.51 mmol) in dioxane (10 mL), was added methyl 3 -bromobenzoate (220 mg, 1.02 mmol), followed by the addition of Cs2CO3 (500 mg, 1.535 mmol) and RuPhos-Pd-G3 (43 mg, 0.051 mmol). The reaction was stirred under N2 at 85 °C overnight. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 78a (210 mg, 83%). MS (ESI) m / z 493.2 (M+H)+.

[0842] Step 78b: (R)-3-(3-(7- methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzoic acid

[0843] To a solution of methyl Intermediate 78a (210 mg, 0.43 mmol) in THF (3 mL), was added LiOH (51 mg, 2.13 mmol), followed by the addition of H2O (1 mL). The reaction was stirred under N2 at rt for 2 days. The reaction was neutralized with 1.0 N HC1 solution. The solvent was removed. The product was dried under vacuum and used without further workup. MS (ESI) m / z 479.2 (M+H)+.

[0844] Intermediate 79: rac-3-((3R,4R)-3-hydroxy-4-(7-methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzoic acid

[0845]

[0846] Intermediate 79 was prepared by following the same procedure as that described in Intermediate 78 by using Intermediate 68 and 55. MS (ESI) m / z 495.2 (M+H)+.

[0847] Intermediate 80: (R)-3-(3-(7-methyl-5-(5-(5-methyl-1H-l,2,4-triazol-l-yl)pyridin-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzoic acid

[0848]

[0849] Intermediate 80 was prepared by following the same procedure as that described in Intermediate 78 by using Intermediate 73. MS (ESI) m / z 480.2 (M+H)+.

[0850] SYNTHESIS OF EXAMPLES:

[0851] Example 1-1: (R)-7V,7V-dimethyl-4-(2-(l -(pyri din-2 -yl)pyrrolidin-3-yl)-2H-indazol-5-yl)benzamide, TFA salt

[0852]

[0853] To a solution of Intermediate 3 (20 mg, 0.058 mmol) in dioxane (1 mL) and H2O (0.1 mL), was added (4-(dimethylcarbamoyl)phenyl)boronic acid (23 mg, 0.12 mmol), followed by the addition of K3PO4 (37 mg, 0.18 mmol) and PdC12(dppf) (4.3 mg, 0.0058 mmol). The reaction was stirred under N2 at 80 °C for 2 h. The solvent was removed. The crude product was purified by reverse phase chromatography to give Example 1-1 (27 mg, 89%). MS (ESI) m / z 412.2 (M+H)+. ¹H NMR (500MHz, DMSO-d₆, ppm) δ 8.61 (s, 1H), 8.07 (d, J=5.8 Hz, 1H), 8.05 (s, 1H), 7.88 (br t, J=7.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.72 (d, J=9.0 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.02 - 6.97 (m, 1H), 6.86 (br t, J=6.1 Hz, 1H), 5.65 - 5.57 (m, 1H), 4.19 - 4.12 (m, 1H), 4.07 (br dd, J=11.6, 3.5 Hz, 1H), 3.89 - 3.83 (m, 1H), 3.80 - 3.74 (m, 1H), 2.99 (br d, J=l.l Hz, 6H), 2.75 - 2.60 (m, 2H). Analytical HPLC: RT = 1.18 min (Method E) and 1.61 min (Method F).

[0854] The examples listed in Table 1 were prepared following this general procedure described in Example 1-1 from the appropriate commercially available starting substances and / orintermediates described above. Palladium catalyzed reactions, such as Suzuki coupling reaction, were performed using PdCl₂(dppf), or other appropriate catalysts, such as Xphos- Pd-G2, Xphos-Pd-G3, etc., in suitable solvents, such as dioxane, toluene, DMF, DMSO, H2O, Q

[0855] etc., at various temperatures. Removal of the common protection groups, wherever necessary, k X z—* _

[0856] were carried out using literature methods except otherwise stated. Enantiomers were obtained in some examples by resolving the racemates with chiral SFC chromatography using the appropriate chiral columns and solvents as eluents.

[0857] Table 1.

[0858] HPLC LCMS Method,

[0859] Ex# Structure NameJHNMR(5 ppm)

[0860] (M+H)+ RT

[0861] (min.)

[0862] (400 MHz, CD3OD, ppm) δ 8.42 (s, 1H), 8.08 (ddd, °=f J=9.1, 7.2, 1.7 Hz, 1H),

[0863] (R)-N, N- 7.98 (dt, J=6.5, 0.8 Hz, dimethyl-4- 1H), 7.81 (d, J=0.9 Hz, (7-methyl-2- 1H), 7.77 - 7.72 (m, 2H), (l-(pyridin- 7.54 - 7.49 (m, 2H), 7.42 - 1-2 2- 426.2 C: 1.22 7.36 (m, 1H), 7.24 (d,

[0864] yl)pyrrolidin D: 1.72 J=9.3 Hz, 1H), 7.07 - 6.99 -3-yl)-2H- (m, 1H), 5.72 - 5.58 (m, indazol-5- 1H), 4.34 - 4.19 (m, 2H), d yl)benzamid 4.14 - 4.04 (m, 1H), 3.92

[0865] e, TFA salt (ddd, J=10.1, 8.1, 5.2 Hz,

[0866] 1H), 3.20 - 3.04 (m, 6H), 2.94 - 2.70 (m, 2H), 2.58 (s, 3H).

[0867] (400MHz, DMSO-d6, ppm) δ 8.54 (s, 1H), 8.16 (S)-N, N- (s, 1.3 FA salt), 8.11-8.09 dimethyl-4- (m, 1H), 8.03-8.02 (m, (2-(l- 1H), 7.75-7.70 (m, 3H), (pyridin-2- 7.61 (dd, JI = 1.6 Hz, J2 = 1-3 yl)pyrrolidin 412.0 G: 1.46 8.8 Hz, 1H), 7.54-7.48 (m, -3-yl)-2H- 3H), 6.61-6.58 (m, 1H), indazol-5- 6.54 (d, J = 8.8 Hz, 1H), yl)benzamid 5.52-5.46 (m, 1H), 4.05- e 4.00 (m, 1H), 3.95-3.92

[0868] (m, 1H), 3.77-3.71 (m,

[0869]

[0870] 1H), 3.66-3.61 (m, 1H),HPLC

[0871] LCMS Method,

[0872] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[0873] (min.)

[0874] 2.99 (s, 6H), 2.80-2.60 (m, 2H).

[0875] (500 MHz, DMSO-d6) 6 8.65 (s, 1H), 8.17 (s, 1H), a 8.08 (d,,7=4.8 Hz, 1H),

[0876] 8.01 (d,,7=8.4 Hz, 2H), (7?)-5-(4-(l- 7.89 (d,,7=8.5 Hz, 2H), methyl-1H- 7.86 (d,,7=1.8 Hz, 1H), imidazol-2- 7.82 (d,,7=2.1 Hz, 1H), yl)phenyl)-2- 7.87 - 7.80 (m, 1H), 7.78 - 1-4 o

[0877] X(l-(pyridin- 421.1 E: 1.03

[0878] N' 7.75 (m, 1H), 7.73 - 7.69 2- F: 1.67

[0879] (m, 1H), 6.99 - 6.90 (m, yl)pyrrolidin

[0880] 1H), 6.86 - 6.80 (m, 1H), d -3-yl)-2H- 5.68 - 5.57 (m, 1H), 4.18 - indazole,

[0881] 4.12 (m, 1H), 4.09 - 4.03 TFA salt

[0882] (m, 1H), 3.93 (s, 3H), 3.89 - 3.82 (m, 1H), 3.80 - 3.75 (m, 1H), 2.75 - 2.61 (m, 2H)

[0883] (500 MHz, DMSO-d6) 6 8.61 (s, 1H), 8.55 (d,.7=2,4 o Hz, 1H), 8.07 (d,,7=5.1 Hz,

[0884] 1H), 8.05 (s, 1H), 7.94 (d, (7?)-5-(4-,7=8.7 Hz, 2H), 7.92 - 7.86 (IH-pyrazol- (m, 1H), 7.83 (d, J=8.7 Hz, 1-yl)phenyl)- 2H), 7.78 (d,,7=1.3 Hz, 2-(l- 1H), 7.73 - 7.70 (m, 1H), 1-5 E: 1.4

[0885] (pyridin-2- 407.2 0

[0886] 7.67 - 7.63 (m, 1H), 7.07 - F: 1.96

[0887] yl)pyrrolidin 6.99 (m, 1H), 6.87 (brt, -3-yl)-2H-,7=6.0 Hz, 1H), 6.58 (t, 0 indazole,.7=2,0 Hz, 1H), 5.66 - 5.57

[0888] TFA salt (m, 1H), 4.16 (dd,,7=11.4,

[0889] 6.5 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.91 - 3.84 (m, 1H), 3.82 - 3.75 (m, 1H),

[0890]

[0891] 2.76 - 2.62 (m, 2H)HPLC

[0892] LCMS Method,

[0893] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[0894] (min.)

[0895] (500 MHz, DMSO-d6) 6 8.57 (s, 1H), 8.09 - 8.04 (A)-N, N,3- (m, 1H), 7.92 - 7.85 (m, trimethyl-4- 1H), 7.70 - 7.63 (m, 2H), (2-(l- 7.34 (s, 1H), 7.29 (s, 2H), (pyridin-2- 1-6 E: 1.23 7.27 - 7.24 (m, 1H), 7.02 - yl)pyrrolidin 426.2

[0896] ^N' F: 1.73 6.98 (m, 1H), 6.90 - 6.83

[0897] -3-yl)-2H- (m, 1H), 5.64 - 5.56 (m, indazol-5- 1H), 4.23 - 4.03 (m, 2H), yl)benzamid

[0898] 3.95 - 3.73 (m, 2H), 2.99 e, TFA salt

[0899] (br s, 6H), 2.76 - 2.61 (m, (5° 2H), 2.28 (s, 3H)

[0900] (500 MHz, CD3OD) δ 8.48 (s, 1H), 8.08 (ddd, J=9.1, 7.2, 1.7 Hz, 1H), 8.02 - (7?)-7- 7.96 (m, 3H), 7.92 (dd, methyl-5-(4- •7=1.5, 0.6 Hz, 1H), 7.87 - (1-methyl- 7.81 (m, 2H), 7.72 (d, IH-imidazol- 7=2.1 Hz, 1H), 7.68 (d, 2-yl)phenyl)- 1-7 2-(l- 435.1 C: 1.00 7=2.1 Hz, 1H), 7.49 - 7.44

[0901] Oi

[0902] XD: 1.76 (m, 1H), 7.24 (d, 7=9.2 Hz, N' (pyridin-2- 1H), 7.07 - 7.01 (m, 1H), yl)pyrrolidin

[0903] 5.71 - 5.63 (m, 1H), 4.36 - d -3-yl)-2H- 4.22 (m, 2H), 4.11 (dt, indazole,

[0904] 7=10.1, 7.7 Hz, 1H), 4.01 TFA salt

[0905] (s, 3H), 3.93 (ddd, 7=10.1, 8.3, 5.1 Hz, 1H), 2.95 - 2.76 (m, 2H), 2.61 (s, 3H) (500 MHz, DMSO-d6) 6 W

[0906] 8.66 (s, 1H), 8.05 (d, J=5.3 / YA (A)-4-(6- Hz, 1H), 7.98 - 7.89 (m, \= / F fluoro-2-(l- 2H), 7.62 - 7.56 (m, 2H),

[0907] (pyridin-2- 7.54 - 7.46 (m, 3H), 7.07 yl)pyrrolidin (br d, 7=9.5 Hz, 1H), 6.91 1-8 -3-yl)-2H- 430.1 E: 1.20 (t, 7=6.5 Hz, 1H), 5.65 - M indazol-5- F: 1.67 5.57 (m, 1H), 4.19 - 4.12XN'

[0908] yl)-A, A- (m, 1H), 4.07 (br dd, dimethylben 7=11.6, 3.6 Hz, 1H), 3.90 - d zamide, TFA 3.83 (m, 1H), 3.81 - 3.77 salt (m, 1H), 2.99 (br d, 7=16.6

[0909] Hz, 6H), 2.76 - 2.67 (m,

[0910]

[0911] 1H), 2.66 - 2.59 (m, 1H)HPLC

[0912] LCMS Method,

[0913] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[0914] (min.)

[0915] (500 MHz, DMSO-d6) 6 8.69 (s, 1H), 8.04 (br d, J=6.1 Hz, 1H), 8.00 (d, (7?)-6-fluoro-. / =8,0 Hz, 1H), 7.95 (brt, 5-(4-(l-. / =7,9 Hz, 1H), 7.92 - 7.87 methyl-1H- (m, 2H), 7.86 - 7.81 (m, \=\Fimidazol-2- 3H), 7.79 (d, J=1.9 Hz, yl)phenyl)-2- 1H), 7.54 (d, J=12.4 Hz, 1-9 E: 1.3

[0916] (l-(pyridin- 439.0 4

[0917] 1H), 7.08 (br d, J=9.1 Hz, OXN' i F: 1.74

[0918] 2- 1H), 6.92 (t, J=6.3 Hz, yl)pyrrolidin 1H), 5.68 - 5.57 (m, 1H), d -3-yl)-2H- 4.17 (br dd, J=11.2, 6.7 indazole, Hz, 1H), 4.10 - 4.05 (m, TFA salt 1H), 3.92 (s, 3H), 3.89 - 3.77 (m, 2H), 2.75 - 2.67 (m, 1H), 2.67 - 2.59 (m, 1H)

[0919] (500 MHz, DMSO-d6) 6 8.72 (d, J=2.6 Hz, 1H), 8.01 (d,. / =6,2 Hz, 1H), U

[0920] / (R)-4-(7- 7.98 - 7.93 (m, 1H), 7.91 fluoro-2-(l- (d,,7=0.8 Hz, 1H), 7.76 (d, (pyridin-2- J=8.3 Hz, 2H), 7.52 - 7.41 yl)pyrrolidin (m, 3H), 7.08 (d, J=2.1 Hz, 1- XjV

[0921] -3-yl)-2H- FA 430.1 E: 1.53 1H), 6.92 (t,.7=6,4 Hz, 10XN' indazol-5- F: 1.75 1H), 5.70 - 5.59 (m, 1H), yl)-N, N- 4.20 - 4.15 (m, 1H), 4.09 6 dimethylben (dd, <7=11.6, 3.4 Hz, 1H),N=Z zamide, TFA 3.91 - 3.85 (m, 1H), 3.82 - W salt 3.77 (m, 1H), 2.98 (br d,

[0922] <7=17.8 Hz, 6H), 2.80 - 2.70 (m, 1H), 2.69 - 2.61 (m, 1H)

[0923] (7?)-7-fluoro- (500 MHz, DMSO-d6) 6 O' 5-(4-(l- 8.78 (d, J=2.5 Hz, 1H), methyl-1H- 8.06 - 7.99 (m, 4H), 7.96 imidazol-2- (br t, <7=7.9 Hz, 1H), 7.88 yl)phenyl)-2- (d, <7=8.5 Hz, 2H), 7.82 (d, 1- E: 1.33

[0924] (l-(pyridin- 439.0 <7=1.8 Hz, 1H), 7.78 (d, 11 H

[0925] XF: 1.76

[0926] N' 2- <7=1.8 Hz, 1H), 7.57 (d, yl)pyrrolidin <7=13.1 Hz, 1H), 7.10 (d, 0 -3-yl)-2H- <7=9.1 Hz, 1H), 6.93 (t, indazole, J=6.6 Hz, 1H), 5.73 - 5.63

[0927]

[0928] a TFA salt (m, 1H), 4.20 (dd, <7=11.7,HPLC

[0929] LCMS Method,

[0930] Ex# Structure Name ‘HNMR(5 ppm) (M+H)+RT

[0931] (min.)

[0932] 6.8 Hz, 1H), 4.10 (br dd, 7=11.6, 3.6 Hz, 1H), 3.91 (s, 3H), 3.87 (br d, 7=7.6 Hz, 1H), 3.83 - 3.78 (m, 1H), 2.77 - 2.70 (m, 1H), 2.69 - 2.63 (m, 1H) (500 MHz, DMSO-d6) 6 8.67 (s, 1H), 8.10 (br d, 7=4.0 Hz, 1H), 8.03 (d, w / o(R)-4-(7- 7=1.1 Hz, 1H), 7.77 (d, chloro-2-(l- 7=8.2 Hz, 2H), 7.73 (d, (pyridin-2- 7=1.0 Hz, 1H), 7.57 - 7.51 Cl yl)pyrrolidin (m, 1H), 7.49 (d, 7=8.2 Hz, 1- E: 1.29

[0933] -3-yl)-2H- 446.2 2H), 6.64 - 6.59 (m, 1H), 12 M

[0934] Xi F: 1.79

[0935] N' indazol-5- 6.56 (d, 7=8.5 Hz, 1H), yl)-#^V- 5.57 - 5.49 (m, 1H), 4.08 - d dimethylben 4.00 (m, 1H), 3.97 - 3.91 zamide (m, 1H), 3.80 - 3.71 (m, 0 1H), 3.67 - 3.59 (m, 1H),

[0936] 2.99 (br d, 7=13.1 Hz, 6H), 2.71 - 2.59 (m, 2H) (500 MHz, DMSO-d6) 6 8.79 (s, 1H), 8.17 (s, 1H), 8.09 - 8.00 (m, 3H), 7.97 - (7?)-7-chloro- O' 7.92 (m, 1H), 7.89 (d,

[0937] 5-(4-(l- 7=8.2 Hz, 2H), 7.85 - 7.82 methyl-1H- (m, 2H), 7.80 (s, 1H), 7.07 imidazol-2- (br d, 7=8.6 Hz, 1H), 6.91 1- Cl yl)phenyl)-2- E: 1.07

[0938] 455.1 (t, 7=6.4 Hz, 1H), 5.70 - 13 M (l-(pyridin- F: 1.80

[0939] XN' 5.61 (m, 1H), 4.20 (br dd,

[0940] 2- 7=11.3, 6.8 Hz, 1H), 4.10 yl)pyrrolidin

[0941] (br dd, 7=11.4, 3.9 Hz, -3-yl)-2H- 1H), 3.92 (s, 3H), 3.88 (br indazole

[0942] d, 7=7.2 Hz, 1H), 3.79 (br dd, 7=15.0, 8.6 Hz, 1H),

[0943]

[0944] 2.78 - 2.67 (m, 2H)HPLC

[0945] LCMS Method,

[0946] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[0947] Q

[0948] (min.)

[0949] (500 MHz, DMSO-d6) 6 8.55 (s, 1H), 8.05 - 7.95 (R)-4-(7- (m, 2H), 7.76 (d, 7=8.2 Hz, / O methoxy-2- 2H), 7.57 (d, 7=1.1 Hz, (l-(pyridin- 1H), 7.48 (d, 7=8.2 Hz, 2- 2H), 7.14 (d, 7=9.1 Hz, V J— OMe yl)pyrrolidin

[0950] 1- E: 1.46 1H), 6.99 - 6.90 (m, 2H),

[0951] -3-yl)-2H- 442.2

[0952] 14 H F: 1.66 5.65 - 5.54 (m, 1H), 4.23 -XN' indazol-5- 4.14 (m, 1H), 4.08 (br dd, yl)-#^V- 7=11.5, 4.0 Hz, 1H), 3.97 0 dimethylben

[0953] (s, 3H), 3.90 - 3.85 (m, zamide, TFA

[0954] 1H), 3.83 - 3.77 (m, 1H), w salt

[0955] 2.98 (br d, 7=11.7 Hz, 6H), 2.76 - 2.62 (m, 2H) (500 MHz, DMSO-d6) 6 8.56 (s, 1H), 8.05 (br d, (R)-N, N- / 7=2.6 Hz, 1H), 7.57 - 7.43 dimethyl-4- (m, 4H), 7.41 (br d, 7=6.7 o (4-methyl-2- Hz, 2H), 7.16 (br d, 7=8.9 _ YA (l-(pyridin- Hz, 1H), 6.60 (br t, 7=5.5 1- 2- E: 1.20

[0956] 426.2 Hz, 1H), 6.53 (br d, 7=8.0 15 OXyl)pyrrolidin F: 1.69

[0957] N' Hz, 1H), 5.50 - 5.38 (m, -3-yl)-2H- 1H), 4.04 - 3.97 (m, 1H), indazol-5- 0 3.93 - 3.88 (m, 1H), 3.88 - N_ / yl)benzamid

[0958] 3.79 (m, 2H), 3.04 - 2.93 o e

[0959] (m, 6H), 2.62 (br s, 2H), 2.42 (s, 3H)

[0960] (500 MHz, CD3OD) 8 ppm 2.21 (quin, 7=7.56 Hz, 2 H) 2.56 (s, 3 H) 2.62 (t, 7=8.11 Hz, 2 H) 2.74 - (A)-l-(4-(7- 2.89 (m, 2 H) 3.90 (ddd, methyl-2-(l- 7=10.06, 8.25, 5.13 Hz, 1 (pyridin-2- H) 3.97 (t, J=7.07 Hz, 2 H) yl)pyrrolidin

[0961] 4.03 - 4.11 (m, 1 H) 4.18 - 1- -3-yl)-2H- E: 1.37

[0962] 438.1 4.29 (m, 2 H) 5.58 - 5.64 16 indazol-5- F: 1.87

[0963] (m, 1 H) 7.01 (t, 7=6.73 yl)phenyl)py

[0964] Hz, 1 H) 7.21 (d, 7=9.29 rrolidin-2- Hz, 1 H) 7.36 (s, 1 H) 7.63 one, TFA

[0965] - 7.70 (m, 4 H) 7.73 (s, 1 salt

[0966] H) 7.96 (dd, 7=6.38, 0.83 Hz, 1 H) 8.05 (ddd, 7=9.09, 7.21, 1.60 Hz, 1 H)

[0967]

[0968] 8.37 (s, 1 H)HPLC

[0969] LCMS Method,

[0970] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[0971] (min.)

[0972] (500 MHz, DMSO-d6) 6 8.56 (s, 1H), 8.03 (br d,. / =5,4 Hz, 1H), 7.94 (br d, J=6.2 Hz, 1H), 7.84 (s, M / ° (R)-4-(7- 1H), 7.73 (br d, J=8.0 Hz, ethyl-2-(l- 2H), 7.48 (br d, J=8.0 Hz, (pyridin-2- 2H), 7.38 (s, 1H), 7.08 (s, yl)pyrrolidin

[0973] 1H), 6.92 (t, J=6.6 Hz, 1- vVEt-3-yl)-2H- E: 1.36

[0974] 440.3 1H), 5.58 (br d, J=4A Hz, 17 M indazol-5- F: 1.94

[0975] XN' 1H), 4.19 - 4.13 (m, 1H), yl)-N, N- 4.09 (br dd, J=10.9, 3.5 dimethylben

[0976] d Hz, 1H), 3.91 - 3.85 (m, zamide, TFA

[0977] 1H), 3.81 - 3.75 (m, 1H), salt

[0978] 2.98 (br d, J=6.3 Hz, 6H), 2.93 (q,. / =7,4 Hz, 2H), 2.73 - 2.61 (m, 2H), 1.30 (t,, / =7.5 Hz, 3H)

[0979] (500 MHz, DMSO-d6) 6 (7?)-2- 8.46 (d, J=2.9 Hz, 2H), \l-N methyl-4-(4- 8.11 - 8.05 (m, 1H), 7.85 - (7-methyl-2- 7.78 (m, 3H), 7.77 - 7.71 (l-(pyridin- (m, 2H), 7.56 - 7.49 (m, 2- 1H), 7.39 (s, 1H), 6.60 (dd, 1- yl)pyrrolidin E: 1.25

[0980] 452.2 J=6.6, 5.4 Hz, 1H), 6.54 (d, 18 -3-yl)-2H- F: 1.73

[0981] J=8.3 Hz, 1H), 5.50 - 5.43 indazol-5- (m, 1H), 4.05 - 3.97 (m, yl)phenyl)- 1H), 3.96 - 3.89 (m, 1H), 2,4-dihydro- a°' 3.77 - 3.67 (m, 1H), 3.60 - 3H- 1,2,4- 3.54 (m, 4H), 2.68 - 2.59 triazol-3-one

[0982] (m, 2H), 2.56 (s, 3H) (500 MHz, DMSO-d6) 6 8.54 (s, 1H), 8.05 (d, J=6.2 (R)-4- °— \ Hz, 1H), 7.95 (s, 1H), 7.79 methyl-3-(4- (s, 1H), 7.71 (d, J=8.6 Hz, (7-methyl-2- 2H), 7.55 (d, J=8.6 Hz, ((7?)-l- 2H), 7.08 - 7.01 (m, 2H), 0 (pyridin-2- 1- E: 1.39 6.89 (t, J=6.4 Hz, 1H), jri yl)pyrrolidin 454.1

[0983] 19 F: 1.93 5.58 (brt, J=5.5 Hz, 1H),

[0984] -3-yl)-2H- 4.74 - 4.65 (m, 1H), 4.58 indazol-5- (t, J=8.3 Hz, 1H), 4.16 (dd, yl)phenyl)ox

[0985] J=11.4, 6.6 Hz, 1H), 4.10 - azolidin-2- 4.00 (m, 2H), 3.94 - 3.83 one

[0986] (m, 1H), 3.81 - 3.71 (m,

[0987]

[0988] 1H), 2.73 (s, 3H), 2.72 -HPLC

[0989] LCMS Method,

[0990] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[0991] (min.)

[0992] 2.63 (m, 2H), 1.25 (d, J=6.2 Hz, 3H)

[0993] (500 MHz, DMSO-d6) 6 8.51 (s, 1H), 8.05 - 7.99 (m, 1H), 7.94 - 7.86 (m, (5)-4- 1H), 7.78 (s, 1H), 7.74 - methyl-3-(4- < XN3. 7.65 (m, 2H), 7.54 (d, (7-methyl-2- J=8.7 Hz, 2H), 7.07 (s, 1H), 7.05 - 6.99 (m, 1H), 1- 0 (pyridin-2- E: 1.41

[0994] 6.93 - 6.81 (m, 1H), 5.60 - yl)pyrrolidin 454.2

[0995] 20 F: 1.93 5.49 (m, 1H), 4.72 - 4.62 -3-yl)-2H- (m, 1H), 4.60 - 4.52 (m, indazol-5- 1H), 4.20 - 4.11 (m, 1H), yl)phenyl)ox

[0996] a°' 4.09 - 4.00 (m, 2H), 3.92 - azolidin-2- 3.80 (m, 1H), 3.66 - 3.61 one

[0997] (m, 1H), 2.73 (s, 3H), 2.72 - 2.62 (m, 2H), 1.24 (d, J=6.0 Hz, 3H)

[0998] (500 MHz, DMSO-d6) 6 (R)-4-(4-(7- 12.01 (br s, 1H), 8.58 (s, HN-N methyl-2-(l- 1H), 8.44 (d, J=1.5 Hz, O^N-^ (pyridin-2- 1H), 8.06 (dd, J=6.0, 1.0 yl)pyrrolidin Hz, 1H), 7.95 (br d, J=2.9 -3-yl)-2H- Hz, 1H), 7.84 (d,. / =0,8 Hz, 0

[0999] 1- indazol-5- C: 1.10 1H), 7.82 - 7.75 (m, 4H),

[1000] 438.0

[1001] 21 yl)phenyl)- D: 1.57 7.44 - 7.40 (m, 1H), 7.17 - 2,4-dihydro- 6.99 (m, 1H), 6.90 (br s, 3H- 1,2,4- 1H), 5.60 (quin, J=5.7 Hz, triazol-3- 1H), 4.23 - 4.06 (m, 2H), ao' '

[1002] one, TFA 3.93 - 3.85 (m, 1H), 3.81 - salt 3.75 (m, 1H), 2.77 - 2.65 (m, 2H), 2.55 (s, 3H) (500 MHz, DMSO-d6) 6 / = (7?)-7- NxN8.54 (s, 1H), 8.03 - 7.96 methyl-5-(4- (m, 2H), 7.95 - 7.88 (m, (1-methyl- 2H), 7.85 (s, 4H), 7.47 - 0 1H-1,2,4- 1- E: 1.25 7.41 (m, 1H), 7.18 - 7.09 triazol-5- 436.1 (m, 1H), 6.99 - 6.93 (m, 22 yl)phenyl)-2- F: 1.77

[1003] 1H), 5.72 - 5.35 (m, 1H), (l-(pyridin- 4.22 - 4.15 (m, 1H), 4.11 - 2- 4.03 (m, 1H), 3.98 - 3.88 cr0^ yl)pyrrolidin

[1004] (m, 4H), 3.83 - 3.75 (m, -3-yl)-2H-

[1005]

[1006] 1H), 2.77 - 2.72 (m, 1H),HPLC

[1007] LCMS Method,

[1008] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[1009] (min.)

[1010] indazole, 2.72 (s, 3H), 2.70 - 2.61 TFA salt (m, 1H)

[1011] (400 MHz, DMSO-d6): 6 \i— (A, A- 8.58 (s, 1H), 8.14-8.12 (m, o= / dimethyl-4- 1H), 7.84 (d, J = 0.8 Hz,

[1012] (7-methyl-2- 1H), 7.74 (dd, J= 1.6, 6.4 ((3R,5S)-5- Hz, 2H), 7.54-7.47 (m, methyl-1- 3H), 7.41 (t, J = 1.6 Hz, 1- 7 V- Me

[1013] (pyridin-2- 440.2 G: 2.06 1H), 6.63-6.59 (m, 2H), 23 H

[1014] XN' yl)pyrrolidin 5.34-5.31 (m, 1H), 4.26- -3-yl)-2H- 4.24 (m, 1H), 4.17-4.06 0 indazol-5- (m, 2H), 2.99 (s, 6H), yl)benzamid 2.89-2.86 (m, 1H), 2.59 (s, * e 3H), 2.50-2.40 (m, 1H),

[1015] 1.27 (d, J = 6.0 Hz, 3H). (500 MHz, DMSO-d6) 6 ppm 2.55 (s, 3 H) 2.59 - 2.67 (m, 2 H) 2.77 (s, 3 H) Ox / 3.60 (dt, 7=10.13, 6.76 Hz,

[1016] 7-methyl-5- 1 H) 3.69 - 3.77 (m, 1 H) (4- 3.90 - 3.98 (m, 1 H) 3.97 - 0 (m ethyl sulfin

[1017] 4.06 (m, 1 H) 5.42 - 5.52 yl)phenyl)-2- 1- E: 1.20 (m, 1 H) 6.53 (d, 7=8.54 ((7?)-l- 417.1

[1018] 24 F: 1.66 Hz, 1 H) 6.59 (dd, 7=6.48,

[1019] (pyridin-2- 5.11 Hz, 1 H) 7.40 (s, 1 H) yl)pyrrolidin

[1020] N Nl / 7.52 (ddd, 7=8.56, 7.00, -3-yl)-2H- 1.91 Hz, 1 H) 7.74 (d, u indazole

[1021] 7=8.47 Hz, 2 H) 7.83 - 7.89 (m, 3 H) 8.08 (dd, 7=4.92, 1.11 Hz, 1 H) 8.48 (s, 1 H)

[1022] (7?)-2,5- (500 MHz, DMSO-d6) 6 \l-N dimethyl-4- 8.58 (s, 1H), 8.06 - 8.01 J \V (4-(7- (m, 1H), 7.98 - 7.91 (m, methyl-2-(l- 1H), 7.88 - 7.85 (m, 1H), (pyridin-2- 7.84 - 7.79 (m, 2H), 7.51 - 1- 0 E: 1.29

[1023] yl)pyrrolidin 466.1 7.45 (m, 2H), 7.42 (s, 1H), 25 A -3-yl)-2H- F: 1.73 7.08 (s, 1H), 6.95 - 6.89 indazol-5- (m, 1H), 5.68 - 5.51 (m, yl)phenyl)- 1H), 4.23 - 4.14 (m, 1H), cr0^ 2,4-dihydro- 4.12 - 4.06 (m, 1H), 3.93 - 3H- 1,2,4- 3.85 (m, 1H), 3.82 - 3.73

[1024]

[1025] triazol-3- (m, 1H), 3.36 (s, 3H), 2.76HPLC

[1026] LCMS Method,

[1027] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[1028] (min.)

[1029] one, TFA - 2.64 (m, 2H), 2.54 (br s, salt 3H), 2.12 (s, 3H)

[1030] (500 MHz, DMSO-d6) 6 8.83 (s, 1H), 8.44 (d, J=1.4 YJ— Hz, 1H), 8.30 (d, J=1.4 Hz, o= / (R)-4-(7- 1H), 8.07 (br d, J=5.5 Hz, cyano-2-(l- 1H), 7.81 (d,. / =8,3 Hz, (pyridin-2- 2H), 7.77 (brt,.7=7,4 Hz, yl)pyrrolidin 1H), 7.52 (d,.7=8.3 Hz, 1- -3-yl)-2H- E: 1.24 2H), 6.86 (br d, J=8.6 Hz,

[1031] 437.1

[1032] 26

[1033] H indazol-5- F: 1.71 1H), 6.79 (t,.7=6,4 Hz,XN' yl)-A, A- 1H), 5.69 - 5.60 (m, 1H), dimethylben 4.17 - 4.11 (m, 1H), 4.05 d zamide, (br dd, J=11.3, 3.4 Hz, TFA salt 1H), 3.87 - 3.80 (m, 1H),

[1034] 3.76 - 3.70 (m, 1H), 2.98 (br d, <7=18.5 Hz, 6H), 2.73 - 2.63 (m, 2H)

[1035] (500 MHz, DMSO-d6) 6 12.02 (br s, 1H), 8.76 (d, H (A)-4-(4-(7- <7=2.8 Hz, 1H), 8.45 (d, N'NS^O fluoro-2-(l- <7=1.4 Hz, 1H), 8.07 (dd, W (pyridin-2- <7=6.1, 1.1 Hz, 1H), 7.96 yl)pyrrolidin (br s, 1H), 7.91 (d, <7=1.1 -3-yl)-2H- Hz, 1H), 7.87 - 7.84 (m, 1- indazol-5- C: 1.07 2H), 7.83 - 7.79 (m, 2H),

[1036] 442.0

[1037] 27 yl)phenyl)- D: 1.54 7.50 (dd, <7=13.2, 1.4 Hz,

[1038] MXN' 2,4-dihydro- 1H), 7.09 (br d, <7=9.7 Hz,

[1039] 3H- 1,2,4- 1H), 6.92 (brt, <7=6.2 Hz, d triazol-3- 1H), 5.72 - 5.61 (m, 1H), one, TFA 4.23 - 4.16 (m, 1H), 4.15 - 0

[1040] salt 4.09 (m, 1H), 3.93 - 3.85 (m, 1H), 3.84 - 3.76 (m,

[1041]

[1042] 1H), 2.78 - 2.62 (m, 2H)HPLC

[1043] LCMS Method,

[1044] Ex# Structure Name1H NMR (δ ppm) (M+H)+RT (min.)

[1045] (500 MHz, DMSO-d6) 6 8.82 (s, 1H), 8.07 (br d, J=5.3 Hz, 1H), 7.85 (brt, «7?)-4-(4-,7=8.0 Hz, 1H), 7.65 (d, fluoro-2-(l-.7=7,6 Hz, 2H), 7.56 (d, (pyridin-2- <7=8.8 Hz, 1H), 7.52 (d, yl)pyrrolidin.7=8,2 Hz, 2H), 7.43 (t, 1- -3-yl)-2H- E: 1.25 <7=8.2 Hz, 1H), 6.96 (br d,

[1046] 430.2

[1047] 28 indazol-5- F: 1.76 <7=8.4 Hz, 1H), 6.84 (t, yl)-#^V- J=6.3 Hz, 1H), 5.64 - 5.57 dimethylben (m, 1H), 4.18 - 4.12 (m, zamide, 1H), 4.10 - 4.05 (m, 1H), TFA salt 3.87 - 3.81 (m, 1H), 3.78 - 3.73 (m, 1H), 2.99 (br d, <7=15.0 Hz, 6H), 2.72 - 2.62 (m, 2H)

[1048] (500 MHz, DMSO-d6) 6 8.57 (s, 1H), 8.01 (br d, (7?)-7- J=6.6 Hz, 2H), 7.86 (br s, methyl-5-(4- 1H), 7.81 (br d, <7=8.3 Hz, (5-methyl- 2H), 7.63 - 7.54 (m, 3H), IH-pyrazol- 7.43 (br s, 1H), 7.16 (br d, 1-yl)phenyl)- 1- E: 1.50 <7=8.9 Hz, 1H), 6.96 (brt,

[1049] 2-(l- 435.2

[1050] 29 F: 2.21 <7=5.8 Hz, 1H), 6.30 (br s, b (pyridin-2- 1H), 5.60 (br s, 1H), 4.21 - yl)pyrrolidin

[1051] 4.17 (m, 1H), 4.12 - 4.08 -3-yl)-2H- (m, 1H), 3.93 - 3.89 (m, indazole,

[1052] 1H), 3.82 - 3.78 (m, 1H), TFA salt

[1053] 2.74 - 2.65 (m, 2H), 2.53 (br s, 3H), 2.37 (s, 3H) (500 MHz, DMSO-d6) 6 8.52 (s, 1H), 8.09 - 8.03 (A)-3-(4-(7- (m, 1H), 7.87 (brt, J=1.6 methyl-2-(l- Hz, 1H), 7.77 (s, 1H), 7.74 (pyridin-2- - 7.68 (m, 2H), 7.67 - 7.61 yl)pyrrolidin

[1054] 1 0 (m, 2H), 7.38 (s, 1H), 6.99 - -3-yl)-2H- E: 1.36

[1055] xx 440.2 (br d,.7=9,2 Hz, 1H), 6.86 30 indazol-5- F: 2.01

[1056] (t,.7=6,0 Hz, 1H), 5.61 - yl)phenyl)ox

[1057] 5.51 (m, 1H), 4.51 - 4.43 azolidin-2- (m, 2H), 4.17 - 4.04 (m, one, TFA

[1058] 4H), 3.89 - 3.83 (m, 1H), salt

[1059] 3.78 - 3.73 (m, 1H), 2.71 -

[1060]

[1061] 2.64 (m, 2H), 2.53 (s, 3H)HPLC

[1062] LCMS Method,

[1063] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[1064] (min.)

[1065] NH2(400 MHz, DMSO-d6) 6 (5)-3-amino- 8.52-8.48 (m, 4H), 8.07 l-(4-(7- (dd, J= 1.2, 5.6 Hz, 1H), methyl-2- 7.78-7.73 (m, 5H), 7.38 (s, O)-1- 1H), 6.96-6.80 (m, 2H), (pyridin-2- 1- 5.56-5.53 (m, 1H), 4.29 yl)pyrrolidin 453.2 G: 2.61

[1066] 32 (bs, 2H), 4.17-4.09 (m, Mi -3-yl)-2H-XN' 1H), 4.05-4.02 (m, 1H), indazol-5- 3.97-3.82 (m, 4H), 3.73- yl)phenyl)py

[1067] d 3.62 (m, 1H), 2.68-2.66 N—Z rrolidin-2- (m, 1H), 2.54 (s, 3H), one

[1068] 2.10-2.05 (m, 1H) (400 MHz, DMSO-d6): 6 8.46 (s, 1H), 8.10 (d, J = (5)-3- 0.80 Hz, 1H), 7.76-7.79 hydroxy-1- (m, 3H), 7.70 (t, J = 2.00 (4-(7- Hz, 2H), 7.51-7.55 (m, methyl-2- 1H), 7.37 (s, 1H), 6.59- ((7?)-l- 6.62 (m, 1H), 6.55 (d, J = 1- Me (pyridin-2- 8.80 Hz, 1H), 5.77 (d, J =

[1069] 454.2 G: 1.27

[1070] 33 Ml yl)pyrrolidin 6.00 Hz, 1H), 5.47 (d, J =

[1071] XN'

[1072] -3-yl)-2H- 1.20 Hz, 1H), 4.32-4.34 indazol-5- (m, 1H), 4.01-4.02 (m, yl)phenyl)py 1H), 3.95-3.96 (m, 1H), rrolidin-2- 3.80-3.72 (m, 3H), 3.62- one 3.60 (m, 1H), 2.66-2.61 (m, 2H), 2.56 (s, 3H),2.49- 2.50 (m, 1H), 1.88 (m, 1H) (400 MHz, DMSO-d6): 6 8.46 (s, 1H), 8.09-8.11 (m, (7?)-3- 1H), 7.76-7.79 (m, 3H), hydroxy-1- 7.70 (dd, J = 2.00, 6.80 Hz, (4-(7- 2H), 7.51-7.55 (m, 1H), " M methyl-2- 7.37 (t, J = 1.20 Hz, 1H), vJ>

[1073] O)-1- 6.59-6.61 (m, 1H), 6.55 (d, 1- Me (pyridin-2- J = 8.40 Hz, 1H), 5.77 (d, J 454.2 G: 1.28

[1074] 34 o

[1075] XN- yl)pyrrolidin = 6.00 Hz, 1H), 5.47 (s, -3-yl)-2H- 1H), 4.32-4.34 (m, 1H), N— indazol-5- 4.02 (d, J = 6.80 Hz, 1H), o yl)phenyl)py 3.95 (d, J = 4.80 Hz, 1H), rrolidin-2- 3.80-3.63 (m, 3H), 3.63 one (m, 1H), 2.66-2.61 (m,

[1076] 2H), 2.56 (s, 3H), 2.49-2.50

[1077]

[1078] (m, 1H), 1.88-1.87 (m, 1H)HPLC

[1079] LCMS Method,

[1080] Ex# Structure Name 'H NMR (δ ppm) (M+H)+RT

[1081] (min.)

[1082] (400 MHz, DMSO-d6) 6 3-((7?)-3-(5- 8.46 (s, 1H), 8.16 (s, 1H), (4-0-3-H2N*^^ 7.91-7.87 (m,lH), 7.78- amino-2- 7.76 (m, 3H), 7.71-7.69 <^A oxopyrrolidi

[1083] (m, 2H), 7.37(t, J= 1.2 Hz, n-1- 1H), 7.28-7.23 (m, yl)phenyl)-7- 1- ^A_ 2H),7.17-7.11(m, 2H), methyl-2H- 495.2 G: 1.39

[1084] 35 6.78-6.76 (m, 1H), 5.61-XN' indazol-2- 4.91(m, 1H), 3.92-3.90 (m, yl)pyrrolidin

[1085] 1H), 3.83-3.80 (m, 3H), H2N 3.79-3.47 (m, 3H), 2.68- yl)benzamid

[1086] c / ~O 2.65 (m, 2H), 2.56 (s, 3H), e, formic

[1087] 2.43-2.40 (s, 1H), 1.91-1.77 acid salt

[1088] (m, 1H)

[1089] 3-((7?)-3-(5- (400 MHz, DMSO-d6) 6 ^ ^ (4-((7?)-3- 8.46 (s, 1H), 7.89-7.85 (m, amino-2- 1H) 7.79-7.76 (m, 3H), / oxopyrrolidi 7.72-7.70 (m, 2H), 7.37 (s, n-1- 1H), 7.28-7.24 (m, 2H), yl)phenyl)-7- 7.17-7.11 (m, 1H), 6.79- 1- AA

[1090] methyl-2H- 495.2 G: 1.40 6.76 (m, 1H), 5.52-5.49 36 M

[1091] XN' indazol-2- (m, 1H), 3.94-3.90 (s, 1H), yl)pyrrolidin 3.84-3.81 (m, 3H), 3.80- H2N -1- 3.68 (m, 1H), 3.66-3.49 (s, yl)benzamid 1H), 2.65-2.51 (m, 1H), dMD

[1092] e, formic 2.50 (s, 3H), 2.45-2.41 (s, acid salt 1H), 1.91-1.84 (m,lH) (400 MHz, DMSO-d6): 8 H 4-(4-(7- 12.00 (s, 1H), 8.60 (s, 1H), N'V° methyl-2-(3- 8.43 (s, 1H), 8.07-8.08 (m, methyl-1- 1H), 7.75-7.80 (m, 5H), (pyridin-2- 7.50-7.51 (m, 1H), 7.39- yl)pyrrolidin 7.39 (m, 1H), 6.57-6.59 1- ( V Me

[1093] -3-yl)-2H- 452.0 G: 1.42 (m, 1H), 6.49 (d, J = 8.40 37

[1094] Oi indazol-5- Hz, 1H), 4.37 (dd, 1H), Me? [Rae] yl)phenyl)- 3.83 (d, J=11.20 Hz, 1H), 0 2,4-dihydro- 3.60-3.63 (m, 1H), 3.50- N__z

[1095] 3H- 1,2,4- 3.52 (m, 1H), 3.02-2.99 w triazol-3-one (m, 1H), 2.57 (s, 3H), 1.80

[1096]

[1097] (s, 3H)HPLC

[1098] LCMS Method,

[1099] Ex# Structure Name ‘HNMR(5 ppm) (M+H)+RT

[1100] (min.)

[1101] (400 MHz, DMSO-d6): 8 8.60 (s, 1H), 8.07-8.08 (m, 2V>

[1102] 1H), 7.80-7.81 (m, 1H), dimethyl-4- 7.71-7.73 (m, 2H), 7.39- (7-methyl-2- 7.49 (m, 3H), 7.38-7.39 (3 -methyl- 1- (m, 1H), 6.57-6.58 (m, 1- (pyridin-2- 440.0 G: 1.70 1H), 6.49 (d, J = 8.40 Hz, 38 yl)pyrrolidin

[1103] 1H), 4.38 (d, J =11.20 Hz, -3-yl)-2H- 1H), 3.83 (d, J =11.20 Hz, indazol-5- 1H), 3.60-3.64 (m, 1H), yl)benzamid

[1104] 3.51-3.54 (m, 1H), 2.99 (s, e

[1105] 6H), 2.57 (s, 3H), 1.80 (s, 3H)

[1106] (500 MHz, DMSO-d6) 6 8.46 (s, 1H), 8.12 - 8.08 (m, 1H), 7.85 (s, 1H), 7.73 rac-4-(2- (d,.7=8,2 Hz, 2H), 7.57 - ((3R,4R)-4- 7.51 (m, 1H), 7.48 (d, D < hydroxy-1-.7=8,2 Hz, 2H), 7.40 (s, ® 1 o (pyridin-2- 1H), 6.63 (dd, <7=6.6, 5.4 yl)pyrrolidin Hz, 1H), 6.55 (d,,7=8.4 Hz, 1- E: 1.16

[1107] -3-yl)-7- 442.2 1H), 5.86 (d, <7=4.9 Hz, 39 F: 1.57

[1108] OJu ° methyl-2H- 1H), 5.21 - 5.14 (m, 1H), x.x^ o indazol-5- 4.76 (quin,.7=5,3 Hz, 1H), yl)-N, N- 4.14 - 4.06 (m, 1H), 3.97 dimethylben (dd, <7=11.1, 5.4 Hz, 1H), zamide 3.91 (dd, 7=10.8, 6.3 Hz,

[1109] 1H), 3.40 (dd, 7=10.9, 5.0 Hz, 1H), 2.98 (br d, J=4.4 Hz, 6H), 2.56 (s, 3H). (500 MHz, DMSO-d6) 6 \— rac-4-(2- 8.35 (s, 1H), 8.14 - 8.08 °=z ((3R,4R)-4- (m, 1H), 7.83 (s, 1H), 7.72 hydroxy-4- (d, 7=8.2 Hz, 2H), 7.57 - methyl-1- 7.51 (m, 1H), 7.47 (d, (pyridin-2- 7=8.2 Hz, 2H), 7.37 (s, 1- yl)pyrrolidin 456.3 E: 1.31 1H), 6.62 (dd, 7=6.4, 5.2 40 [ Rac ] w -3-yl)-7- F: 1.64 Hz, 1H), 6.55 (d, 7=8.5 Hz,

[1110] A OH methyl-2H- 1H), 5.62 (br d, 7=1.4 Hz, a- indazol-5- 1H), 5.07 (br d, 7=5.0 Hz, yl)-#^V- 1H), 4.18 (dd, 7=11.6, 6.6 dimethylben Hz, 1H), 4.04 (br d,,7=10.6 o

[1111] zamide Hz, 1H), 3.73 - 3.66 (m,

[1112]

[1113] 1H), 3.64 - 3.58 (m, 1H),HPLC

[1114] LCMS Method,

[1115] Ex# Structure Name 'H NMR (δ ppm)

[1116] (M+H)+RT

[1117] (min.)

[1118] 2.98 (br s, 6H), 2.55 (s, 3H), 0.88 (s, 3H)

[1119] (500 MHz, DMSO-d6) 6 8.46 (s, 1H), 8.41 (s, 1H), Rac- 4-(4-(2- 8.11 (br d, J=5.3 Hz, 1H), ((35,4S)-4-N^° 7.84 (s, 1H), 7.82 - 7.72 hydroxy-1- / A (m, 4H), 7.55 (br t, J=7.2 (pyridin-2- Hz, 1H), 7.41 (s, 1H), 6.67 yl)pyrrolidin

[1120] 1- - 6.61 (m, 1H), 6.56 (d, O- -3-yl)-7- 454.4 E: 1.03

[1121] . / =8,6 Hz, 1H), 5.18 (q, 41 OXmethyl-2H- F: 1.38

[1122] N' i

[1123] . / =5,7 Hz, 1H), 4.76 (q, indazol-5-, / =5.0 Hz, 1H), 4.16 - 4.07 yl)phenyl)- N— / (m, 1H), 3.99 (br dd,

[1124] 2,4-dihydro- o J=11.1, 5.5 Hz, 1H), 3.91

[1125] 3H- 1,2,4- (br dd, J=10.7, 6.1 Hz, triazol-3-one

[1126] 1H), 3.53 (br dd, J=3.4, 1.7 Hz, 1H), 2.57 (s, 3H) (500 MHz, DMSO-d6) 6 8.57 (s, 1H), 8.06 (br d, rac-(3R,4R)-. / =5,2 Hz, 1H), 8.00 - 7.96 4-(7-methyl- (m, 3H), 7.86 (d, J=8.5 Hz, 5-(4-(l- 3H), 7.80 (d, J=1.8 Hz, methyl-1H- 1H), 7.76 (d, J=1.8 Hz, 1- imidazol-2- 1H), 7.49 (s, 1H), 6.97 (br yl)ph 451.2 E: 1.03

[1127] enyl)- d,. / =8,8 Hz, 1H), 6.87 (t, 42 O

[1128] Xi F: 1.59

[1129] N' 2H-indazol-, / =6.4 Hz, 1H), 5.33 - 5.25 [Rael " 2-yl)-l- (m, 1H), 4.78 (q, J=5.5 Hz,1-1^A*°H

[1130] (pyridin-2- 1H), 4.23 (br dd, J=11.3, N=Z yl)pyrrolidin 7.7 Hz, 1H), 4.11 (br dd, -3-ol J=11.4, 5.3 Hz, 1H), 4.03 - 3.99 (m, 2H), 3.91 (s, 3H),

[1131]

[1132] 2.55 (s, 3H)

[1133] Example 2-1: (R)-3-(3-(7-fluoro-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2H-indazol-2- yl)pyrrolidin-l-yl)benzamide, TFA salt

[1134]

[1135] To a vial charged with Intermediate 64 (40 mg, 0.087 mmol), was added 4 M HC1 in dioxane (0.5 mL, 2.00 mmol) at rt. The reaction was stirred at 50 °C for 30 min. The solvent was removed. The obtained intermediate was dissolved in NMP (1 mL), then 3- bromobenzonitrile (23.7 mg, 0.13 mmol), NaO'Bu (42 mg, 0.43 mmol) and RuPhos-Pd-G3 (14.5 mg, 0.017 mmol) were added. After stirring at 100 °C for 3 h. The reaction was cooled to rt. The reaction was diluted with 0.5 mL DMSO. Then K2CO3 (48 mg, 0.35 mmol), and H2O2 (30% aq. solution, 0.1 mL, 0.9 mmol) were added at rt. The reaction was stirred at rt for 1 h. The reaction mixture was purified by reverse phase chromatography to provide Example 2-1 (8.1 mg, 15%). MS (ESI) m / z 481.2 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 8.71 (d, J=2.3 Hz, 1H), 8.05 - 7.99 (m, 3H), 7.89 (br d, J=7.4 Hz, 3H), 7.84 (br s, 1H), 7.80 (br s, 1H), 7.57 (br d, J=12.3 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.17 (d, J=7.7 Hz, 1H), 7.12 (s, 1H), 6.78 (dd, J=8.0, 1.7 Hz, 1H), 5.65 - 5.53 (m, 1H), 4.00 - 3.88 (m, 1H), 3.92 (br s, 3H), 3.83 (br dd, J=10.5, 4.0 Hz, 1H), 3.72 - 3.64 (m, 1H), 3.56 - 3.50 (m, 1H), 2.75 - 2.63 (m, 2H). Analytical HPLC: RT = 1.24 min (Method C) and 1.57 min (Method D).

[1136] The examples in Table 2 were prepared by similarly to Example 2-1 from the appropriate starting materials and intermediates. The Buckwald C-N coupling might be conducted under slightly modified conditions such as using different catalyst, base, solvent or temperature.

[1137] Table 2

[1138] HPLC LCMS

[1139] Ex# Structure Name Method,1HNMR (6 ppm)

[1140] (M+H)+

[1141] RT (min.)

[1142] (400 MHz, DMSO-d6) 6 8.50 - 8.47 (m, 1H), 7.83 —1 / \=° (A)-A, A- (d, J = 0.9 Hz, 1H), 7.75 - dimethyl-4- 7.68 (m, 2H), 7.52 - 7.45 (7-methyl- (m, 2H), 7.41 - 7.38 (m,

[1143] 1H), 7.24 - 7.16 (m, 2H), 2-(l- 2- phenylpyrr 6.66 - 6.60 (m, 3H), 5.53 - 425.3 G: 2.76

[1144] 2 lO 'NXolidin-3- 5.44 (m, 1H), 3.90 - 3.82 yl)-2H- (m, 1H), 3.75 (dd, J = 4.6, indazol-5- 10.2 Hz, 1H), 3.66 - 3.58 d yl)benzami (m, 1H), 3.45 (td, J = 7.0,

[1145] 9.2 Hz, 1H), 2.99 (br s, de ^3 6H), 2.67 - 2.61 (m, 2H), 2.57 (s, 3H)

[1146]

[1147] HPLC

[1148] LCMS

[1149] Ex# Structure Name Method, 'H NMR (δ ppm)

[1150] (M+H)+

[1151] RT (min.)

[1152] (400 MHz, DMSO-d6) 8 8.54 - 8.51 (m, 1H), 8.10 - (R)-N, N- \=o 8.05 (m, 2H), 7.85 - 7.82 dimethyl-4- (m, 2H), 7.75 - 7.70 (m, O (7-methyl- 2H), 7.51 - 7.46 (m, 2H), 2-(l- 7.43 - 7.37 (m, 1H), 5.56 - (pyrazin-2- 2-3 427.2 G: 2.03 5.47 (m, 1H), 4.11 - 4.05 rO

[1153] 'NZyl)pyrrolidi

[1154] (m, 1H), 4.04 - 3.96 (m, n-3-yl)-2H- 6 1H), 3.87 - 3.77 (m, 1H), indazol-5- \_— N 3.70 (td, J = 6.8, 10.3 Hz, yl)benzamid

[1155] o 1H), 3.03 - 2.94 (m, 6H), N^7e

[1156] 2.69 - 2.64 (m, 2H), 2.61 (br s, 1H), 2.55 (s, 3H) (400 MHz, DMSO-d6) 6 8.54 - 8.51 (m, 1H), 7.83 (d, (R)-N, N- J = 0.9 Hz, 1H), 7.75 - 7.70 dimethyl-4- (m, 2H), 7.50 - 7.45 (m, (7-methyl- 2H), 7.41 - 7.37 (m, 1H), 2-(l- 7.21 - 7.17 (m, 1H), 6.79 (d, 2-4 (thiazol-2- 432.0 J = 3.6 Hz, 1H), 5.56 - 5.49

[1157] G: 2.07

[1158] O yl)pyrrolidi (m, 1H), 4.05 (dd, J = 6.7, n-3-yl)-2H- 10.8 Hz, 1H), 3.92 (dd, J = indazol-5- 4.2, 10.8 Hz, 1H), 3.77 (td, yl)benzamid J = 7.4, 9.5 Hz, 1H), 3.67 - e 3.58 (m, 1H), 2.99 (br s,

[1159] 7H), 2.75 - 2.57 (m, 3H), 2.55 (s, 3H)

[1160] (400 MHz, DMSO-d6) 6 8.49 - 8.47 (m, 1H), 7.82 (d, (R)-4-(2-(l- J = 0.9 Hz, 1H), 7.74 - 7.69 (6- \=0 (m, 2H), 7.52 (t, J = 7.8 Hz,

[1161] (hydroxyme

[1162] 1H), 7.49 - 7.44 (m, 2H), o thyl)pyridin

[1163] 7.41 - 7.37 (m, 1H), 6.71 (d, -2- J = 7.3 Hz, 1H), 6.43 - 6.37 2-5 yl)pyrrolidi 456.2 G: 1.45 (m, 1H), 5.50 - 5.42 (m, 'NXn-3-yl)-7- 1H), 5.14 (br s, 1H), 4.40 methyl-2H- (br s, 2H), 4.06 - 3.98 (m, 6 indazol-5- \_-N 1H), 3.95 - 3.87 (m, 1H), f v\ yl)-#^V- X-z / OH 3.74 (td, J = 7.1, 10.0 Hz, dimethylben

[1164] 1H), 3.60 (td, J = 6.9, 10.1 zamide

[1165] Hz, 1H), 2.64-2.59 (m, 2H),

[1166]

[1167] 2.99 (br s, 6H), 2.56 (s, 3H)HPLC

[1168] LCMS

[1169] Ex# Structure Name Method, 'H NMR (δ ppm)

[1170] (M+H)+

[1171] RT (min.)

[1172] (400 MHz, DMSO-d6) 8 (R)-4-(2-(l- 8.52(s, 1H), 8.12- \=o (3- o 8.11(m,lH), 7.83(d, J= 0.8 chloropyridi

[1173] Hz, 1H), 7.47-7.68(m, 3H), n-2- 7.49(d, J= 2 Hz, 2H), Me — fi yl)pyrrolidi

[1174] 2-6 7.47(d, J= 1.6 Hz, 1H), i n-3-yl)-7- 460.0

[1175] O G: 3.03

[1176] 'i\r 7.39(t, J= 1.6 Hz, 1H), 6.80- methyl-2H- 6.77(m, 1H), 5.42- O Cl indazol-5- 5.39(m,lH), 4.23-4.12(m, yl)-#^V- 2H), 3.97-3.93(m, 1H), dimethylben

[1177] 3.86-3.82(m,lH), 2.99(s, zamde

[1178] 6H), 2.56-2.49(m, 5H) — r / (R)-4-(2-(l- (400 MHz, DMSO-d6) 6 \=o (5- 8.49(s, 1H), 8.09(d, J= 1.4 fluoropyridi Hz,lH), 7.83(d, J= 1.2 Hz, n-2- 1H), 7.74-7.71(m, 2H), Me — V p yl)pyrrolidi 7.54-7.46(m, 3H), 7.39(t, J= 2-7 tO n-3-yl)-7- 444.0

[1179] 't\r G: 2.60 0.6 Hz, 1H), 6.59-6.56(m, methyl-2H- 1H), 4.03-3.99(m, 1H), indazol-5- 3.94-3.90(m,lH), 3.75- yl)-N, N- 3.72(m, 1H), 3.61-3.59(m, v)

[1180] F dimethylben 1H), 2.99(s, 6H), 2.68- zamide 2.61(m, 2H), 2.49 (m, 3H)

[1181] (400 MHz, DMSO-d6) 6 8.52(s, 1H), 7.94-7.93 (R)-4-(2-(l- (m,lH), 7.83(d, J= 0.8 Hz, (3- 1H), 7.74(d, J= 0.8 Hz, 1H), fluoropyridi 7.72(d, J= 1.6 Hz, 1H), n-2- 7.49(d, J= 1.6 Hz, 2H), yl)pyrrolidi 7.47-7.44(m, 1H), 7.44- 2-8 n-3-yl)-7- 444.0 G: 2.69 7.39(m, 1H), 6.69- methyl-2H- 6.65(m,lH), 5.45-5.42(m, indazol-5- 1H), 4.18-4.17(m, 1H), yl)-A^V- 4.16-4.09(m, 1H), 3.94- dimethylben 3.91(m,lH), 3.82-3.72(m, zamide 1H), 2.99(s, 6H), 2.68- 2.63(m, 2H), 2.55-2.49 (m,

[1182]

[1183] 3H)HPLC

[1184] LCMS

[1185] Ex# Structure Name Method,1H NMR (δ ppm)

[1186] (M+H)+

[1187] RT (min.)

[1188] (400 MHz, DMSO-d6) δ = 8.49 - 8.47 (m, 1H), 7.84 (d, \=o dimethyl-4- J = 0.9 Hz, 1H), 7.79 - 7.69

[1189] (7-methyl- (m, 3H), 7.53 - 7.45 (m, 2-(l -(6-oxo- 3H), 7.40 (d, J = 1.1 Hz, 1,6- 1H), 7.37 - 7.29 (m, 1H), 2-9 dihydropyri 442.2 5.84 - 5.70 (m, 1H), 5.50 - G: 2.07

[1190] iO

[1191] 'NXdin-2- 5.40 (m, 1H), 4.03 - 3.94 yl)pyrrolidi (m, 1H), 3.94 - 3.85 (m, 6 n-3-yl)-2H- 1H), 3.70 (td, J = 7.3, 10.1 \_-NH indazol-5- Hz, 1H), 3.57 (td, J = 6.9, yl)benzamid 9.9 Hz, 1H), 3.00 (br s, 8H), e 2.60 (br s, 2H), 2.57 (s, 3H),

[1192] 2.58 - 2.56 (m, 1H) (400 MHz, DMSO-d6) δ — N7

[1193] \=O (R)-4-(2-(l- 8.53 - 8.48 (m, 1H), 7.83 (d,

[1194] (3- J = 0.9 Hz, 1H), 7.76 - 7.70 cyanopheny (m, 2H), 7.52 - 7.43 (m, l)pyrrolidin- 2H), 7.41 - 7.34 (m, 2H), 2- — 3-yl)-7- 450.2 7.06 - 7.00 (m, 2H), 6.97 (s,

[1195] G: 2.71

[1196] 10 iO

[1197] 'NXmethyl-2H- 1H), 5.59 - 5.48 (m, 1H), 6 indazol-5- 3.98 - 3.88 (m, 1H), 3.86 - yl)-7V,7V- 3.77 (m, 1H), 3.71 - 3.61 CN dimethylben (m, 1H), 3.57 - 3.44 (m, zamide 1H), 2.99 (br s, 6H), 2.72 - 2.61 (m, 3H), 2.56 (s, 3H). (400 MHz, DMSO-d6) δ 8.53 - 8.48 (m, 1H), 8.04 (d, J = 2.9 Hz, 1H), 7.90 (dd, J — l /

[1198] )=O (R)-N, N- = 1.2, 4.6 Hz, 1H), 7.83 (d, dimethyl-4- J= 1.0 Hz, 1H), 7.78 - 7.71 (7-methyl- (m, 2H), 7.52 - 7.45 (m, 2-(l- 2H), 7.43 - 7.38 (m, 1H), 2- (pyri din-3 - 426.0 7.21 (dd, J = 4.6, 8.4 Hz, G: 1.52

[1199] 11 yl)pyrrolidi 1H), 7.05 - 6.95 (m, 1H),

[1200] 'NX

[1201] n-3-yl)-2H- 5.56 - 5.47 (m, 1H), 3.95 - 6 indazol-5- 3.86 (m, 1H), 3.81 (dd, J = yl)benzamid 4.6, 10.4 Hz, 1H), 3.68 (td, e J = 7.1, 9.3 Hz, 1H), 3.51 (td, J = 6.9, 9.4 Hz, 1H), 2.99 (br s, 6H), 2.70 - 2.59

[1202]

[1203] (m, 2H), 2.57 (s, 3H)HPLC

[1204] LCMS

[1205] Ex# Structure Name Method, 'H NMR (δ ppm)

[1206] (M+H)+

[1207] RT (min.)

[1208] —it (R)-N, N- (400 MHz, DMS0-d6) 8 = \=° dimethyl-4- 8.47 - 8.45 (m, 1H), 7.85 - (7-methyl- 7.82 (m, 1H), 7.76 - 7.71 2-(l-(l- (m, 2H), 7.51 - 7.46 (m, 2- methyl-1H- 2H), 7.44 - 7.38 (m, 2H), —

[1209] pyrazol-3- 429.2 G: 2.20 5.58 - 5.55 (m, 1H), 5.45 - 12 'NXyl)pyrrolidi 5.36 (m, 1H), 3.79 - 3.71 n-3-yl)-2H- (m, 1H), 3.69 - 3.63 (m, d indazol-5- 4H), 3.59 - 3.51 (m, 1H), yl)benzamid 3.41 - 3.36 (m, 1H), 2.99 e (br s, 6H), 2.58 (s, 4H) (400 MHz, DMSO-d6) δ —it (R)-N, N- 8.56 - 8.50 (m, 2H), 7.83 (d, \=°

[1210] dimethyl-4- J= 1.0 Hz, 1H), 7.76 - 7.70 (7-methyl- (m, 2H), 7.51 - 7.45 (m, 2-(l- 2H), 7.41 - 7.33 (m, 2H), 2- (pyridazin- 7.00 - 6.95 (m, 1H), 5.58 - 3- 427.2 G: 1.61 5.49 (m, 1H), 4.15 - 4.08 13 IO '1ST yl)pyrrolidi (m, 1H), 4.08 - 4.00 (m, n-3-yl)-2H- 1H), 3.83 (td, J = 7.3, 10.3 6 indazol-5- Hz, 1H), 3.71 (td, J = 6.9, \__ N

[1211] " N yl)benzamid 10.3 Hz, 1H), 2.99 (br s, e 6H), 2.73 - 2.62 (m, 2H),

[1212] 2.56 (s, 3H)

[1213] — f / (R)-4-(2-(l- (400 MHz, DMSO-d6) δ \=o (6- 8.52 (s, 1H),7.99(S,1H),<f z cyanopyridi 7.89-7.70(m,3H),7.49- n-2- 7.47(d, 2H),7.42- 2- Me - fi yl)pyrrolidi 7.39(m,lH),7.20- iOn-3-yl)-7- 451.0 G: 2.88 7.17(m,lH), 6.95-6.90(m, 14 'bT

[1214] methyl-2H- 1H), 5.49-5.20(m, 1H),4. O9- indazol-5- 3.95(m, 2H), 3.80- yl)-N, N- 3.65(m,2H), 2.99(s, 6H), NC dimethylben 2.68-2.63(m, 2H), 2.54-

[1215]

[1216] zamide 2.49(m, 3H)HPLC

[1217] LCMS

[1218] Ex# Structure Name Method, 'H NMR (δ ppm)

[1219] (M+H)+

[1220] RT (min.)

[1221] (400 MHz, DMS0-d6) 8 — t / (R)-4-(2-(l- 8.49(s, 1H), 8.11- \=o

[1222] (5- 8.10(m,lH), 7.83(d, J= 0.8 chloropyridi Hz, 1H), 7.74-7.71(m, 2H), n-2- 7.61-7.59(m, 1H), 7.49- 2- Me— AA yl)pyrrolidi 7.47(m, 2H), 7.39(t, J= 1.2 rOn-3-yl)-7- 460.0 G: 3.04 Hz, 1H), 6.61-6.51(m,lH), 15 'NZ

[1223] methyl-2H- 5.51-5.46(m, 1H), 4.05- 6 __ indazol-5- 4.00(m, 1H), 3.95- y\)-N, N- 3.92(m,lH), 3.76-3.73(m, Q dimethylben 1H), 3.66-3.62(m, 1H), Cl zamide 2.99(s, 6H), 2.68-2.63(m,

[1224] 2H), 2.55-2.49(m, 3H) — N7(R)-N, N- \=0 (400 MHz, DMSO-d6) δ dimethyl-4- 8.53(s, 1H), 7.91- AA (7-methyl- 7.83(m,lH), 7.46 -7.25(m, 2-(l-(6- 2H), 7.49-7.47(m, 2H), 2- Me — \ methylpyrid

[1225] 7.45-7.39(m, 1H), 6.63- H in-2- 440.0

[1226] 't G: 2.05

[1227] 16 \r 6.62(m, 1H), 5.56- yl)pyrrolidi

[1228] 5.47(m,lH), 4.11-3.71(m, n-3-yl)-2H- 4H), 2.99(s, 6H), 2.68- indazol-5- 2.67(m, 2H), 2.5 l(s, 3H), yl)benzamid

[1229] 2.41-42.33(m, 3H) e

[1230] (400 MHz, DMSO-d6) δ 8.47(s, 1H), 8.17(dd, J=0.2 — i / (7?)-2-(3-(5- Hz, J=1.4Hz,lH),7.85- \=o (4- 7.82(m, 2H),7.74(d, J=2 Hz, ZA (dimethylca lH),7.73(d, J=2Hz,lH), rbamoyl)ph 7.58(dd, J=7.2 Hz, J=2.4, 2- Me — fl p enyl)-7- 1H), 7.49(d, J=2Hz,lH), methyl-2H- 469.0 G: 4.12 7.47(d, J=1.6 Hz,lH), 17 H

[1231] 'NXindazol-2- 7.39(t, J=1.6Hz,2H),6.70- CONH2yl)pyrrolidi 6.67(m,lH), 5.43- n-1- 5.40(m,lH), 4.01- "0 yl)nicotina 3.92(m,2H), 3.81-3.78(m, mide 1H), 3.70-3.60(m, 1H),

[1232] 2.99(s,6H), 2.59-2.49(m,

[1233]

[1234] 5H)HPLC

[1235] LCMS

[1236] Ex# Structure Name Method, 'H NMR (δ ppm)

[1237] (M+H)+

[1238] RT (min.)

[1239] (500 MHz, DMSO-d6) 6 (7?)-(6-(3- 8.74 (d, J=2.4 Hz, 1H), 8.02 N (7-fluoro-5- (d, J=8.7 Hz, 3H), 7.88 (d, (4-(l- O J=8.3 Hz, 2H), 7.82 (s, 1H), methyl-1H- 7.79 (d, J=1.6 Hz, 1H), 7.74FH imidazol-2- (br t, J=7.7 Hz, 1H), 7.56 yl)phenyl)- 2- iO (d, J=13.1 Hz, 1H), 6.82 (d,

[1240] 'NZ2H-indazol- 469.2 E: 1.00

[1241] J=7.5 Hz, 1H), 6.69 (br d, 18 2- F: 1.66

[1242] 6 J=8.7 Hz, 1H), 5.65 - 5.54 yl)pyrrolidi

[1243] (m, 1H), 4.50 (s, 2H), 4.15 - n-1- 4.09 (m, 1H), 4.06 - 4.01 yl)pyridin- (m, 1H), 3.91 (s, 3H), 3.84 - 1? 2- 3.78 (m, 1H), 3.76 - 3.69 yl)methanol

[1244] (m, 1H), 2.71 - 2.63 (m,, TFA salt

[1245] 2H)

[1246] H (R)-6-(3-(7- O=~AN (500 MHz, DMSO-d6) 6 fluoro-5-(4- 8.67 (s, 1H), 8.41 (s, 1H), (5-oxo-l,5- 7.94 (br s, 1H), 7.89 (s, 1H), dihydro-4H- 7.86 - 7.82 (m, 2H), 7.81 - 1,2,4- 7.75 (m, 2H), 7.69 (t, J=7.9 2-F^O triazol-4- iO 'NXyl)phenyl)- 485.2 E: 1.39 Hz, 1H), 7.51 - 7.40 (m, 19 F: 1.44 2H), 7.28 (d, J=7.3 Hz, 1H),

[1247] 2H-indazol- 6.75 (br d, J=8.4 Hz, 1H), 2- 5.58 - 5.49 (m, 1H), 4.17 - yl)pyrrolidi

[1248] 4.03 (m, 2H), 3.83 - 3.77H2p

[1249] N-p n-1- (m, 1H), 3.69 (m, 1H), 2.73 yl)picolina

[1250] - 2.59 (m, 2H)

[1251] mide

[1252] H (R)-4-(4-(7- (500 MHz, DMSO-d6) 8 O^ / WN'N fluoro-2-(l- 8.64 (d, J=2.4 Hz, 1H), 8.41

[1253] (6- (s, 1H), 7.89 (s, 1H), 7.86 - (hydroxyme 7.80 (m, 2H), 7.77 (br d, thyl)pyridin J=8.6 Hz, 2H), 7.53 (t, -2- J=7.8 Hz, 1H), 7.46 (br d, 2-F^O yl)pyrrolidi J=13.2 Hz, 1H), 6.71 (d, H ' n-3-yl)-2H- 472.5 E: 1.05

[1254] i\r J=7.2 Hz, 1H), 6.41 (d, 20 F: 1.43

[1255] indazol-5- J=8.5 Hz, 1H), 5.54 - 5.48 yl)phenyl)- (m, 1H), 4.40 (s, 2H), 4.05 - 2.4- 3.99 (m, 1H), 3.93 (br dd, dihydro-3H- J=12.0, 3.5 Hz, 1H), 3.74 - 1.2.4- 3.70 (m, 1H), 3.65 - 3.63 triazol-3- (m, 1H), 2.69 - 2.58 (m,

[1256]

[1257] one 2H)HPLC

[1258] LCMS

[1259] Ex# Structure Name Method, 'H NMR (δ ppm)

[1260] (M+H)+

[1261] RT (min.)

[1262] (500 MHz, DMS0-d6) 6 8.73 (d, J=2.8 Hz, 1H), 8.06 (R)-6-(3-(7- - 8.02 (m, 3H), 7.92 (br d, fluoro-5-(4- J=2.8 Hz, 1H), 7.90 (s, 1H), (1-methyl- 7.89 - 7.88 (m, 1H), 7.87 (d, 1H- J=1.9 Hz, 1H), 7.83 (d, imidazol-2- J=1.8 Hz, 1H), 7.69 (dd, 2- yl)phenyl)- J=8.3, 7.4 Hz, 1H), 7.57 IO

[1263] ' 482.3 C: 1.20

[1264] ir 2H-indazol- (dd, J=13.2, 1.2 Hz, 1H), 21 D: 1.58

[1265] 2- 7.47 (br d, J=2.6 Hz, 1H), 6 yl)pyrrolidi 7.28 (d, J=6.9 Hz, 1H), 6.76 n-1- (d, J=8.0 Hz, 1H), 5.62 - p

[1266] yl)picolina 5.54 (m, 1H), 4.19 - 4.04 H2N-^

[1267] mide, 2 (m, 2H), 3.93 (s, 3H), 3.84 - TFA salt 3.78 (m, 1H), 3.74 - 3.69 (m, 1H), 2.74 - 2.62 (m, 2H)

[1268] (400 MHz, DMS0-d6) 8 — f / (A)-4-(2-(l- \=o 8.44(s,lH), 7.83(d, J=0.8 (6- Hz,lH),7.73(d, J=8.4 Hz, aminopyridi

[1269] 2H),7.48(d, J=8 Hz, n-2- lH),7.42-7.39(m, 1H), Me — & y 2- yl)pyrrolidi

[1270] 7.16(t, J=8 Hz,lH), 5.74(d, 441.0 iOn-3-yl)-7- G: 1.48 'FT J=7.6 Hz,lH), 5.65(d, J=8 22

[1271] methyl-2H- Hz,lH), 5.480(s, 1H), indazol-5- 5.41(t, J=6 Hz, 1H), 3.97- y\)-N, N- 0 3.847(m,2H), 3.67- dimethylben H2N 3.51(m,2H),2.99(s,6H), zamide

[1272] 2.57-2.49 (m,5H) rac-3- (500 MHz, DMSO-d6) 6 ((3R,4S)-3- 8.57 (s, 1H), 8.50 (s, 1H), methyl-4- 7.90 (br s, 1H), 7.87 - 7.80 (7-methyl- (m, 3H), 7.77 (br d, J=8.6 A 5-(4-(l- Hz, 2H), 7.42 (s, 1H), 7.30 - vJ* methyl-5- 7.25 (m, 1H), 7.22 (br s, 2- oxo- 1,5- 1H), 7.17 (br d, J=7.5 Hz,

[1273] E: 1.74 508.1 dihydro-4H- 1H), 7.10 (br s, 1H), 6.75 Oi 23 F: 1.70XN' 1,2,4- (br d, J=7.9 Hz, 1H), 5.14 - [Rac]

[1274] triazol-4- 5.03 (m, 1H), 3.99 - 3.92 H2N /

[1275] yl)phenyl)- (m, 1H), 3.90 - 3.79 (m,

[1276] 2H), 3.54 - 3.50 (m, 1H), 2H-indazol- 2- 3.43 (s, 3H), 3.08 - 2.98 (m,

[1277] 1H), 2.59 (s, 3H), 1.14 (br yl)pyrrolidi

[1278] n-1- d, J=6.5 Hz, 3H)

[1279]

[1280] HPLC

[1281] LCMS

[1282] Ex# Structure Name Method, 'H NMR (δ ppm)

[1283] (M+H)+

[1284] RT (min.)

[1285] yl)benzamid

[1286] e

[1287] (7?)-2- fluoro-3-(3- (500 MHz, DMSO-d6) 6 (7-methyl- 11.62 (s, 1H), 8.53 (s, 1H), 5-(4-(3- 7.86 (d, J=1.0Hz, 1H), 7.83 methyl-5- - 7.78 (m, 2H), 7.66 (br s, oxo- 1,5- 1H), 7.52 (br s, 1H), 7.50 - dihydro-4H- 2- 7.45 (m, 2H), 7.44 - 7.39

[1288] 1,2,4- 512.3 C: 1.42

[1289] (m, 1H), 7.12 - 7.04 (m, 24 triazol-4- D: 1.48

[1290] 1H), 6.97 - 6.90 (m, 2H), yl)phenyl)- 5.50 - 5.43 (m, 1H), 4.01 - O 2H-indazol- 3.88 (m, 2H), 3.78 - 3.72 2- (m, 1H), 3.57 - 3.52 (m, yl)pyrrolidi

[1291] 1H), 2.66 - 2.59 (m, 2H), n-1- 2.58 (s, 3H), 2.12 (s, 3H) yl)benzamid

[1292] e, TFA salt

[1293] (R)-2- fluoro-3-(3- (500 MHz, CD3OD) δ 8.88 N JLF (7-methyl- (t, J=1.7Hz, 1H), 8.48 (s,

[1294] 5-(5-(5- 1H), 8.29 (d, J=0.8 Hz, 1H), ZA methyl-1H- 8.23 (s, 1H), 8.16 (d, J=1.7

[1295] 1,2,4- Hz, 2H), 7.84 - 7.80 (m, 2- ZA

[1296] triazol-1- 4 C: 1.39 H 497.1 1H), 7.16 - 7.10 (m, 2H), 25 yl)pyridin- D: 1.47 7.05 - 6.98 (m, 1H), 5.47 - 2-yl)-2H- 5.41 (m, 1H), 4.02 (dd, F \i_ /

[1297] H2N \ / indazol-2- J=5.5, 2.2 Hz, 2H), 3.89 - yl)pyrrolidi 3.80 (m, 1H), 3.65 - 3.56 c / v /

[1298] n-1- (m, 1H), 2.68 (s, 3H), 2.66 yl)benzamid (s, 3H), 2.77 - 2.60 (m, 2H)

[1299]

[1300] e, TFA salt

[1301] Example 3-1: (R)-3-(3-(7-methyl-5-(5-(5-methyl-1H-pyrazol-l-yl)pyridin-2-yl)-2H-indazol- 2-yl)pyrrolidin-l-yl)benzamide, TFA salt

[1302]

[1303] Example 3-la: (A)-3-(3-(7-methyl-5-(5-(5-methyl-1H-pyrazol-l-yl)pyridin-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrile

[1304]

[1305] To a solution of Intermediate 10 (39.8 mg, 0.093 mmol) in dioxane (2 mL) and H2O (0.2 mL), was added Intermediate 40 (15 mg, 0.077 mmol) followed by the addition of K3PO4 (41.1 mg, 0.194 mmol) and XPhos-Pd-G2 (6.10 mg, 7.75 pmol). The reaction was stirred under N2 at 90 °C for 1 h. The solvent was removed. The crude product was purified by normal phase chromatography to give Example 3-la (14 mg, 39%). MS (ESI) m / z 460.2 (M+H)+.

[1306] Example 3-lb: (A)-3-(3-(7-methyl-5-(5-(5-methyl-1H-pyrazol-l-yl)pyridin-2-yl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzamide, TFA salt

[1307]

[1308] To a solution of Example 3-la (14 mg, 0.030 mmol) in DMSO (1 mL), was added K2CO3 (16.8 mg, 0.12 mmol), followed by the addition of hydrogen peroxide (30%, 0.031 mL, 0.31 mmol). The reaction was stirred under N2 at rt for 1 h. The crude product was purified by reverse phase chromatography to provide Example 3-1 (15 mg, 83%). ESI m / z 478.1 (M+H)+. 'HNMR (500 MHz, DMSO-d6) δ 8.83 (dd, J=2.6, 0.6 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J=0.8 Hz, 1H), 8.13 (dd, J=8.6, 0.6 Hz, 1H), 8.04 (dd, J=8.6, 2.6 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.65 (d, J=1.5 Hz, 1H), 7.29 - 7.20 (m, 2H), 7.17 (d, J=7.8 Hz, 1H), 7.12 (d, J=1.9 Hz, 1H), 6.78 (dd, J=8.0, 1.8 Hz, 1H), 6.36 (dd, J=1.7, 0.8 Hz, 1H), 5.57 - 5.49 (m, 1H), 3.93 (dd, J=10.3, 6.9 Hz, 1H), 3.83 (dd, J=10.3, 4.6 Hz, 1H), 3.72 - 3.66 (m, 1H), 3.52 (dt, J=9.3, 7.0 Hz, 1H), 2.68 (q, J=6.9 Hz, 2H), 2.59 (s, 3H), 2.43 (s, 3H). Analytical HPLC: RT = 1.55 min (Method C) and 1.69 min (Method D).The examples listed in Table 3 were prepared by following similar procedures to that described in Example 3-1 from the appropriate commercially available starting materials and / or intermediates described above.

[1309] Table 3

[1310] HPLC LCMS Method,

[1311] Ex# Structure Name 'H NMR (δ ppm)

[1312] (M+H)+RT

[1313] (min.)

[1314] (500 MHz, DMSO-d6) 6 8.67 (d, 7=1.4 Hz, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 8.09 (br d, 7=4.1 Hz, 1H), (R)-N, N- 8.02 (d, 7=8.5 Hz, 1H), ft dimethyl-6- 7.89 (dd, 7=8.3, 2.0 Hz, (7-methyl-2- 1H), 7.85 (s, 1H), 7.55 - (l-(pyridin- 7.49 (m, 1H), 6.63 - 6.58 3-2 A 2- E: 1.12

[1315] vT 427.1 (m, 1H), 6.54 (d,,7=8.5 Hz, yl)pyrrolidin F: 1.53

[1316] 1H), 5.53 - 5.42 (m, 1H), -3-yl)-2H- 4.07 - 4.00 (m, 1H), 3.94 indazol-5- (dd, 7=11.3, 4.4 Hz, 1H), yl)nicotinami

[1317] 3.77 - 3.71 (m, 1H), 3.60 de

[1318] (br dd, 7=9.8, 6.9 Hz, 1H), 3.01 (br d, 7=7.2 Hz, 6H), 2.64 (q, 7=6.8 Hz, 2H), 2.56 (s, 3H)

[1319] (500 MHz, DMSO-d6) 6 8.77 (d, 7=2.3 Hz, 1H), 8.52 (s, 1H), 8.29 (s, 1H), methyl-5-(5- 8.09 (d, 7=8.7 Hz, 1H), N (5-methyl- 8.05 (br d, 7=4.7 Hz, 1H), IH-pyrazol- 8.00 (dd, 7=8.6, 2.4 Hz, 3-3 1-yl)pyridin- 436.1 E: 1.35 1H), 7.84 (s, 1H), 7.63 (s,

[1320] 2-yl)-2-(l- F: 1.91 1H), 7.57 - 7.48 (m, 1H), (pyridin-2- 6.64 - 6.58 (m, 1H), 6.54 yl)pyrrolidin (d, 7=8.5 Hz, 1H), 6.35 (s,

[1321] 1H), 5.49 - 5.40 (m, 1H), -3-yl)-2H- 4.01- 3.61 (s, 4H), 2.67 - indazole

[1322] 2.60 (m, 2H), 2.56 (s, 3H), 2.39 (s, 3H)

[1323]

[1324] HPLC

[1325] LCMS Method,

[1326] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1327] (min.)

[1328] (400 MHz, CD3OD) δ 8.17 (dd, J=8.2, 3.5 Hz, 1H), 8.17 (dd, J=8.2, 3.5 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.97 (d, J=8.2 Hz, (A)-3-(3-(7- 1H), 7.75 (s, 1H), 7.75 (s, methyl-5-(4- 1H), 7.75 (s, 1H), 7.59 (d, (5-oxo-4,5- J=7.4 Hz, 1H), 7.45 (dd, dihydro-1H- J=8.1, 7.4 Hz, 1H), 7.39 (s, 1,2,4-triazol- 1H), 7.15 (s, 1H), 7.09 (d, 3-4 1-yl)phenyl)- 480.1 J=8.1 Hz, 1H), 5.07 (dddd,

[1329] C: 1.53

[1330] H 2H-indazol- J=8.7, 7.5, 6.5, 5.3 Hz,XN'

[1331] 2- 1H), 4.09 (dd, J=5.3, -7.9 yl)pyrrolidin Hz, 1H), 3.68 (dd, J=6.5, - d

[1332] H2N -1- 7.9 Hz, 1H), 3.49 (ddd, yl)benzamid J=10.7, 7.3, 3.2 Hz, 1H), e, TFA salt 3.41 (ddd, J=10.7, 7.3, 6.0

[1333] Hz, 1H), 2.70 (s, 3H), 2.63 (dddd, J=12.7, 7.5, 7.3, 3.2 Hz, 1H), 2.54 (dddd, J=12.7, 8.7, 7.3, 6.0 Hz, 1H)

[1334] (500 MHz, DMSO-d6) 6 8.52 (s, 1H), 8.06 (br d,, / =5.8 Hz, 1H), 7.89 - 7.82 3 -hydroxy- 1- (m, 1H), 7.77 (br d, J=6.0 (4-(7- Hz, 3H), 7.70 (br d, J=8.6 methyl-2- Hz, 2H), 7.38 (s, 1H), 6.96 O)-1- (br d,. / =8,5 Hz, 1H), 6.84 (pyridin-2- (br t, J=6.3 Hz, 1H), 5.60 - 3-5 yl)pyrrolidin 455.1 E: 1.22

[1335] M, 5.52 (m, 1H), 4.36 - 4.30

[1336] -3-yl)-2H- F: 1.67

[1337] XN' (m, 1H), 4.17 - 4.11 (m, indazol-5- 1H), 4.09 - 4.04 (m, 1H), yl)phenyl)py

[1338] 3.88 - 3.83 (m, 1H), 3.79 N— / rrolidin-2- (br d,,7=8.6 Hz, 1H), 3.77 - one, TFA

[1339] 3.73 (m, 2H), 2.74 - 2.64 salt

[1340] (m, 2H), 2.54 (s, 3H), 2.47 - 2.39 (m, 1H), 1.95 - 1.82

[1341]

[1342] (m, 1H)HPLC

[1343] LCMS Method,

[1344] Ex# Structure Name

[1345] CJHNMR(5 ppm) f (M+H)+RT

[1346] (min.)

[1347] 8.38 (s, 1H), 8.05 (br d,. / =4,9 Hz, 1H), 7.71 (s, (A)-l-(4-(7- 1H), 7.65 - 7.57 (m, 4H), methyl-2-(l- 7.55 - 7.49 (m, 1H), 7.33 (pyridin-2- (s, 1H), 6.86 (s, 1H), 6.60 yl)pyrrolidin (dd, J=6.6, 5.4 Hz, 1H), 3-6 E: 1.25

[1348] -3-yl)-2H- 439.2 6.53 (d,.7=8.5 Hz, 1H), F: 1.74

[1349] indazol-5- 5.46 - 5.39 (m, 1H), 3.99 yl)phenyl)im (dd, 7=11.1, 6.8 Hz, 1H), idazolidin-2- 3.92 - 3.85 (m, 3H), 3.60 - one 3.56 (m, 1H), 3.42 (brt,

[1350] 7=7.9 Hz, 2H), 2.66 - 2.57 (m, 2H), 2.53 (s, 3H) (500 MHz, METHANOL- N

[1351] (A)-3-(3-(7- d4) δ 8.87 (dd, 7=2.2, 1.2 tr methyl-5-(5- Hz, 1H), 8.42 (s, 1H), 8.29

[1352] (5-methyl- (d, 7=0.8 Hz, 1H), 8.19 (s, 1H-1,2,4- 1H), 8.18 - 8.13 (m, 2H), triazol-1- 7.86 - 7.82 (m, 1H), 7.37 - 3-7 yl)pyridin-2- 479.2 C: 1.369 7.31 (m, 1H), 7.24 - 7.19 Oi yl)-2H- D: 1.43 (m, 2H), 6.94 - 6.86 (m, indazol-2- 1H), 5.56 - 5.51 (m, 1H), yl)pyrrolidin 4.04 - 3.92 (m, 2H), 3.83 - d

[1353] H2N / -1- 3.74 (m, 1H), 3.65 - 3.56 yl)benzamid (m, 1H), 2.84 - 2.70 (m, e, TFA salt 2H), 2.69 (s, 3H), 2.65 (s,

[1354] 3H)

[1355] (500 MHz, DMSO-d6) 6 8.45 (s, 1H), 7.88 (br s, (A)-4-(2-(l- 1H), 7.59 (d, 7=0.8 Hz, (3- w° 1H), 7.34 (d, 7=7.6 Hz, / carbamoylph

[1356] 1H), 7.29 - 7.25 (m, 1H), enyl)pyrrolid

[1357] 7.23 (br s, 1H), 7.16 (d, in-3-yl)-7- 7=7.8 Hz, 1H), 7.15 - 7.13 methyl-2H- 3-8 E: 1.55 (m, 1H), 7.12 - 7.10 (m, o indazol-5- 498.2

[1358] XNZF: 1.58 1H), 7.10 (d, 7=1.4 Hz, yl)-3- 1H), 7.04 (dd, 7=7.6, 1.5 methoxy- d Hz, 1H), 6.77 (dd, 7=8.1, H2N - / N, N- 1.7 Hz, 1H), 5.55 - 5.46 dimethylben

[1359] (m, 1H), 3.95 - 3.89 (m, zamide, TFA

[1360] 1H), 3.83 - 3.79 (m, 1H), salt

[1361] 3.78 (s, 3H), 3.71 - 3.63

[1362]

[1363] (m, 1H), 3.54 - 3.48 (m,HPLC

[1364] LCMS Method,

[1365] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1366] (min.)

[1367] 1H), 3.00 (br s, 6H), 2.70 - 2.62 (m, 2H), 2.53 (s, 3H) (500 MHz, DMSO-d6) 6 8.45 (s, 1H), 7.91 (br s, (R)-3-(3-(7- 1H), 7.77 (s, 1H), 7.66 (br methyl-5-(4- d, 7=8.3 Hz, 2H), 7.36 (s, (2- 1H), 7.33 (br d, 7=8.2 Hz, oxopiperidin 2H), 7.29 - 7.21 (m, 2H), -1- 7.18 - 7.14 (m, 1H), 7.10 3-9 yl)phenyl)- 494.0 E: 1.69 (s, 1H), 6.77 (br d, 7=7.2

[1368] Mi

[1369] X2H-indazol- F: 1.71 Hz, 1H), 5.56 - 5.42 (m, N'

[1370] 2- 1H), 3.95 - 3.88 (m, 1H), yl)pyrrolidin 3.80 (br dd, 7=9.9, 3.9 Hz, 6

[1371] H2N -1- 1H), 3.69 - 3.58 (m, 4H), dMD yl)benzamid 2.70 - 2.61 (m, 2H), 2.56 e (br s, 3H), 2.40 (br t, 7=6.1

[1372] Hz, 2H), 1.94 - 1.79 (m, 4H)

[1373] (500 MHz, DMSO-d6) 6 8.49 (s, 1H), 8.42 (s, 1H), H N (7?)-3-(3-(5- 7.90 (br s, 1H), 7.77 (s, (3-(2-NC' " O 2H), 7.51 - 7.46 (m, 1H), cyanamido- 7.45 - 7.41 (m, 2H), 7.35 4,5-dihydro- (s, 1H), 7.30 - 7.21 (m, IH-imidazol- 2H), 7.16 (br d, 7=7.9 Hz, 3- 7 Me 1-yl)phenyl)- 5 E: 1.60 1H), 7.11 (s, 1H), 6.82 - 7-methyl- 505.2

[1374] 10 Mi F: 1.66 6.74 (m, 1H), 5.60 - 5.43

[1375] XN' 2H-indazol- (m, 1H), 4.15 (t, 7=8.5 Hz, 2- 2H), 3.95 - 3.88 (m, 1H), 0 yl)pyrrolidin

[1376] o / =( 3.81 (dd, 7=10.1, 4.4 Hz,

[1377] -1- H2NZ1H), 3.70 - 3.65 (m, 1H), yl)benzamid

[1378] 3.61 (br t, 7=8.7 Hz, 2H), e

[1379] 3.54 - 3.48 (m, 1H), 2.70 -

[1380]

[1381] 2.62 (m, 2H), 2.57 (s, 3H)HPLC

[1382] LCMS Method,

[1383] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1384] (min.)

[1385] \0(400 MHz, DMSO-d6): 8

[1386] (7?)-2-(2-(l- 2.68-2.61 (m, 2H), 3.05 (s, (3- 6H), 3.57-3.56 (m, 1H), carbamoyl-2- 3.76-3.74 (m, 1H), 3.91- ' h fluorophenyl

[1387] 3.90 (m, 1H), 4.00-4.00 )pyrrolidin- 3- £jVF(m, 1H), 5.53 (m, 1H),

[1388] 3-yl)-7- 492.0 G: 2.20 6.95-6.91 (m, 2H), 7.10- 11XN' fluoro-2H- 7.06 (m, 1H), 7.52 (s, 1H), indazol-5- 7.66 (s, 1H), 8.00 (dd, J = yl)-N, N-. d 0.80, 13.40 Hz, 1H), 8.77H2NV_ / dimethylpyri

[1389] (d, J = 0.80 Hz, 1H), 8.87 midine-5- (d, J = 2.80 Hz, 1H), 8.98 carboxamide

[1390] (s, 1H)

[1391] (400 MHz, DMSO-d6): 6 (7?)-2-fluoro- 2.68-2.60 (m, 2H), 3.57- 3-(3-(7- 3.55 (m, 1H), 3.76-3.74 cr

[1392] fluoro-5-(4- (m, 1H), 3.81 (s, 3H), (1-methyl- 3.98-3.91 (m, 1H), 4.00- IH-imidazol- 3.99 (m, 1H), 5.52-5.51 3- Xjv 2-yl)phenyl)- (m, 1H), 6.96-6.91 (m,

[1393] 2H-indazol- 499.0 G: 2.04 2H), 7.01 (d, J = 1.20 Hz, 12 o

[1394] XN' 2- 1H), 7.10-7.07 (m, 1H), yl)pyrrolidin 7.28 (d, J = 1.20 Hz, 1H),. 0

[1395] H2N \ Z -1- 7.52-7.48 (m, 2H), 7.66 (s, yl)benzamid 1H), 7.80-7.78 (m, 2H), e, 0.2 formic 7.85-7.82 (m, 2H), 7.93 (d, acid salt J = 1.20 Hz, 1H), 8.70 (d, J = 2.80 Hz, 1H) (7?)-2-fluoro- (400 MHz, DMSO-d6): 6 H

[1396] N 3-(3-(7- 8.47 (s, 1H), 7.73 (d, J = cr methyl-5-(4- 0.80 Hz, 1H), 7.61-7.65 (2- (m, 5H), 7.51 (s, 1H), 7.35 oxoimidazoli (d, J = 1.20 Hz, 1H), 7.08 3- p — Me din-1- (t, J = 7.60 Hz, 1H), 6.91- yl)phenyl)- 499.0 G: 2.30 6.95 (m, 3H), 5.44 (t, J = 13 o

[1397] XN' 2H-indazol- 4.80 Hz, 1H), 3.87-3.97

[1398] 2- (m, 4H), 3.74 (d, J = 7.20. d

[1399] o / =( yl)pyrrolidin Hz, 1H), 3.55 (d, J = 7.60 H2N -1- Hz, 1H), 3.43 (t, J = 7.20 yl)benzamid Hz, 2H), 2.56-2.63 (m,

[1400]

[1401] e 2H), 2.54 (s, 3H).HPLC

[1402] ZE LCMS Method,

[1403] Ex# Structure NameJHNMR(5 ppm) ° 1 1 (M+H)+RT

[1404] (min.)

[1405] C u

[1406] \ 7 T iz" (400 MHz, DMSO-d6): 8

[1407] (7?)-2-fluoro- 8.51 (s, 1H), 7.80 (d, J = (D 3-(3-(7- 0.80 Hz, 1H), 7.70-7.72 methyl-5-(4- (m, 2H), 7.66 (s, 1H), 7.51 (3- (s, 1H), 7.46-7.49 (m, 2H), oxomorpholi

[1408] 3- 7.38 (t, J = 1.20 Hz, 1H), no)phenyl)- 514.0 G: 2.29 7.08 (t, J = 8.00 Hz, 1H), 14 2H-indazol- 6.91-6.94 (m, 2H), 5.46 (t, 2- J = 4.80 Hz, 1H), 4.23 (s, yl)pyrrolidin

[1409] 2H), 3.95-4.01 (m, 3H), -1- 3.89-3.91 (m, 1H), 3.80- yl)benzamid

[1410] 3.73 (m, 3H), 3.55.3.53 (d, e

[1411] 1H), 2.61.-2.57 (m, 5H) (400 MHz, DMSO-d6): 6 r^N (7?)-2-fluoro- 8.54 (s, 1H), 8.03 (d, J = S-? 3-(3-(7- 2.00 Hz, 2H), 7.95 (d, J = methyl-5-(4- 3.20 Hz, 1H), 7.89 (s, 1H), (thiazol-2- 7.84 (d, J = 2.00 Hz, 1H), 3- v Me yl)phenyl)- 7.80-7.83 (m, 3H), 7.66 (s,

[1412] 498.0

[1413] M 2H-indazol- G: 2.68 1H), 7.52 (s, 1H), 7.44 (s, 15XN' 2- 1H), 7.08 (t, J = 7.60 Hz, yl)pyrrolidin 1H), 6.91-6.94 (m, 2H), FX0

[1414] -1- 3.95-3.98 (m, 1H), 3.90 (d, yl)benzamid J = 2.40 Hz, 1H), 3.76-3.74 e (d, 1H), 3.56-3.54 (d, 1H),

[1415] 2.64-2.58 (m, 5H)

[1416] 0 (400 MHz, DMSO-d6): 6 GN9.02 (d, J = 2.00 Hz, 1H),

[1417] (7?)-2-fluoro- 8.54 (s, 1H), 7.98 (d, J = 3-(3-(5-(4- 8.40 Hz, 2H), 7.86 (t, J = (isoxazol-3- 8.40 Hz, 3H), 7.66 (s, 1H), yl)phenyl)-7- 7.52 (s, 1H), 7.44 (s, 1H), 3- <( V- Me

[1418] methyl-2H- 482.2 7.21 (d, J = 1.60 Hz, 1H),

[1419] G: 2.96

[1420] 16 H indazol-2- 7.08 (t, J = 8.00 Hz, 1H),

[1421] XN'

[1422] yl)pyrrolidin 6.93-6.96 (m, 2H), 5.44- -1- 5.50 (m, 1H), 3.95-4.00. 0 yl)benzamid (m, 1H), 3.87-3.91 (m, e 1H), 3.77-3.72 (m, 1H), «zb 3.57-3.52 (m, 1H), 2.58-

[1423]

[1424] 2.51 (m, 5H)HPLC

[1425] LCMS Method,

[1426] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1427] (min.)

[1428] (400 MHz, DMSO-d6): 8 (7?)-2-fluoro- 8.49 (s, 1H), 7.77 (s, 1H), 3-(3-(7- 7.70-7.73 (m, 2H), 7.63- methyl-5-(4- 7.66 (m, 2H), 7.51 (s, 1H), (2- 7.37 (d, J = 1.20 Hz, 1H), N oxooxazolidi

[1429] N5 7.08 (t, J = 7.60 Hz, 1H), 3- n-3- M 500.0 6.91-6.95 (m, 2H), 5.45 (t, e — Z \ yl)phenyl)- G: 2.43

[1430] 17 J = 4.80 Hz, 1H), 4.47 (dd,

[1431] 2H-indazol- J = 6.40, 9.00 Hz, 2H), 2- o 4.09-4.13 (m, 2H), 3.96 (t, yl)pyrrolidin

[1432] J = 4.40 Hz, 1H), 3.89 (q, J -1- °xo3 = 6.00 Hz, 1H), 3.75-3.72 yl)benzamid

[1433] (d, 1H), 3.55-3.53 (d, 1H), e

[1434] 2.61-2.52 (m, 5H) 500 MHz, DMSO-d6) 6 8.48 (s, 1H), 7.88 (br s, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.71 (d,. / =8,6 Hz, (R)-3-(3-(7- 2H), 7.49 - 7.47 (m, 2H), c>°

[1435] methyl-5-(4- 7.40 - 7.36 (m, 1H), 7.29 - (3- 7.24 (m, 1H), 7.23 (br s, oxomorpholi 1H), 7.17 (d, J=7.8 Hz, 3- no)phenyl)- 1H), 7.13 - 7.09 (m, 1H),

[1436] 496.2 C: 1.51

[1437] 2H-indazol- 6.78 (dd, J=8.1, 1.9 Hz, 18 Oi D: 1.54

[1438] XN' 2- 1H), 5.56 - 5.48 (m, 1H), yl)pyrrolidin 4.25 - 4.21 (m, 2H), 4.04 - 0 -1- 3.97 (m, 2H), 3.95 - 3.88 H2N /

[1439] yl)benzamid (m, 1H), 3.84 - 3.80 (m, e, TFA salt 1H), 3.80 - 3.76 (m, 2H),

[1440] 3.71 - 3.64 (m, 1H), 3.51 (dt, J=9.2, 6.9 Hz, 1H), 2.69 - 2.63 (m, 2H), 2.57

[1441]

[1442] (s, 3H)HPLC

[1443] LCMS Method,

[1444] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1445] (min.)

[1446] (500 MHz, DMSO-d6) 6 8.76 (d, J=2.2 Hz, 1H), 8.50 (s, 1H), 8.17 (s, 1H),Hy° (7?)-3-(3-(5- 8.10 (dd, <7=8.8, 2.4 Hz, (5- 1H), 7.91 (br d, <7=8.8 Hz, acetamidopy 2H), 7.79 (s, 1H), 7.33 - ridin-2-yl)-7- 7.20 (m, 2H), 7.17 (d, 3- methyl-2H- 454.9 E: 1.26 <7=7.6 Hz, 1H), 7.11 (s, 19 o

[1447] Xindazol-2- F: 1.41 1H), 6.78 (dd, <7=8.1, 1.9 N'

[1448] yl)pyrrolidin Hz, 1H), 5.55 - 5.45 (m, -1- 1H), 3.95 - 3.89 (m, 1H), d

[1449] H2N / = / yl)benzamid 3.81 (dd, <7=10.3, 4.5 Hz, e 1H), 3.73 - 3.63 (m, 1H),

[1450] 3.55 - 3.47 (m, 1H), 2.66 (q, <7=6.8 Hz, 2H), 2.56 (s, 3H), 2.10 (s, 3H)

[1451] (500 MHz, DMSO-d6) 6 8.50 (s, 1H), 8.23 (s, 1H), 7.94 (br s, 1H), 7.82 (d, 3-((3R)-3-(5- <7=8.4 Hz, 1H), 7.78 (s, (5-(3- 1H), 7.67 (d, <7=8.2 Hz, hydroxy-2- 1H), 7.30 - 7.24 (m, 1H), oxopyrrolidi 7.21 (br s, 1H), 7.14 (d, O'1n-l-yl)-6- <7=7.6 Hz, 1H), 7.09 (s, 3- methylpyridi 1H), 6.78 (dd, <7=8.5, 1.8 E: 1.24

[1452] n-2-yl)-7- 511.0 Hz, 1H), 5.52 - 5.44 (m, 20 O

[1453] Xi

[1454] N' F: 1.41

[1455] methyl-2H- 1H), 4.39 - 4.28 (m, 1H), indazol-2- 3.94 - 3.87 (m, 1H), 3.83 -H2Nyl)pyrrolidin 3.76 (m, 1H), 3.71 - 3.67

[1456] -1- (m, 2H), 3.64 - 3.56 (m, yl)benzamid 1H), 3.53 - 3.44 (m, 1H), e 2.70 - 2.61 (m, 2H), 2.56

[1457] (br s, 3H), 2.49 - 2.43 (m, 1H), 2.39 (s, 3H), 1.98 (dq,

[1458]

[1459] <7=12.4, 8.7 Hz, 1H)HPLC

[1460] LCMS Method,

[1461] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1462] (min.)

[1463] (400 MHz, DMSO-d6): 8 8.49 (s, 1H), 7.79-7.81 (m, HC^ 2-fluoro-3- 3H), 7.71 (d, J = 8.80 Hz, O)-3-(5-(4- 1H), 7.65 (s, 1H), 7.51 (s, ((5)-3- 1H), 7.37 (s, 1H), 7.08 (t, J hydroxy-2- = 7.60 Hz, 1H), 6.93 (q, J oxopyrrolidi

[1464] = 8.40 Hz, 2H), 5.76 (d, J 3- Me n-1- = 6.00 Hz, 1H), 5.45 (s, 21 MXl yl)phenyl)-7- 514.0

[1465] N' G: 2.17

[1466] 1H), 4.32-4.34 (m, 1H), methyl-2H- 3.95-3.97 (m, 1H), 3.81- indazol-2- 3.90 (m, 1H), 3.78-3.75 yl)pyrrolidin

[1467] (m, 1H), 3.74-3.73 (m, -1- 3H), 3.55-3.53 (m, 1H), yl)benzamid

[1468] 2.61-2.60 (m, 2H), 2.49 (s, e

[1469] 3H), 2.44-2.42 (m, 1H), 1.9-1.85 (m, 1H)

[1470] (400 MHz, DMSO-d6): 6 2-fluoro-3- „O 8.49 (s, 1H), 7.77-7.79 (m,

[1471] O)-3-(5-(4- D < 3H), 7.70 (t, J = 2.00 Hz, O)-3- 2H), 7.65 (s, 1H), 7.51 (s, hydroxy-2- i ■ • 1H), 7.37 (s, 1H), 7.06- oxopyrrolidi

[1472] 7.10 (m, 1H), 6.91-6.95 3- JO. ° # A— Me n-1- (m, 2H), 5.77 (m, 1H), T ' H yl)phenyl)-7- 514.0 G: 2.16

[1473] 22 5.44-5.46

[1474] CXN' (m, 1H), 4.31- N Z methyl-2H- X 4.35 (m, 1H), 3.95-3.97 indazol-2- (m, 1H), 3.81-3.89 (m, o Y_- / yl)pyrrolidin

[1475] 1H), 3.80-3.73 (m, 3H), -1- H2N 3.55-3.53 (m, 1H), 2.61- yl)benzamid

[1476] 2.49 (m, 5H), 2.49-2.43 e

[1477] (m, 1H), 1.9-1.85 (m, 1H) (7?)-2-fluoro- (400 MHz, DMSO-d6): 6 3-(3-(7- 8.57 (s, 1H), 7.94-7.99 (m, methyl-5-(4- 5H), 7.65 (s, 1H), 7.52 (s, (m ethyl sulfo 1H), 7.44 (s, 1H), 7.08 (t, J 3- nyl)phenyl)- = 7.60 Hz, 1H), 6.91-6.95

[1478] 2H-indazol- 493.1 G: 2.45 (m, 2H), 5.48 (m, 1H), 23

[1479] 2- 3.96-3.99 (m, 1H), 3.88- yl)pyrrolidin 3.89 (m, 1H), 3.72-3.78 -1- (m, 1H), 3.52-3.58 (m, yl)benzamid 1H), 3.25 (s, 3H), 2.67-

[1480]

[1481] e 2.62 (m, 1H), 2.58 (s, 3H)HPLC

[1482] LCMS Method,

[1483] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1484] (min.)

[1485] (400 MHz, DMSO-d6): 8 9.76 (s, 1H), 8.48 (s, 1H), o (7?)-2-fluoro- — S-NH 7.74 (d, J = 0.80 Hz, 1H),

[1486] 3-(3-(7-6?=\ 7.65 (d, J = 2.00 Hz, 3H), methyl-5-(4- 7.51 (s, 1H), 7.34 (s, 1H), (m ethyl sulfo

[1487] 7.29 (q, J = 2.00 Hz, 2H), 3- Me namido)phen

[1488] 508.1 7.08 (t, J = 7.60 Hz, 1H), H yl)-2H- G: 2.36

[1489] 24XN' 6.92 (t, J = 8.00 Hz, 2H), indazol-2- 5.45 (t, J = 4.80 Hz, 1H), yl)pyrrolidin

[1490] . O

[1491] H23.94-3.99 (m, 2H), 3.86- N \ Z -1- 3.90 (m, 1H), 3.71-3.75 yl)benzamid

[1492] (m, 1H), 3.01 (s, 3H), e

[1493] 2.61-2.58 (m, 1H), 2.51 (s, 3H)

[1494] (400 MHz, DMSO-d6): 6 O^N9.73 (s, 1H), 8.55 (s, 1H),

[1495] (7?)-3-(3-(5- 8.12 (q, J = 1.60 Hz, 2H), (4-(l,2,4- 7.91 (t, J = 1.60 Hz, 3H), Q oxadiazol-3- 7.66 (s, 1H), 7.52 (s, 1H), yl)phenyl)-7- 3- Me 7.46 (s, 1H), 7.08 (t, J = methyl-2H- 483.0 G: 2.87 7.60 Hz, 1H), 6.93-6.96 25 H

[1496] XN' indazol-2- (m, 2H), 5.46-5.49 (m, yl)pyrrolidin

[1497] 1H), 3.96-4.00 (m, 1H),. 0 -l-yl)-2- H2N \ Z 3.87-3.91 (m, 1H), 3.72- fluorobenza

[1498] 3.78 (m, 1H), 3.57-3.52 mide

[1499] (m, 1H), 2.64-2.59 (m, 2H), 2.51 (s, 3H) (400 MHz, DMSO-d6): 6 8.68 (d, J = 0.80 Hz, 1H), O^N(7?)-2-fluoro- 8.51 (s, 1H), 8.49 (d, J = 3-(3-(7- 0.80 Hz, 1H), 7.87 (t, J = methyl-5-(4- 2.00 Hz, 3H), 7.77 (q, J = (oxazol-4- 2.00 Hz, 2H), 7.65 (s, 1H), 3- Me yl)phenyl)- 7.52 (s, 1H), 7.42 (s, 1H), H| 2H-indazol- 482.0 G: 2.81

[1500] 27XN' 7.08 (t, J = 8.00 Hz, 1H),

[1501] 2- 6.91-6.94 (m, 2H), 5.43- yl)pyrrolidin

[1502] 5.49 (m, 1H), 3.96-4.002F b

[1503] H N \ Z -1- (m, 1H), 3.86-3.91 (m, yl)benzamid

[1504] c / ~O 1H), 3.77-3.72 (m, 1H), e

[1505] 3.57-3.52 (m, 1H), 2.63-

[1506]

[1507] 2.60 (m, 2H), 2.51 (s, 3H)HPLC

[1508] LCMS Method,

[1509] Ex# Structure NameJHNMR(5 ppm) (M+H)+RT

[1510] (min.)

[1511] (500 MHz, DMSO-d6) 6 10.40 (s, 1H), 9.04 (s, 2H), (7?)-3-(3-(5- 8.60 (s, 1H), 8.58 (s, 1H), (5- 8.04 (s, 1H), 7.89 (br s, b acetamidopy 1H), 7.31 - 7.21 (m, 2H), rimidin-2- 7.17 (br d,. / =7,9 Hz, 1H), 3- yl)-7-methyl- 7.11 (s, 1H), 6.78 (br d, E: 1.43

[1512] HXN 2H-indazol- 456.1, / =9.3 Hz, 1H), 5.55 - 5.46 28 ' F: 1.40

[1513] 2- (m, 1H), 3.96 - 3.89 (m, yl)pyrrolidin 1H), 3.81 (br dd, J=10.0, H2N d -1- 4.2 Hz, 1H), 3.73 - 3.64 MO yl)benzamid (m, 1H), 3.56 - 3.46 (m, e 1H), 2.67 (q,. / =6,5 Hz,

[1514] 2H), 2.57 (s, 3H), 2.13 (s, 3H)

[1515] (400 MHz, DMSO-d6) 8 = (7?)-2-fluoro- 8.51 (s, 1H), 7.80 (brs, 3-(3-(7- c>° 1H), 7.72 (d, J = 8.4 Hz, methyl-5-(4- 2H), 7.65 (brs, 1H), 7.51 (4-methyl-2- O (brs, 1H), 7.42-7.37 (m, oxopiperazin

[1516] 3H), 7.08 (t, J = 8.0 Hz, 3- %— Me -1- 1H), 6.95-6.91 (m, 2H), yl)phenyl)- 497.2 G: 2.07

[1517] 29 H 5.48-5.43 (m, 1H), 3.98- N' 2H-indazol- 3.95 (m, 1H), 3.90-3.87 2- (m, 1H), 3.81-3.72 (m,, 6

[1518] H2N \ J yl)pyrrolidin

[1519] 3H), 3.57-3.52 (m, 1H), -1- 3.31 (s, 2H), 2.66-2.60 (m, yl)benzamid

[1520] 4H), 2.57 (s, 3H), 2.50 (s, e

[1521] 3H)

[1522] (500 MHz, DMSO-d6) 6 10.31 (br s, 1H), 8.47 (s, H

[1523] N (R)-3-(3-(7- 1H), 7.88 (br s, 1H), 7.83 - methyl-5-(4- tr 7.77 (m, 3H), 7.75 - 7.71

[1524] (2-oxo-2,3- (m, 2H), 7.43 - 7.37 (m, dihydro-1H- O 1H), 7.29 - 7.25 (m, 1H), imidazol-1- 3- 7.23 (br s, 1H), 7.17 (d, yl)phenyl)- C: 1.53 479.1 J=7.6 Hz, 1H), 7.12 (d, 30 D: 1.49 Mi 2H-indazol-XN' J=2.1 Hz, 1H), 7.02 (dd,

[1525] 2- J=3.1, 2.1 Hz, 1H), 6.78 yl)pyrrolidin

[1526] (dd, J=8.2, 1.8 Hz, 1H), -1- H2N 6.65 - 6.59 (m, 1H), 5.56 - yl)benzamid

[1527] 5.47 (m, 1H), 3.96 - 3.90 MO e, TFA salt

[1528] (m, 1H), 3.82 (dd, J=10.3, 4.6 Hz, 1H), 3.71 - 3.65

[1529]

[1530] HPLC

[1531] LCMS Method,

[1532] Ex# Structure Name1HNMR (6 ppm)

[1533] (M+H)+RT

[1534] (min.)

[1535] (m, 1H), 3.54 - 3.48 (m, 1H), 2.72 - 2.64 (m, 2H),

[1536]

[1537] 2.58 (s, 3H)

[1538] Example 4-1: (A)-3-(3-(7-methyl-5-(4-(5-methyl-1H-l,2,4-triazol-l-yl)phenyl)-2H-indazol- 2-yl)pyrrolidin-l-yl)benzamide, TFA salt

[1539]

[1540] To a solution of Intermediate 7 (60 mg, 0.16 mmol) in dioxane (3 mL) and H2O (0.3 mL), was added Intermediate 39 (100 mg, 0.24 mmol), followed by the addition of K3PO4 (84 mg, 0.40 mmol) and Xphos-Pd-G2 (12.4 mg, 0.016 mmol). The reaction was stirred under N2 at 90 °C for 1 h. The solvent was removed. The crude product was purified by normal phase chromatography. The obtained product was dissolved in DMSO (1 mL). Then K2CO3 (65 mg, 0.47 mmol) and hydrogen peroxide (30%, 0.13 mL, 1.26 mmol) were added. The reaction was stirred at rt for 30 min. The crude product was purified by reverse phase chromatography to provide Example 4-1 as a white solid (74 mg, 79%). ESI m / z 478.2 (M+H)+. 'HNMR (500 MHz, DMSO-d6) 88.51 (s, 1H), 8.10 (s, 1H), 7.93 - 7.84 (m, 4H), 7.68 - 7.63 (m, 2H), 7.44 (s, 1H), 7.29 - 7.25 (m, 1H), 7.24 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H), 6.78 (dd, J=8.1, 1.9 Hz, 1H), 5.58 - 5.47 (m, 1H), 3.96 - 3.90 (m, 1H), 3.83 (dd, J=10.4, 4.4 Hz, 1H), 3.72 - 3.64 (m, 1H), 3.56 - 3.48 (m, 1H), 2.67 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 2.54 (s, 3H). Analytical HPLC: RT = 1.49 min (Method C) and 1.59 min (Method D).

[1541] The examples listed in Table 4 were prepared by following similar or slightly modified procedures to that described in Example 4-1, from the appropriate commercially available starting materials and / or intermediates described above.

[1542] Table 4HPLC

[1543] LCMS Method,

[1544] Ex# Structure Name1H NMR (δ ppm)

[1545] (M+H)+RT

[1546] (min.)

[1547] (400 MHz, DMSO-d6) 6 12.01 (br s, 1H), 8.67 (d, 7=2.8 Hz, 1H), 8.45 H (R)-3-(3-(7- (d, 7=1.4 Hz, 1H), 7.90 N

[1548] fluoro-5-(4- (d, 7=1.1 Hz, 1H), 7.87 - (5-oxo-l,5- 7.83 (m, 2H), 7.82 - dihydro-4H- 7.77 (m, 2H), 7.48 (dd, 1,2,4- 7=13.2, 1.3 Hz, 1H), triazol-4- 7.29 - 7.24 (m, 1H), 4-2 C: 1.38

[1549] yl)phenyl)- 484.1 7.24 (br s, 1H), 7.17 (d, M D: 1.41

[1550] XN' 2H-indazol- 7=7.8 Hz, 1H), 7.12 (s,

[1551] 2- 1H), 6.78 (dd, 7=8.2, 1.7 0 yl)pyrrolidi Hz, 1H), 6.52 (s, 1H), H2N / -= / n-1- 5.61 - 5.52 (m, 1H), yl)benzamid 3.97 - 3.91 (m, 1H), e, TFA salt 3.83 (dd, 7=10.6, 4.0 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.55 - 3.49 (m, 1H), 2.72 - 2.62 (m, 2H) (500 MHz, DMSO-d6) 6 8.49 (s, 1H), 7.90 (br s, 1H), 7.85 (s, 1H), 7.81 (A)-3-(3-(7- (br d, 7=8.4 Hz, 2H), methyl-5- 7.63 - 7.55 (m, 3H), (4-(5- 7.43 (s, 1H), 7.30 - 7.21 methyl-1H- (m, 2H), 7.17 (br d, pyrazol-1- 7=7.7 Hz, 1H), 7.11 (s, 4-3 yl)phenyl)- 477.2 E: 1.92 1H), 6.78 (br d, 7=7.7 MXN' 2H-indazol- F: 1.95 Hz, 1H), 6.30 (s, 1H),

[1552] 2- 5.60 - 5.46 (m, 1H), O yl)pyrrolidi 3.98 - 3.88 (m, 1H), y~ / ~\ n-1- 3.81 (br dd, 7=10.1, 4.3 H2N Y— /

[1553] yl)benzamid Hz, 1H), 3.72 - 3.65 (m, e 1H), 3.54 - 3.50 (m,

[1554] 1H), 2.70 - 2.63 (m, 2H), 2.58 (s, 3H), 2.38

[1555]

[1556] (s, 3H)HPLC

[1557] LCMS Method,

[1558] Ex# Structure Name1H NMR (δ ppm)

[1559] (M+H)+RT

[1560] (min.)

[1561] (500 MHz, DMSO-d6) 6 8.68 (d, J=2.3 Hz, 1H), 8.00 - 7.90 (m, 2H), (R)-6-(3-(7- N-N 7.85 (d,. / =8,5 Hz, 2H), fluoro-5-(4- 7.69 (t,. / =7,9 Hz, 1H), (5-methyl- 7.63 - 7.55 (m, 3H), IH-pyrazol- 7.49 (d, J=13.4 Hz, 1H), 1- 7.45 (br d, J=1.3 Hz, 4-4 fV

[1562] MFyl)phenyl)- 481.9 E; 1.80

[1563] 1H), 7.28 (d,. / =7,2 Hz, 2H-indazol- F: 1.92

[1564] 1H), 6.75 (d,.7=8.3 Hz, 2- 1H), 6.30 (s, 1H), 5.62 - H2NNyl)pyrrolidi

[1565] 5.51 (m, 1H), 4.17 - n-1- 4.03 (m, 2H), 3.85 - yl)picolina

[1566] 3.78 (m, 1H), 3.75 - mide

[1567] 3.65 (m, 1H), 2.73 - 2.60 (m, 2H), 2.39 (s, 3H)

[1568] (400 MHz, DMSO-d6) 6 8.70 (d, 7=2.8 Hz, 1H), (R)-3-(3-(7- 8.07 (s, 1H), 7.99 - 7.84 N"^N

[1569] fluoro-5-(4- (m, 4H), 7.71 - 7.63 (m, (5-methyl- 2H), 7.51 (dd, 7=13.2, O 1H-1,2,4- 1.3 Hz, 1H), 7.30 - 7.20

[1570] (m, 2H), 7.17 (d, J=7.8 triazol-1- yl)phenyl)- Hz, 1H), 7.12 (s, 1H), 4-5 M 482.2 C: 1.55

[1571] XN' 2H-indazol- D: 1.59 6.78 (dd, J=8.2, 1.7 Hz,

[1572] 2- 1H), 5.63 - 5.51 (m,

[1573] 1H), 3.98 - 3.92 (m, yl)pyrrolidi

[1574] 0 M n-1- 1H), 3.86 - 3.81 (m, H2N \= / 1H), 3.70 - 3.65 (m, yl)benzamid

[1575] 1H), 3.57 - 3.49 (m, e, TFA salt

[1576] 1H), 2.77 - 2.61 (m, 2H), 2.54 (s, 3H)

[1577]

[1578] HPLC

[1579] LCMS Method,

[1580] Ex# Structure Name1H NMR (δ ppm)

[1581] (M+H)+RT

[1582] (min.)

[1583] (500 MHz, DMSO-d6) 6 8.69 (d, 7=2.8 Hz, 1H), 7.93 (d, 7=1.1 Hz, 1H), 7.90 - 7.82 (m, 3H), (A)-3-(3-(7- 7.64 - 7.56 (m, 3H), O' fluoro-5-(4- 7.50 (dd, 7=13.2, 1.2 (5-methyl- Hz, 1H), 7.30 - 7.21 (m, IH-pyrazol- 2H), 7.17 (d, 7=7.8 Hz, 1- 1H), 7.12 (s, 1H), 6.78 4-6 yl)phenyl)- 481.2 C: 1.79

[1584] (dd, 7=8.2, 1.8 Hz, 1H), OXN' 2H-indazol- D: 1.83

[1585] 6.34 - 6.29 (m, 1H), 2- 5.61 - 5.53 (m, 1H), yl)pyrrolidi

[1586] O 3.94 (dd, 7=10.5, 6.9 n-1- Hz, 1H), 3.83 (dd, H2N \= / yl)benzamid

[1587] 7=10.5, 4.2 Hz, 1H), e, TFA salt

[1588] 3.70 - 3.65 (m, 1H), 3.52 (td, 7=8.6, 5.8 Hz, 1H), 2.75 - 2.60 (m, 2H), 2.40 (s, 3H) (A)-3-(3-(7- (500 MHz, CD3OD) 6 methyl-5- 8.14 (s, 1H), 7.94 (d, (4-(4- J=8.9 Hz, 2H), 7.86 (s, methyl-5- 1H), 7.70 - 7.66 (m, oxo-4,5- 3H), 7.39 - 7.34 (m, dihydro-1H- 1H), 7.33 - 7.28 (m, 1,2,4- 1H), 7.24 - 7.13 (m, 4-7 triazol-1- 494.1 C: 1.62

[1589] 2H), 6.82 (dd, J=8.2, 1.8 O D: 1.63

[1590] N' yl)phenyl)- Hz, 1H), 5.47 - 5.40 (m, 2H-indazol- 1H), 4.01 - 3.88 (m, d

[1591] H2N 2- 2H), 3.78 - 3.68 (m, yl)pyrrolidi 1H), 3.58 (td, J=8.9, 5.1 dMZ / n-1- Hz, 1H), 3.38 (s, 3H), yl)benzamid 3.33 (dt, J=3.3, 1.7 Hz,

[1592]

[1593] e, TFA salt 2H), 2.76 - 2.63 (m, 5H)HPLC

[1594] LCMS Method,

[1595] Ex# Structure Name1H NMR (δ ppm)

[1596] (M+H)+RT

[1597] (min.)

[1598] (500 MHz, DMSO-d6) 6 (A)-3-(3-(7- 8.67 (d, J=2.6 Hz, 1H),Ni~ofluoro-5-(4- 8.53 (s, 1H), 7.94 - 7.84

[1599] (1-methyl- (m, 4H), 7.82 - 7.75 (m, Q 5-oxo- 1,5- 2H), 7.48 (dd, J=13.2, dihydro-4H- 1.1 Hz, 1H), 7.30 - 7.20 1,2,4- (m, 2H), 7.17 (d, J=7.8 4-9 O

[1600] XI

[1601] N' triazol-4- 498.2 C: 1.47 Hz, 1H), 7.12 (s, 1H), yl)phenyl)- D: 1.49 6.78 (dd, J=8.2, 1.8 Hz, d 2H-indazol- 1H), 5.62 - 5.52 (m, O _ _ / 2- 1H), 3.98 - 3.90 (m, H2N \= / yl)pyrrolidi 1H), 3.83 (dd, J=10.4, n-1- 4.0 Hz, 1H), 3.72 - 3.62 yl)benzamid (m, 1H), 3.55 - 3.48 (m, e, TFA salt 1H), 3.42 (s, 3H), 2.74 - 2.60 (m, 2H)

[1602] (500 MHz, DMSO-d6) 6 (A)-6-(3-(7- 8.69 (d, J=2.8 Hz, 1H), fluoro-5-(4- 8.53 (s, 1H), 7.93 (br d, J=2.4 Hz, 1H), 7.90 (d, 5-oxo-1,5- J=1.1 Hz, 1H), 7.89 - dihydro-4H- 7.84 (m, 2H), 7.82 - 1,2,4- 7.78 (m, 2H), 7.69 (dd, 4- triazol-4- J=8.4, 7.3 Hz, 1H), 7.48

[1603] C: 1.41

[1604] yl)phenyl)- 499.1 (dd, J=13.2, 1.3 Hz, 10 o D: 1.52

[1605] XN' 2H-indazol- 2H), 7.28 (d, J=6.9 Hz,

[1606] 2- 1H), 6.75 (d, J=8.2 Hz, O N— / ^ yl)pyrrolidi 1H), 5.59 - 5.52 (m, n-1- 1H), 4.17 - 4.04 (m, yl)picolina 2H), 3.84 - 3.78 (m, mide, TFA 1H), 3.73 - 3.67 (m, salt 1H), 3.42 (s, 3H), 2.73 -

[1607]

[1608] 2.60 (m, 2H)HPLC

[1609] LCMS Method,

[1610] Ex# Structure Name1H NMR (δ ppm)

[1611] (M+H)+RT

[1612] (min.)

[1613] (500 MHz, DMSO-d6) 6 8.44 (s, 1H), 7.90 (br s, \i— 1H), 7.45 (s, 1H), 7.31 o= / (A)-4-(2-(l- (s, 1H), 7.29 - 7.21 (m,

[1614] (3- 4H), 7.16 (br d, 7=7.5 carbamoylp Hz, 1H), 7.11 (s, 1H), henyl)pyrrol 7.01 (s, 1H), 6.77 (br d, 4- idin-3-yl)-7- 482.2 E: 1.70 J=6.7 Hz, 1H), 5.56 - 11 O

[1615] Xi methyl-2H- F: 1.72 5.45 (m, 1H), 3.94 - N'

[1616] indazol-5- 3.88 (m, 1H), 3.81 (br yl)-N, N,3- dd, J=10.2, 4.3 Hz, 1H), 6

[1617] H2N trimethylbe 3.71 - 3.65 (m, 1H), nzamide 3.56 - 3.40 (m, 1H),

[1618] 2.98 (br s, 6H), 2.70 - 2.62 (m, 2H), 2.54 (br s, 3H), 2.26 (s, 3H) (500 MHz, DMSO-d6) 6 (7?)-2- 8.72 (d, 7=2.6 Hz, 1H), N^N fluoro-3-(3- 8.08 (s, 1H), 7.96 (d, / Khf (7-fluoro-5- J=1.1 Hz, 1H), 7.94 - (4-(5- 7.88 (m, 2H), 7.72 - methyl-1H- 7.62 (m, 3H), 7.55 - 1,2,4- 7.48 (m, 2H), 7.13 - 4- triazol-1- 500.3 C: 1.48 7.05 (m, 1H), 6.98 -

[1619] XN' yl)phenyl)- D: 1.55 6.90 (m, 2H), 5.57 - 2H-indazol- 5.47 (m, 1H), 4.03 - 2- 3.96 (m, 1H), 3.93 - H2N \ / yl)pyrrolidi 3.86 (m, 1H), 3.75 (q, n-1- J=7.4 Hz, 1H), 3.56 (td, yl)benzamid J=7.5, 6.2 Hz, 1H), 2.69 e, TFA salt - 2.57 (m, 2H), 2.54 (s,

[1620] 3H)

[1621] H 3-((37?)-3- (500 MHz, DMSO-d6) 6 CL N „

[1622] (5-(4-(2,5- 10.83 (br s, 1H), 8.44 HN— (

[1623] dioxoimidaz (br d, J=15.8 Hz, 2H), olidin-4- 7.91 (br s, 1H), 7.78 (s, W

[1624] yl)phenyl)- 1H), 7.71 (br d, J=7.9 4- ZA_ 7-methyl- 495.1 C: 1.42 Hz, 2H), 7.41 - 7.34 (m, 13 Ml 2H-indazol- D: 1.43 3H), 7.31 - 7.20 (m,XN'

[1625] 2- 2H), 7.16 (br d, J=7.6 yl)pyrrolidi Hz, 1H), 7.10 (br s, 1H), H2N n-1- 6.77 (br d, J=8.4 Hz, yl)benzamid 1H), 5.55 - 5.43 (m,

[1626]

[1627] e, TFA salt 1H), 5.20 (s, 1H), 3.95 -HPLC

[1628] LCMS Method,

[1629] Ex# Structure Name1H NMR (δ ppm)

[1630] (M+H)+RT

[1631] (min.)

[1632] 3.87 (m, 1H), 3.80 (br dd, 7=10.6, 4.1 Hz, 1H), 3.68 - 3.64 (m, 1H), 3.62 - 3.59 (m, 1H), 2.68 - 2.61 (m, 2H), 2.56 (br s, 3H)

[1633] 3 -((35,45)- 3-methoxy- H 4-(7- (400 MHz, DMSO-d6) 6 N'N-y=: O methyl-5- 12.00 (s, 1H), 8.53 (s, W (4-(5-oxo- 1H), 8.43 (s, 1H), 7.89- 1,5- 7.57 (m, 5H), 7.42 (d, dihydro-4H- J=1.6 Hz, 1H), 7.29- 4- Me 1,2,4- 510.2 7.25 (m, 2H), 7.20-7.13

[1634] G: 2.20

[1635] 14 H triazol-4- (m, 2H), 6.81-6.79 (m,

[1636] XN'

[1637] 0^°Meyl)phenyl)- 1H), 5.45-5.43 (m, 1H),

[1638] 2H-indazol- 4.59-4.55 (m, 1H), 4.00- H2NOC— 2- 3.84 (m, 3H), 3.44-3.31 vz yl)pyrrolidi (m, 4H), 2.57-2.49 (m, n-1- 3H)

[1639] yl)benzamid

[1640] e

[1641] 3-((3S,4S)- 3-methoxy- 4-(7- (400 MHz, DMSO-d6) 6 methyl-5- 8.54 (d, J=10.4 Hz,2H), (4-(l- ir 7.88-7.76 (m, 6H), 7.42 methyl-5- (t, J=1.2 Hz, 1H), 7.30- v_ / oxo-1, 5- 7.25 (m, 2H), 7.21-7.19 4- dihydro-4H- <( }— Me (m, 1H), 7.15-7.13 (m,

[1642] 1,2,4- 524.2 G: 2.34

[1643] 15 O 1H), 6.82-6.79 (m, 1H), triazol-4- 5.46-5.44 (m, 1H), 4.59- yl)phenyl)- C-^*OMe4.57 (m, 1H), 4.01-3.85

[1644] 2H-indazol- H2NOC-- / =\ (m, 3H), 3.45-3.41(m, V / 2- 4H), 3.36(s, 3H), 2.58(s, yl)pyrrolidi

[1645] 3H)

[1646] n-1- yl)benzamid

[1647]

[1648] eHPLC

[1649] LCMS Method,

[1650] Ex# Structure Name1H NMR (δ ppm)

[1651] (M+H)+RT

[1652] (min.)

[1653] (500 MHz, DMSO-d6) 6 8.58 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.93 (7?)-2-(2-(l- (br s, 1H), 7.64 (s, 1H), (3- 7.30 - 7.24 (m, 1H), carbamoylp

[1654] 7.22 (br s, 1H), 7.15 (br henyl)pyrrol

[1655] d, J=8.1 Hz, 1H), 7.09 idin-3-yl)-7- 4- (s, 1H), 6.77 (br d, methyl-2H- 475.0 E: 1.62

[1656] J=7.0 Hz, 1H), 5.55 - 16 indazol-5- F: 1.56

[1657] 5.44 (m, 1H), 3.93 - yY)-N, N- 3.87 (m, 1H), 3.81 - dimethylthi

[1658] 3.77 (m, 1H), 3.72 - azole- 5- 3.65 (m, 1H), 3.50 - carboxamid

[1659] 3.46 (m, 1H), 3.24 (br s, e

[1660] 3H), 3.02 (br s, 3H), 2.70 - 2.60 (m, 2H), 2.55 (s, 3H)

[1661] 3 -((35,45)- 3-methoxy- (500 MHz, DMSO-d6) 6 4-(7- 8.54 (d, J=10.4 Hz, 2H), methyl-5- 7.88-7.76 (m, 6H), 7.42 v ) (4-(l- (t, J=1.2 Hz, 1H), 7.30- methyl-1H- 7.21 (m, 2H), 7.19-7.14 4- Me

[1662] imidazol-2- 507.0 (m, 1H), 7.14 (m, 1H), H G: 1.59

[1663] 17XN' yl)phenyl)- 6.82-6.79 (m, 1H), 5.46- / X ^OMe 2H-indazol- 5.44 (m, 1H), 4.59-4.57 H2N 2- (m, 1H), 4.01-3.85 (m, yl)pyrrolidi 3H), 3.45-3.41 (m, 4H), n-1- 3.36 (s, 3H), 2.67-2.49 yl)benzamid (m, 3H)

[1664] e

[1665] (400 MHz, DMSO-d6): 6-(3-(5-(4- 6 8.62 (s, 1H), 7.94 (d, J (dimethylca = 2.40 Hz, 1H), 7.81 (d, rbamoyl)ph J = 0.80 Hz, 1H), 7.73 enyl)-7- (d, J = 2.00 Hz, 1H), 4- ^A_Me methyl-2H- 7.72 (d, J = 1.60 Hz, indazol-2- 483.2 G: 2.40 1H), 7.63-7.67 (m, 1H), 18 H

[1666] „ N' yi)-3- 7.47-7.49 (m, 3H), 7.39 methylpyrro (t, J = 1.20 Hz, 1H), lidin- 1- 7.24 (d, J = 6.80 Hz, yl)picolina 1H), 6.69 (dd, J = 8.40, mide Hz, 1H), 4.52 (d, J =

[1667]

[1668] 11.60 Hz, 1H), 3.92 (d,HPLC

[1669] LCMS Method,

[1670] Ex# Structure Name1H NMR (δ ppm)

[1671] (M+H)+RT

[1672] (min.)

[1673] J= 11.60 Hz, 1H), 3.68 (q, J = 8.40 Hz, 1H), 3.58-3.52 (m, 1H), 3.07- 3.02 (m, 6H), 2.57 (s, 3H), 1.82 (s, 3H) (400 MHz, DMSO-d6): 6 11.99 (s, 1H), 8.61 (s, 6-(3- H 1H), 8.43 (s, 1H), 7.94 N methyl-3- (d, J = 2.40 Hz, 1H), (7-methyl- 7.75-7.79 (m, 5H), 7.65 5-(4-(5-oxo- (q, J = 7.20 Hz, 1H), 1,5- 7.49 (d, J = 2.80 Hz, dihydro-4H- ( / Me 1H), 7.39 (t, J= 1.60 4- 1,2,4- H 495. Hz, 1H), 7.24 (d, J = triazol-4- 2 G: 2.22

[1674] 19 6.80 Hz, 1H), 6.69 (d, J Me "i [R^] yl)phenyl)- = 8.40 Hz, 1H), 4.53 2H-indazol- ft (dd, J= 11.60, Hz, 1H),

[1675] 2- 3.92 (d, J = 11.60 Hz, yl)pyrrolidi

[1676] 1H), 3.67 (t, J = 8.00 n-1- H2N Hz, 1H), 3.57-3.51 (m, yl)picolina

[1677] 1H), 3.07-3.01 (m, 1H), mide

[1678] 2.58 (s, 3H), 1.83 (s, 3H)

[1679] (R)-3-(3-(7- (400 MHz, DMSO-d6): methyl-5- 6 1.95-1.84 (m, 4H), (4-(l- 2.63 (s, 3H), 3.19-3.13 methyl-5- (m, 1H), 3.49-3.42 (m, oxo-1, 5- 1H), 4.48-4.42 (m, 1H), dihydro-4H- yy

[1680] 4.59 (dd, J = 3.20, 13.20 4- 1,2,4- Me— \ Hz, 1H), 6.91 (dd, J = triazol-4- 508.2 G: 2.33

[1681] 20 H 2.40, 8.20 Hz, 1H), 'hr yl)phenyl)- 7.17-7.15 (m, 1H), 7.21 2H-indazol- (s, 1H), 7.28 (t, J = 8.00 2- Hz, 1H), 7.41 (s, 1H), yl)piperidin

[1682] 7.79-7.76 (m, 2H), 7.85- -1- 7.82 (m, 4H), 8.42 (s, yl)benzamid

[1683] 1H), 8.52 (s, 1H) e

[1684]

[1685] HPLC

[1686] LCMS Method,

[1687] Ex# Structure Name1H NMR (δ ppm)

[1688] (M+H)+RT

[1689] (min.)

[1690] (400 MHz, DMSO-d6): 3-(3- 6 11.99 (s, 1H), 8.60 (s, methyl-3- 1H), 8.43 (s, 1H), 7.80- H

[1691] (7-methyl- 7.87 (m, 1H), 7.75-7.79 N'NX-~O

[1692] w 5-(4-(5-oxo- (m, 5H), 7.39 (t, J =

[1693] 1,5- 1.60 Hz, 1H), 7.23 (q, J dihydro-4H- = 2.80 Hz, 2H), 7.13 (d, 4- Me 1, J = 7.60 Hz, 1H), 7.07 (d, J = 2.00 Hz, 1H), 494.2

[1694] Xl

[1695] 21 N', _ _ G: 2.28 (d, J = 2.00 Hz, 1H), Me Y |Rac| yl)phenyl)- 2.93 (dd, J = 0.80, Hz,

[1696] 1H), 6.72 (q, J = 2.002H-indazol- Q

[1697] 2- Hz, 1H), 4.24 (d, J = o f)

[1698] 10.00 Hz, 1H), 3.74 (d, yl)pyrrolidi

[1699] H2N

[1700] n-1- J= 10.40 Hz, 1H), 3.55- 3.46 (m, 1H), 3.06-2.99 yl)benzamid

[1701] (m, 1H), 2.58 (s, 3H), e

[1702] 1.83 (s, 3H)

[1703] (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 7.81 (d, J = 0.80 Hz, 1H), 7.73 (q, o= / 4-(2-(l-(3- J= 1.60 Hz, 2H), 7.48 fA carbamoylp

[1704] (q, J = 2.00 Hz, 2H), henyl)-3- 7.39 (d, J = 1.20 Hz, Me methylpyrro

[1705] 4- 1H), 7.22-7.26 (m, 2H), lidin-3 -yl)- 482.2 O G: 2.46 7.13 (d, J = 8.00 Hz,XN', -. 22 Me 1 |Rac| 7-methyl- 1H), 7.07 (d, J= 1.60 2H-indazol- 0 Hz, 1H), 4.24 (d, J =

[1706] 5-yl)-7V,7V- 10.40 Hz, 1H), 3.74 (d, dimethylben

[1707] J= 10.40 Hz, 1H), 3.47- zamide H2N 3.52 (m, 2H), 2.99-3.07

[1708] (m, 7H), 2.58 (s, 3H), 1.83 (s, 3H)

[1709] (500 MHz, DMSO-d6) 6 M° (R)-4-(2-(l- 8.62 (s, 1H), 7.91 (br s, / / =\

[1710] 1H), 7.50 (s, 1H), 7.36 - (3- 7.20 (m, 5H), 7.16 (br d, carbamoylp

[1711] J=7.6 Hz, 1H), 7.13 - henyl)pyrrol

[1712] 4- idin-3-yl)-7- E: 1.68 7.04 (m, 2H), 6.78 (br d, 486.0

[1713] M 23 fluoro-2H- F: 1.69 J=8.0 Hz, 1H), 5.62 -XN'

[1714] indazol-5- 5.50 (m, 1H), 3.97 - 3.90 (m, 1H), 3.82 (br yl)-N, N,3- 0

[1715] H2N / == / dd, J=10.5, 3.8 Hz, 1H), trimethylbe

[1716] 3.71 - 3.65 (m, 1H), nzamide

[1717] 3.60 - 3.55 (m, 1H),

[1718]

[1719] HPLC

[1720] LCMS Method,

[1721] Ex# Structure Name1H NMR (δ ppm)

[1722] (M+H)+RT

[1723] (min.)

[1724] 2.98 (br s, 6H), 2.74 - 2.61 (m, 2H), 2.28 (s, 3H)

[1725] (A)-3-(3-(7- (500 MHz, methyl-5- METHANOL-d4) δ 8.31 (4-(3- (s, 1H), 7.92 - 7.76 (m, methyl-5- 3H), 7.50 - 7.39 (m, oxo-1, 5- 3H), 7.36 - 7.31 (m, dihydro-4H- 1H), 7.23 - 7.17 (m, 4- 1,2,4- E: 1.42 2H), 6.89 (dd, J=8.2, 1.9 triazol-4- 494.2

[1726] 24 H

[1727] XF: 1.42 Hz, 1H), 5.55 - 5.45 (m, N' yl)phenyl)- 1H), 4.02 - 3.89 (m, 2H-indazol- 2H), 3.79 - 3.71 (m, d 2- o / ==( 1H), 3.62 - 3.53 (m, yl)pyrrolidi

[1728] H2N A.0 1H), 2.82 - 2.68 (m, n-1- 2H), 2.66 (s, 3H), 2.19 yl)benzamid

[1729] (s, 3H)

[1730] e, TFA salt

[1731] (500 MHz, DMSO-d6) 6 12.01 (br s, 1H), 8.69 (7?)-2- (d, J=2.8 Hz, 1H), 8.45 fluoro-3-(3- HN'% (d, J=1.5 Hz, 1H), 7.90

[1732] (7-fluoro-5- (d, J=1.2 Hz, 1H), 7.87 - (4-(5-oxo-O7.84 (m, 2H), 7.83 - M 1,5- 7.78 (m, 2H), 7.66 (br s, dihydro-4H- 1H), 7.52 (br s, 1H), 4- 1,2,4- E: 1.38 7.48 (dd, J=13.2, 1.3 triazol-4- 502.2

[1733] 25 Oi F: 1.42 Hz, 1H), 7.11 - 7.05 (m,

[1734] KN' yl)phenyl)- 1H), 6.96 - 6.90 (m, 2H-indazol- 2H), 5.55 - 5.48 (m, p 0 2- H2N \ / 1H), 4.02 - 3.96 (m, yl)pyrrolidi

[1735] o^ V / 1H), 3.92 - 3.86 (m, n-1- 1H), 3.74 (q, J=7.4 Hz, yl)benzamid

[1736] 1H), 3.55 (td, J=7.6, 6.0 e, TFA salt

[1737] Hz, 1H), 2.69 - 2.56 (m,

[1738]

[1739] 2H)HPLC

[1740] LCMS Method,

[1741] Ex# Structure Name1H NMR (δ ppm)

[1742] (M+H)+RT

[1743] (min.)

[1744] (500 MHz, DMSO-d6) 6 11.63 (s, 1H), 8.69 (d, (R)-3-(3-(7- 7=2.8 Hz, 1H), 7.92 (d, fluoro-5-(4- H 7=1.1 Hz, 1H), 7.90 - N'Ny=O (3-methyl- 7.83 (m, 3H), 7.53 - 5-oxo-l,5- 7.47 (m, 3H), 7.29 - dihydro-4H- 7.25 (m, 1H), 7.24 (br s, 1,2,4- 4- 1H), 7.17 (d, 7=7.8 Hz, triazol-4- 498.0 E: 1.39

[1745] 1H), 7.14 - 7.10 (m, 26 $ yl)phenyl)- F: 1.43

[1746] 1H), 6.78 (dd, 7=8.2, 1.8 2H-indazol- Hz, 1H), 5.61 - 5.53 (m,H2N / d 2- 1H), 3.97 - 3.90 (m, yl)pyrrolidi

[1747] oH) 1H), 3.83 (dd, 7=10.4, n-1- 4.2 Hz, 1H), 3.71 - 3.64 yl)benzamid

[1748] (m, 1H), 3.55 - 3.49 (m, e, TFA salt

[1749] 1H), 2.75 - 2.61 (m, 2H), 2.12 (s, 3H) (500 MHz, DMSO-d6) 6 8.47 (s, 1H), 7.92 (br s, 1H), 7.83 (s, 1H), 7.72 (br d, 7=8.2 Hz, 2H), (R)-3-(3-(7- 7.59 (br d, 7=8.2 Hz, methyl-5- o= / 2H), 7.39 (s, 1H), 7.30 - (4- 7.21 (m, 2H), 7.16 (br d, (pyrrolidine

[1750] 7=7.0 Hz, 1H), 7.10 (br -1- 4- s, 1H), 6.82 - 6.74 (m, carbonyl)ph 494.1 E: 1.73

[1751] 1H), 5.54 - 5.44 (m, 27 O enyl)-2H- F: 1.78

[1752] Xi

[1753] N' 1H), 3.95 - 3.87 (m, indazol-2- 1H), 3.80 (br dd, H d yl)pyrrolidi

[1754] 2N J=10.5, 4.4 Hz, 1H), n-1- 3.71 - 3.64 (m, 1H), yl)benzamid

[1755] 3.57 - 3.53 (m, 1H), e

[1756] 3.52 - 3.38 (m, 4H), 2.72 - 2.61 (m, 2H), 2.56 (br s, 3H), 1.94 -

[1757]

[1758] 1.76 (m, 4H)HPLC

[1759] LCMS Method,

[1760] Ex# Structure Name1H NMR (δ ppm)

[1761] (M+H)+RT

[1762] (min.)

[1763] (500 MHz, DMSO-d6) 6 (7?)-2- 11.63 (s, 1H), 8.71 (d, fluoro-3-(3- H J=2.8 Hz, 1H), 7.92 (d,

[1764] (7-fluoro-5- N'Ny=O J=1.1 Hz, 1H), 7.89 - (4-(3- 7.84 (m, 2H), 7.83 - methyl-5- 7.79 (m, 1H), 7.73 (dd, oxo-1, 5- J=8.3, 1.1 Hz, 1H), 7.66 dihydro-4H- 4- >yF(br s, 1H), 7.51 - 7.48

[1765] 1,2,4- 516.1 A: 0.76 (m, 3H), 7.11 - 7.05 (m, 28 M triazol-4-XN' 1H), 6.92 (d, J=8.0 Hz, yl)phenyl)- 1H), 5.56 - 5.47 (m, 2H-indazol- 1H), 4.02 - 3.96 (m, H2N V / 2- 1H), 3.92 - 3.87 (m, MO yl)pyrrolidi

[1766] 1H), 3.74 (q, J=7.4 Hz, n-1- 1H), 3.59 - 3.52 (m, yl)benzamid

[1767] 1H), 2.69 - 2.57 (m, e, TFA salt

[1768] 2H), 2.12 (s, 3H) (500 MHz, DMSO-d6) 6 8.41 (s, 1H), 7.90 (br s, H2N 1H), 7.52 (s, 1H), 7.29 - (7?)-3-(3-(5- 7.07 (m, 6H), 6.81 - (4-amino-2- 6.72 (m, 1H), 6.54 (br fluoropheny

[1769] dd, J=8.2, 2.1 Hz, 1H), l)-7-methyl- 4- 6.49 (dd, J=13.4, 1.8

[1770] 2H-indazol- E: 1.48

[1771] M 430.1

[1772] XN' Hz, 1H), 5.55 - 5.43 (m, 29 2- F: 1.64

[1773] 1H), 3.96 - 3.87 (m, yl)pyrrolidi

[1774] 1H), 3.80 (br dd, n-1- J=10.2, 4.5 Hz, 1H), yl)benzamid

[1775] H2NZ3.72 - 3.62 (m, 1H), e

[1776] 3.58 - 3.39 (m, 1H), 2.71 - 2.60 (m, 2H), 2.52 (br s, 3H)

[1777] OH (400 MHz, DMSO-d6):

[1778] 3-((7?)-3-(5- 68.46 (s, 1H), 7.88 (s, (4-((7?)-3- 1H), 7.77 (q, J = 2.00 hydroxy-2- Hz, 3H), 7.70 (q, J = oxopyrrolidi

[1779] 2.00 Hz, 2H), 7.37 (t, J 4- n-1- { y—Me= 1.60 Hz, 1H), 7.25 (q, yl)phenyl)- 496.0 G: 2.09

[1780] 30 M J = 4.00 Hz, 2H), 7.11-Xi

[1781] N' 7-methyl- 7.18 (m, 2H), 6.78-6.79 2H-indazol- (m, 1H), 5.76 (d, J = d 2- O 6.00 Hz, 1H), 5.51 (t, J yl)pyrrolidi

[1782] H2N = 4.80 Hz, 1H), 4.32- n-1-

[1783]

[1784] 4.33 (m, 1H), 3.90-3.94HPLC

[1785] LCMS Method,

[1786] Ex# Structure Name1H NMR (δ ppm)

[1787] (M+H)+RT

[1788] (min.)

[1789] yl)benzamid (m, 1H), 3.74-3.82 (m, e 4H), 3.51-3.49 (d, 1H),

[1790] 2.68-2.62 (m, 2H), 2.56 (s, 3H), 2.49-2.43 (m, 1H), 1.90-1.84 (q, 1H) (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.88 (s, 1H), 7.80 (q, J = 6.80 OH 3-((7?)-3-(5- Hz, 3H), 7.70 (t, J = (4-0-3- 2.00 Hz, 2H), 7.37 (d, J hydroxy-2- = 0.80 Hz, 1H), 7.25 (q, oxopyrrolidi J = 4.00 Hz, 2H), 7.14 n-1- (q, J = 2.00 Hz, 2H), 4- yl)phenyl)- 6.78 (q, J = 1.60 Hz, / y- Me

[1791] 7-methyl- 496.0 G: 2.09 1H), 5.76 (d, J = 6.00 31

[1792] MXN' 2H-indazol- Hz, 1H), 5.51 (t, J =

[1793] 2- 4.80 Hz, 1H), 4.31-4.34

[1794] (m, 1H), 3.91 (t, J = d yl)pyrrolidi

[1795] O n-1- 6.80 Hz, 1H), 3.69-3.80 H2N yl)benzamid (m, 4H), 3.51-3.49 (d, e 1H), 2.68-2.63 (m, 2H),

[1796] 2.56 (s, 3H), 2.51-2.49 (m, 1H), 1.90-1.84 (q, 1H)

[1797] (500 MHz, DMSO-d6) 6 8.48 (s, 1H), 7.92 (br s, 1H), 7.84 (s, 1H), 7.81 F (br d, J=8.2 Hz, 2H), F— / (7?)-3-(3-(5- 7.63 (br d, J=8.0 Hz, (4- 2H), 7.39 (s, 1H), 7.29 - (difluorome

[1798] 7.21 (m, 2H), 7.16 (d, thyl)phenyl)

[1799] J=7.48 Hz, 1H), 7.10 (s, 4- Me -7-methyl- Mi 2H-indaz 447.2 E: 2.02 1H), 7.05 (t, J=56 Hz, ol- 32XN' F: 2.04 1H), 6.81 - 6.74 (m,

[1800] 2- 1H), 5.54 - 5.44 (m, yl)pyrrolidi

[1801] 1H), 3.91 (dd, J=10.5, n-1-. C5 7.0 Hz, 1H), 3.80 (dd, yl)benzamid

[1802] J=10.3, 4.5 Hz, 1H), H2NZV_y e

[1803] 3.71 - 3.63 (m, 1H), 3.53 - 3.46 (m, 1H), 2.71 - 2.60 (m, 2H), 2.56 (s, 3H)

[1804]

[1805] HPLC

[1806] LCMS Method,

[1807] Ex# Structure Name1H NMR (δ ppm)

[1808] (M+H)+RT

[1809] i (min.)

[1810] 'j zI "

[1811] (500 MHz, DMSO-d6) 6 8.54 (s, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.96 - 7.90 (m, 2H), 7.85 (d, (7?)-3-(3-(5- J=8.2 Hz, 2H), 7.46 (s, (4-(azetidin- 1H), 7.31 - 7.21 (m, 1- 2H), 7.16 (br d, J=8.2 ylsulfonyl)p

[1812] Hz, 1H), 7.10 (s, 1H), 4- henyl)-7- 516.3 E: 1.79 6.82 - 6.74 (m, 1H), methyl-2H- 33 F: 1.81 5.56 - 5.48 (m, 1H), indazol-2- 3.92 (dd, J=10.1, 7.1 yl)pyrrolidi

[1813] Hz, 1H), 3.81 (dd, n-1- J=10.3, 4.0 Hz, 1H), yl)benzamid

[1814] 3.76 - 3.64 (m, 4H), e

[1815] 3.50 (m, 3.55 - 3.45, 2H), 2.71 - 2.63 (m, 2H), 2.58 (s, 3H), 2.04 - 1.97 (m, 2H)

[1816] D < (500 MHz, DMSO-d6) 6

[1817] 8.70 (d, J=2.8 Hz, 1H), \ 'z" 8.03 (s, 1H), 7.97 (d, (R)-3-(3-(7- J=1.2 Hz, 1H), 7.94 - fluoro-5-(4- 7.84 (m, 5H), 7.52 (dd, (1-methyl- s J=13.2, 1.2 Hz, 1H),

[1818] 1H-1,2,4- 7.26 (d,. / =7,9 Hz, 1H), triazol-5- 4- 7.24 (br s, 1H), 7.17 (d, yl)phenyl)- 482.3 C: 1.49

[1819] . / =7,8 Hz, 1H), 7.15 - 34 2H-indazol- D: 1.52

[1820] 7.10 (m, 1H), 6.78 (dd, 2- J=8.2, 1.8 Hz, 1H), 5.62 yl)pyrrolidi

[1821] - 5.54 (m, 1H), 4.03 (s, n-1- 3H), 3.97 - 3.91 (m, yl)benzamid

[1822] 1H), 3.83 (dd, J=10.5, e, TFA salt

[1823] 4.1 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.55 - 3.50 (m,

[1824]

[1825] 1H), 2.75 - 2.61 (m, 2H)HPLC

[1826] LCMS Method,

[1827] Ex# Structure Name1H NMR (δ ppm)

[1828] (M+H)+RT

[1829] (min.)

[1830] (500 MHz, DMSO-d6) 6 8.50 (s, 1H), 8.03 (br d,. / =7,9 Hz, 2H), 7.90 (br s, 2H), 7.83 (br d, J=7.9 (7?)-3-(3-(5- Hz, 2H), 7.43 (s, 1H), H O )=\ (4-(l- 7.34 - 7.20 (m, 2H), hydroxycycl 7.16 (br d, J=7.4 Hz, opropyl)phe 1H), 7.11 (br s, 1H), Me

[1831] 4- nyl)-7- 6.78 (br d, J=8.5 Hz, E: 1.98

[1832] H methyl-2H- 453.3 1H), 5.56 - 5.44 (m, 35XN' F: 2.02

[1833] indazol-2- 1H), 3.96 - 3.88 (m, yl)pyrrolidi 1H), 3.81 (br dd, n-1- J=10.2, 4.0 Hz, 1H), H2N yl)benzamid 3.72 - 3.63 (m, 1H), e 3.55 - 3.37 (m, 1H),

[1834] 3.07 (q,. / =6,9 Hz, 2H), 2.72 - 2.61 (m, 2H), 2.57 (s, 3H), 1.11 (brt,, / =7.2 Hz, 3H)

[1835] (500 MHz, DMSO-d6) 6 8.45 (s, 1H), 7.91 (br s, 1H), 7.78 (s, 1H), 7.73 - o (7?)-3-(3-(5- 7.61 (m, 4H), 7.38 (s,

[1836] (4-(3- 1H), 7.30 - 7.21 (m, Ho \=, hydroxyoxe 2H), 7.16 (br d, J=7.3 tan-3 - Hz, 1H), 7.10 (br s, 1H), yl)phenyl)- 6.77 (br d, J=7.4 Hz, 4- Me

[1837] 7-methyl- 469.2 E: 1.51 1H), 5.56 - 5.44 (m, 36 X

[1838] XN' 2H-indazol- F: 1.55 1H), 4.80 (br d, J=6.0

[1839] 2- Hz, 2H), 4.72 (br d, yl)pyrrolidi J=6.0 Hz, 2H), 3.95 - n-1- 3.88 (m, 1H), 3.84 - H2N yl)benzamid 3.76 (m, 1H), 3.72 - e 3.61 (m, 1H), 3.54 - 3.38 (m, 1H), 2.66 (br d, J=4.0 Hz, 2H), 2.56 (br

[1840]

[1841] s, 3H)HPLC

[1842] LCMS Method,

[1843] Ex# Structure Name1H NMR (δ ppm)

[1844] (M+H)+RT

[1845] (min.)

[1846] (500 MHz, DMSO-d6) 6 8.56 (s, 1H), 7.98 - 7.89 (m, 2H), 7.81 - 7.75 (m, (R)-4-(2-(l- 2H), 7.68 (d, 7=7.9 Hz, M° (3- 1H), 7.29 - 7.24 (m, carbamoylp 1H), 7.22 (s, 2H), 7.15 henyl)pyrrol (d, 7=7.5 Hz, 1H), 7.10 idin-3-yl)-7- (s, 1H), 6.78 (br d, 4- methyl-2H- 493.1 E: 1.68 7=8.0 Hz, 1H), 5.59 - 37 OXN' i indazol-5- F: 1.58 5.45 (m, 1H), 3.91 (dd, yl)-3-cyano- 7=10.1, 7.0 Hz, 1H), d N, N- 3.81 (br dd, 7=10.4, 4.0 H2N

[1847] dimethylben Hz, 1H), 3.71 - 3.64 (m, bMZ / zamide, 1H), 3.50 (br d, J=6.2 TFA salt Hz, 1H), 3.01 (br s, 3H),

[1848] 2.95 (br s, 3H), 2.72 - 2.62 (m, 2H), 2.56 (s, 3H)

[1849] (7?)-2- Me (400 MHz, DMSO-d6):

[1850] fluoro-3-(3- 6 1.83 (s, 3H), 2.47-2.45 (7-fluoro-5- (m, 1H), 3.01-2.95 (m, (4-(l- 1H), 3.42 (s, 3H), 3.58 methyl-5- (t, J = 6.40 Hz, 2H), oxo-1, 5- 3.82 (dd, J= 1.60, 10.40 dihydro-4H- 4- XJVF Hz, 1H), 4.30 (d, J =

[1851] 1,2,4- 530.2

[1852] O G: 2.42 9.20 Hz, 1H), 6.90-6.84 38 triazol-4- Me> (m, 2H), 7.04 (t, J = yl)phenyl)- 8.00 Hz, 1H), 7.50-7.46 Sr 2H-indazol- (m, 2H), 7.64 (s, 1H),FxJ. 2-yl)-3- 7.81-7.78 (m, 2H), 7.87- H2NXJ^ J? methylpyrro

[1853] 7.85 (m, 3H), 8.53 (s, lidin- 1- 1H), 8.80 (dd, J = 2.80, yl)benzamid

[1854] Hz, 1H)

[1855]

[1856] eHPLC

[1857] LCMS Method,

[1858] Ex# Structure Name1H NMR (δ ppm)

[1859] (M+H)+RT

[1860] (min.)

[1861] H (7?)-2- N'N'V==O fluoro-3-(3- (400 MHz, DMS0-d6): \L| / (7-fluoro-5- 6 1.83 (s, 3H), 2.50-2.50

[1862] (4-(5-oxo- (m, 1H), 2.99-2.96 (m, 1,5- 1H), 3.58 (t, J = 6.40 dihydro-4H- Hz, 2H), 3.82 (dd, J = Xjv 1,2,4- 2.00, 10.60 Hz, 1H), 4- triazol-4- 516.2 4.30 (d, J = 9.20 Hz, o G: 2.28

[1863] 39 yl)phenyl)- 1H), 6.89-6.84 (m, 2H),

[1864] 2H-indazol- 7.05 (t, J = 8.00 Hz, 2-yl)-3- 1H), 7.50-7.45 (m, 2H), Sr

[1865] FxJ. methylpyrro 7.64 (s, 1H), 7.81-7.78 lidin- 1- (m, 2H), 7.87-7.84 (m, H2NSL J

[1866] yl)benzamid 3H), 8.45 (s, 1H), 8.80 e, formic (d, J = 2.80 Hz, 1H) acid salt

[1867] (7?)-2- (400 MHz, DMS0-d6): fluoro-3-(3- 6 1.82 (s, 3H), 2.48-2.43 methyl-3- (m, 1H), 2.58 (s, 3H), (7-methyl- 3.01-2.95 (m, 1H), 3.58 5-(4-(5-oxo- (t, J = 5.60 Hz, 2H), 1,5- 3.81 (dd, J = 1.60, 10.40 dihydro-4H- Hz, 1H), 4.30 (d, J = 4- 1,2,4- 512.3 G: 2.35 8.80 Hz, 1H), 6.89-6.86 40 triazol-4- (m, 2H), 7.04 (t, J = yl)phenyl)- 2? RT\ 7.60 Hz, 1H), 7.40-7.39

[1868] 2H-indazol- (m, 1H), 7.50 (s, 1H), E l 2- 7.63 (s, 1H), 7.81-7.76 yl)pyrrolidi

[1869] HzN\^S J (m, 5H), 8.43 (s, 1H), n-1- 8.63 (s, 1H), 11.95 (s, yl)benzamid

[1870] 1H) e

[1871] (R)-3-(3-(7- (500 MHz, DMSO-d6) 6 methyl-5- 8.44 (s, 1H), 7.91 (br s, (4-(2- 1H), 7.76 (s, 1H), 7.73 - oxopyrrolidi 7.65 (m, 4H), 7.37 (s, n-1- 1H), 7.30 - 7.20 (m, 4- yl)phenyl)- 480.1 E: 1.78 2H), 7.16 (br d, J=7.6 41 H

[1872] XN' 2H-indazol- F: 1.72 Hz, 1H), 7.10 (s, 1H),

[1873] 2- 6.81 - 6.73 (m, 1H), d yl)pyrrolidi 5.57 - 5.43 (m, 1H), H2N n-1- 3.94 - 3.83 (m, 3H), / ~O yl)benzamid 3.80 (br dd, 7=10.3, 4.4

[1874]

[1875] e Hz, 1H), 3.67 (q, 7=8.4HPLC

[1876] LCMS Method,

[1877] Ex# Structure Name1H NMR (δ ppm)

[1878] (M+H)+RT

[1879] (min.)

[1880] Hz, 1H), 3.53 - 3.45 (m, 1H), 2.71 - 2.61 (m,

[1881] 2H), 2.56 (br s, 3H),

[1882] 2.54 - 2.49 (m, 2H),

[1883] 2.08 (quin,. / =7.5 Hz,

[1884]

[1885] 2H)

[1886] Example 5-1: (A)-4-(2-(l-(6-(hydroxymethyl)pyri din-2 -yl)pyrrolidin-3-yl)-2H-indazol-5-yl)- A, A-dimethylbenzamide

[1887]

[1888] Example 5-la: tert-butyl (A)-3-(5-(4-(dimethylcarbamoyl)phenyl)-2H-indazol-2- yl)pyrrolidine-l -carboxylate

[1889]

[1890] A vial containing (4-(dimethylcarbamoyl)phenyl)boronic acid (0.93 g, 4.8 mmol), Intermediate 2 (1.6 g, 4.4 mmol), Xphos-Pd-G2 (0.17 g, 0.22 mmol), 3 M aqueous K3PO4 (4.4 ml, 13 mmol) and dioxane (11 mL) was sparged with N2, sealed and heated at 80 °C for 1 h. The crude product was purified by silica gel column chromatography with hexanes / EtOAc as the eluant to give Example 5-la (1.9 g, 99%) as a white solid. MS (ESI) m / z 435.0 (M+H)+. 'H NMR (500 MHz, CDCh) δ 8.02 (s, 1H), 7.84 (s, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 5.25 - 5.16 (m, 1H), 4.04 - 3.94 (m, 1H), 3.93 - 3.83 (m, 1H), 3.80 - 3.70 (m, 1H), 3.68 - 3.55 (m, 1H), 3.21 - 2.97 (m, 6H), 2.64 - 2.47 (m, 2H), 1.49 (br s, 9H). Analytical HPLC: RT = 1.75 min (Method C).

[1891] Example 5-lb: (A)-A, A-dimethyl-4-(2-(pyrrolidin-3-yl)-2H-indazol-5-yl)benzamide

[1892]

[1893] To a round-bottom flask containing Example 5-la, was added 10 mL 4 N HC1 in dioxane. The reaction was stirred at 50 °C for 3 h and was concentrated by rotary evaporation. The residue was paritioned between IN NaOH (50 mL) and DCM (50 mL). The organic phase was concentrated to afford Example 5-lb (1.4 g, 95%) as an off-white solid. MS (ESI) m / z 335.1 (M+H)+.

[1894] Example 5-lc: (R)-4-(2-(l -(6-(hy droxymethyl)pyri din-2 -yl)pyrrolidin-3-yl)-2H-indazol-5-yl)-7V, A-dimethylbenzamide

[1895] N;N,i4

[1896]

[1897] To a vial were added 2-bromo-6-(hydroxymethyl)pyridine (32 mg, 0.17 mmol), Example 5-lb (28 mg, 0.084 mmol), sodium / c / 7-butoxide (32 mg, 0.34 mmol), RuPhos Pd G2 (6.5 mg, 8.4 pmol), and it was sparged with N2 for 5 minutes. Then NMP (0.4 mL) was added. The reaction was further sparged with N2. The reaction was sealed and heated at 110 °C for 12 hours. The crude product was purified by reverse phase HPLC to give Example 5-1 (15 mg, 39%). MS (ESI) m / z 442.2 (M+H)+. 'H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.01 (s, 1H), 7.75 - 7.68 (m, 3H), 7.60 (dd, J=9.1, 1.6 Hz, 1H), 7.54 - 7.45 (m, 3H), 6.69 (d, J=7.2 Hz, 1H), 6.38 (d, J=8.2 Hz, 1H), 5.50 - 5.41 (m, 1H), 5.22 (t, J=5.6 Hz, 1H), 4.39 (d, J=5.3 Hz, 2H), 4.03 - 3.96 (m, 1H), 3.90 (dd, J=11.2, 4.1 Hz, 1H), 3.76 - 3.67 (m, 1H), 3.62 -3.58 (m, 1H), 3.05 - 2.92 (m, 6H), 2.65 - 2.55 (m, 2H). Analytical HPLC: RT = 1.16 min (Method E) and 1.52 min (Method F).

[1898] Example 5-2: (A)-6-(3-(5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2H-indazol-2-yl)pyrrolidin- 1 -yl)pyridin-2( lH)-one

[1899] N

[1900] Nz

[1901]

[1902] Example 5-2a: Zc / V-butyl (A)-3-(5-(4-(dimethylcarbamoyl)phenyl)-2H-indazol-2-yl)pyrrolidine-l -carboxylate

[1903] N

[1904] >14 N

[1905] ,i4

[1906]

[1907] To a vial was added 4-(1-methyl-1H-imidazol-2-yl)phenylboronic acid (270 mg, 1.4 mmol), Intermediate 2 (450 mg, 1.2 mmol), Xphos Pd G2 (97 mg, 0.12 mmol), K3PO4 (1.2mL, 3.7 mmol) and dioxane (3 mL). The reaction was sparged with N2 and heated to 80 °C for 1 h. The crude product was purified by silica gel column chromatography with DCM / MeOH as the eluant to give Example 5-2a (540 mg, 99%) as a red oil. MS (ESI) m / z 444.2 (M+H)+. 'HNMR (400 MHz, CDCh) δ 8.02 (s, 1H), 7.88 (d, J=0.6 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.72 (s, 4H), 7.61 (dd, J=9.0, 1.6 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 5.21 (quin, J=5.9 Hz, 1H), 4.06 - 3.95 (m, 2H), 3.81 (s, 3H), 3.66 - 3.53 (m, 2H), 2.61 - 2.49 (m, 2H), 1.49 (br s, 9H). Analytical HPLC: RT = 0.85 min (Method A). Example 5-2b: (A)-5-(4-(l -methyl- IH-imidazol -2 -yl)phenyl)-2-(pyrrolidin-3-yl)-2H-indazole, HC1 salt

[1908]

[1909] To a round-bottom flask containing Example 5-2a (540 mg, 1.22 mmol), was added 2 mL 4 N HC1 in dioxane. The reaction was stirred at rt for 16 h, then was concentrated to afford Example 5-2b (460 g, 99%) as an off-white solid. MS (ESI) m / z 344.1 (M+H)+.

[1910] Analytical HPLC: RT = 0.91 min (Method C).

[1911] Example 5-2: (A)-6-(3-(5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2H-indazol-2-yl)pyrrolidin- 1 -yl)pyridin-2( lH)-one

[1912]

[1913] To a vial was added 2-bromo-6-methoxypyridine (61 mg, 0.32 mmol), Example 5-2b (41 mg, 0.11 mmol), GPhos Pd G6 TES (10 mg, 11 pmol). Then NMP (540 pl) was added. It was sparged with N2 for 5 min before a solution of LiHMDS (IM in toluene, 430 pl, 0.43 mmol) was added. The reaction was heated to 120 °C for 1 h. Then, HC1 solution (12 N, 180 pl, 2.2 mmol) was added, and the reaction mixture was stirred at 120 °C for 16 h. The crude product was purified by reverse phase HPLC to give Example 5-2 (2.2 mg, 5%). MS (ESI) m / z 437.0 (M+H)+.XH NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.14 (s, 1H), 8.00 - 7.93 (m, 2H), 7.87 (d, J=8.2 Hz, 2H), 7.76 (br d, J=11.1 Hz, 2H), 7.73 - 7.65 (m, 2H), 7.32 (t, J=8.0 Hz, 1H), 5.77 - 5.72 (m, 1H), 5.53 - 5.45 (m, 1H), 4.00 - 3.94 (m, 1H), 3.92 - 3.88 (m, 4H), 3.68 (br d, J=9.6 Hz, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.67 - 2.56 (m, 2H). Analytical HPLC: RT = 1.13 min (Method E).Example 5-3: (A)-N-ethyl-N-methyl-4-(2-(l -(pyri din-2 -yl)pyrrolidin-3-yl)-2H-indazol-5-yl)benzamide

[1914]

[1915] Example 5-3a: (R)-4-(2-(l -( / c77-butoxycarbonyl)pyrrolidin-3-yl)-2H-indazol-5-yl)benzoic acid

[1916]

[1917] To a vial was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (57 mg, 0.23 mmol) (57 mg, 0.23 mmol), Intermediate 2 (71 mg, 0.19 mmol), 3 M aqueous K3PO4 (0.19 mL, 0.58 mmol), XPhos Pd G2 (15 mg, 0.019 mmol), and dioxane (0.5 mL). The mixture was sparged with N2 for 5 minutes, sealed, and stirred at 80 °C for 1 h. The crude material was partitioned between 10 mL EtOAc and 10 mL 1 N HC1. The organic layer was concentrated to yield Example 5-3a (89 mg, 49%) as a brown solid. MS (ESI) m / z 408.2 (M+H)+. Analytical HPLC: RT = 0.93 min (Method A).

[1918] Example 5-3b: (A)-4-(2-(pyrrolidin-3-yl)-2H-indazol-5-yl)benzoic acid, HC1 salt

[1919]

[1920] Example 5-3a (89 mg, 0.094 mmol) was dissolved in HC1 in dioxane (4 N, 2 mL). The reaction was stirred at rt for 20 min. Volatiles were evaporated to afford Example 5-3b (58 mg, 49%, relative to Example l-52a). MS (ESI) m / z 307.9 (M+H)+. Analytical HPLC: RT = 0.77 min (Method A).

[1921] Example 5-3c: tert-butyl (R)-3-(5-(4-(dimethylcarbamoyl)phenyl)-2H-indazol-2-yl)pyrrolidine-l -carboxylate

[1922]

[1923] To a vial was added Example 5-3b (75 mg, 0.22 mmol), 2-bromopyridine (92 mg, 0.58 mmol), sodium / c / 7-butoxide (93 mg, 0.97 mmol), RuPhos Pd G2 (15 mg, 0.019 mmol), NMP (1 mL). The mixture was sparged with N2 for 5 minutes, sealed, and stirred at 120 °C for 1 h. The reaction was quenched with 5 mL 1 N HC1, and the mixture was filtered to afford Example 5-3c (39 mg, 52%) as a brown solid. MS (ESI) m / z 384.9 (M+H)+. Analytical HPLC: RT = 0.73 min (Method A).

[1924] Example 5-3: (A)-N-ethyl-N-methyl-4-(2-(l -(pyri din-2 -yl)pyrrolidin-3-yl)-2H-indazol-5-yl)benzamide

[1925]

[1926] To a vial was added HATU (11 mg, 0.029 mmol), Example 5-3c (10 mg, 0.026 mmol), and DMF (0.13 mL). The mixture was stirred at rt for 1 min before adding DIPEA (14 pL, 0.078 mmol) and N-ethylmethylamine (4.6 mg, 0.078 mmol). The reaction mixture was stirred at rt for 1 h. The crude product was purified by reverse phase HPLC to give Example 5-3 (2.2 mg, 20%). MS (ESI) m / z 426.1 (M+H)+. 'H NMR (500 MHz, DMSO-d6) 6 8.52 (s, 1H), 8.10 - 8.05 (m, 1H), 8.01 (s, 1H), 7.77 - 7.69 (m, 3H), 7.60 (dd, J=9.0, 1.3 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.48 - 7.42 (m, 2H), 6.59 (dd, J=6.4, 5.5 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 5.51 - 5.43 (m, 1H), 4.04 - 3.98 (m, 1H), 3.96 - 3.87 (m, 1H), 3.81 - 3.61 (m, 3H), 3.29 - 3.20 (m, 1H), 2.98 - 2.89 (m, 3H), 2.65 - 2.57 (m, 2H), 1.19 - 1.03 (m, 3H). Analytical HPLC: RT = 1.29 min (Method E).

[1927] Example 5-4: (7?)-2-(l-(1H-pyrazol-3-yl)pyrrolidin-3-yl)-5-(4-(l -methyl- IH-imidazol -2-yl)phenyl)-2H-indazole

[1928]

[1929] To a vial was added Example 5-2b (30 mg, 0.079 mmol), 3-bromopyrazole (35 mg, 0.24 mmol), GPhos Pd G6 TES (7.5 mg, 0.008 mmol), and NMP (0.4 mL). The mixture was sparged with N2 for 5 minutes, and LHMDS (1 M in toluene, 0.31 mL, 0.31 mmol) was added. The mixture was sealed and stirred at rt for 16 h. The crude product was purified by reverse-phase HPLC to afford Example 5-4 (4.2 mg, 12%). MS (ESI) m / z 410.1 (M+H)+. 'H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.03 (s, 1H), 7.81 - 7.77 (m, 2H), 7.77 - 7.74 (m,2H), 7.73 - 7.69 (m, 1H), 7.67 - 7.60 (m, 1H), 7.44 (br s, 1H), 7.26 (s, 1H), 6.99 (d, J=l.l Hz, 1H), 5.66 - 5.55 (m, 1H), 5.48 - 5.33 (m, 1H), 3.80 - 3.75 (m, 4H), 3.66 - 3.61 (m, 4H), 3.41 -3.34 (m, 1H), 2.62 - 2.56 (m, 1H). Analytical HPLC: RT = 1.03 min (Method E).

[1930] Example 5-5: (A)-2-(l-(1H-pyrazol-3-yl)pyrrolidin-3-yl)-7-methyl-5-(4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)-2H-indazole

[1931]

[1932] Example 5-5a: tert-butyl (A)-3-(7-methyl-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[1933]

[1934] To a vial was added tert-butyl (A)-3-(5-bromo-7-methyl-2H-indazol-2-yl)pyrrolidine-l -carboxylate (300 mg, 0.79 mmol), Intermediate 13 (230 mg, 0.79 mmol), XPhos Pd G2 (62 mg, 0.079 mmol), 3 M aqueous K3PO4 (0.79 mL, 2.4 mmol), and dioxane (4 mL). The mixture was sparged with N2 for 5 minutes, sealed, and stirred at 100 °C for 16 h. The crude product was purified by silica gel column chromatography with DCM / MeOH as the eluant to give Example 5-5a (380 mg, quantitative) as a yellow oil. MS (ESI) m / z 459.2 (M+H)+. Analytical HPLC: RT = 0.89 min (Method A).

[1935] Example 5-5b: (A)-7-methyl-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-(pyrrolidin-3-yl)-2H-indazole, HC1 salt

[1936]

[1937] Boc

[1938] Example 5-5a (380 mg) was dissolved in 4 N HC1 in dioxane (2 mL) and stirred at 50 °C for 1 h. Volatiles were removed to afford Example 5-5b (330 mg, quantitative) as a yellow solid. MS (ESI) m / z 359.0 (M+H)+. Analytical HPLC: RT = 0.71 min (Method A).Example 5-5c: 7-methyl-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2-((3R)-l-(l-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrrolidin-3-yl)-2H-indazole

[1939]

[1940] To a vial was added Example 5-5b (50 mg, 0.13 mmol), 3-bromo-l-(2-tetrahydropyranyl)-lH-pyrazole (59 mg, 0.25 mmol), RuPhos Pd G2 (10 mg, 0.013 mmol), sodium / c / 7-butoxide (61 mg, 0.63 mmol), and dioxane (0.6 mL). The mixture was sparged with N2 for 5 min, sealed, and stirred at 100 °C for 72 h. The crude product was purified by silica gel column chromatography with DCM / MeOH as the eluant to give Example 5-5c (15 mg, 23%) as a colorless oil. MS (ESI) m / z 509.2 (M+H)+. Analytical HPLC: RT = 0.78 min (Method A).

[1941] Example 5-5: (A)-2-(l-(1H-pyrazol-3-yl)pyrrolidin-3-yl)-7-methyl-5-(4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)-2H-indazole

[1942]

[1943] To a vial was added Example 5-5c (15 mg, 0.029 mmol) and 4 N HC1 in dioxane (1 mL). The mixture was stirred at 80 °C for 1 h. Volatiles were removed by evaporation under reduced pressure, and the crude material was purified by reverse-phase HPLC to afford Example 5-5 (5.2 mg, 9%, relative to Example l-5b). MS (ESI) m / z 425.1 (M+H)+. 'H NMR (500 MHz, DMSO-d6) 6 8.87 - 8.71 (m, 1H), 8.51 (s, 1H), 7.94 (s, 1H), 7.91 - 7.80 (m, 5H), 7.74 (br s, 1H), 7.44 (s, 1H), 5.86 - 5.73 (m, 1H), 5.60 - 5.38 (m, 1H), 3.89 - 3.84 (m, 2H), 3.82 (s, 4H), 3.79 - 3.74 (m, 2H), 2.67 - 2.59 (m, 1H), 2.57 (s, 3H). Analytical HPLC: RT = 1.17 min (Method E).Example 5-6: (A)-3-(3-(7-methyl-5-(4-(5-oxo-l,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzamide

[1944]

[1945] Example 5-6a: tert-butyl (A)-3-(7-methyl-5-(4-(5-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)- 1,5-dihydro-4H- 1,2,4-triazol-4-yl)phenyl)-2H-indazol-2-yl)pyrrolidine- 1 -carboxylate

[1946]

[1947] To a vial was added Intermediate 57 (88 mg, 0.21 mmol), Intermediate 6 (80 mg, 0.21 mmol), 3 M aqueous K3PO4 (0.21 mL mg, 0.63 mmol), and dioxane (0.7 mL). The mixture was sparged with N2 for 5 minutes, sealed, and stirred at 100 °C for 4 h. The crude product was purified by silica gel column chromatography with hexanes / EtOAc as the eluant to give Example 5-6a. MS (ESI) m / z 591.9 (M+H)+. 'HNMR (500 MHz, CDCh) 67.99 (s, 1H), 7.77 (s, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.66 (s, 1H), 7.61 (d, J=8.6 Hz, 2H), 5.28 - 5.19 (m, 3H), 4.04 - 3.92 (m, 2H), 3.91 - 3.84 (m, 1H), 3.77 - 3.72 (m, 2H), 3.69 - 3.53 (m, 2H), 2.68 (s, 3H), 2.57 - 2.44 (m, 2H), 1.49 (br s, 9H), 1.04 - 0.96 (m, 2H), 0.02 (s, 9H) Analytical HPLC: RT = 1.17 min (Method A).

[1948] Example 5-6b: (A)-4-(4-(7-methyl-2-(pyrrolidin-3-yl)-2H-indazol-5-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1949]

[1950] In a microwave vial, Example 5-6a was taken up in EtOH (0.5 mL) and water (0.5 mL). The vial was sealed and microwaved at 160 °C for 3 h. Volatiles were removed to afford Example 5-6b (70 mg, 68%) as a brown solid. MS (ESI) m / z 491.2 (M+H)+.

[1951] Analytical HPLC: RT = 0.91 min (Method A).

[1952] Example 5-6c: (A)-3-(3-(7-methyl-5-(4-(5-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)-l,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzonitrile

[1953]

[1954] To a vial was added Intermediate 5-6b (70 mg, 0.14 mmol), 3 -bromobenzonitrile (52 mg, 0.29 mmol), GPhos Pd G6 (13 mg, 0.014 mmol), sodium / c / 7-butoxide (16 mg, 0.17 mmol), and dioxane (0.7 mL). The mixture was sparged with N2 for 5 minutes, sealed, and stirred at 100 °C for 16 h. The crude product was purified by silica gel column chromatography with hexanes / EtOAc as the eluant to give Example 5-6c (55 mg, 65%). MS (ESI) m / z 591.5 (M+H)+. Analytical HPLC: RT = 1.16 min (Method A).

[1955] Example 5-6: (A)-3-(3-(7-methyl-5-(4-(5-oxo-l,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-2H-indazol-2-yl)pyrrolidin-l-yl)benzamide

[1956]

[1957] To a vial was added Example 5-6c (30 mg, 0.051 mmol), Ghaffar-Parkins catalyst (2.2 mg, 0.0051 mmol), ethanol (0.5 mL), and water (0.5 mL). The mixture was stirred at 100 °C for 4 h. Volatiles were evaporated. DCM (0.5 mL) and TFA (0.5 mL) were added, and the mixture was stirred at rt for 2 h. 6N NH4OH (1 mL) was added, and volatiles were evaporated. The residue was purified by reverse-phase HPLC to yield Example 5-6 (8.6 mg, 34%) as a white solid. MS (ESI) m / z 480.2 (M+H)+. 'H NMR (500 MHz, DMSO-d6) 8 11.98 (br s, 1H), 8.48 (s, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.87 (br s, 1H), 7.82 (s, 1H), 7.81 - 7.78 (m, 2H), 7.78 -7.74 (m, 2H), 7.40 (s, 1H), 7.29 - 7.23 (m, 1H), 7.22 (br s, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.11 (s, 1H), 6.77 (dd, J=8.1, 2.0 Hz, 1H), 5.56 - 5.47 (m, 1H), 3.96 - 3.88 (m, 1H), 3.81 (dd, J=10.3, 4.4 Hz, 1H), 3.70 - 3.62 (m, 1H), 3.58 - 3.46 (m, 1H), 2.71 - 2.61 (m, 2H), 2.57 (s, 3H). Analytical HPLC: RT = 1.45 min (Method C).

[1958] The examples listed in Table 5 were prepared by following the generic procedures above, and procedures similar to those described in the aforementioned Examples.Table 5.

[1959] Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[1960] RT (min.)

[1961] 5-8 — i / m-(2-(i-(3- 445.2 E: 1.76 (500 MHz, DMSO-d6) 6 \=o fluoro-5- 8.50 (s, 1H), 8.02 (s, 1H), hydroxyphenyl 7.76 - 7.69 (m, 3H), 7.60 O )pyrrolidin-3- (dd, 7=9.0, 1.6 Hz, 1H), yl)-2H- 7.48 (d, 7=8.2 Hz, 2H), O indazol-5-yl)- 5.92 - 5.78 (m, 3H), 5.51 - iO N, N- 5.41 (m, 1H), 3.82 (dd, 'hr

[1962] dimethylbenza 7=10.4, 6.9 Hz, 1H), 3.68 mide (dd, 7=10.5, 4.2 Hz, 1H), 6

[1963] 3.43 - 3.39 (m, 3H), 3.01 - 2.94 (m, 6H), 2.64 - 2.55 (m, 2H).

[1964] HO

[1965] 5-9 (R)-4-(2-(l- 401.2 E: 1.22 (500 MHz, DMSO-d6) 6 (1H-pyrazol-3- 12.02 - 11.56 (m, 1H), 8.50 yl)pyrrolidin- (s, 1H), 8.01 (s, 1H), 7.76 - 3-yl)-2H- 7.69 (m, 3H), 7.60 (dd, indazol-5-yl)- 7=9.0, 1.6 Hz, 1H), 7.48 (d, N, N- 7=8.2 Hz, 2H), 7.44 (s, dimethylbenza 1H), 5.59 (s, 1H), 5.48 - O mide 5.38 (m, 1H), 3.78 (dd,

[1966] 7=10.3, 7.0 Hz, 1H), 3.65 (dd, 7=10.2, 4.2 Hz, 1H), 1 ZICl ' 3.60 - 3.52 (m, 1H), 3.39 - 3.35 (m, 2H), 3.04 - 2.92 (m, 6H), 2.64 - 2.56 (m, 1H).

[1967] 5- — r / (R)-4-(2-(l-(6- 442.1 E: 1.80 (500 MHz, DMSO-d6) 6 10 \=o methoxypyridi 8.51 (s, 1H), 8.01 (s, 1H), n-2- 7.73 (d, 7=8.3 Hz, 2H), yl)pyrrolidin- 7.70 (d, 7=9.2 Hz, 1H), 3-yl)-2H- 7.60 (dd, 7=9.0, 1.6 Hz, indazol-5-yl)- 1H), 7.47 (d, 7=8.3 Hz, N, N- 2H), 7.42 (t, 7=8.0 Hz, "hT dimethylbenza 1H), 6.03 (d, 7=7.9 Hz, mide 1H), 5.98 (d, 7=7.9 Hz,

[1968] 1H), 5.48 - 5.42 (m, 1H), \=N 4.01 (dd, 7=11.2, 6.7 Hz,

[1969] 1H), 3.93 - 3.85 (m, 1H), CH

[1970] 3.76 (s, 3H), 3.72 - 3.69 (m, 2H), 3.02 - 2.90 (m,

[1971]

[1972] 6H), 2.65 - 2.54 (m, 2H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[1973] RT (min.)

[1974] 5- (7?)-(6-(3-(5- 451.2 E: 0.96 (500 MHz, DMSO-d6) 6 13 (4-(l-methyl- 8.60 (s, 1H), 8.15 (s, 1H), lH-imidazol-2- 7.99 (d, J=8.5 Hz, 2H), o yl)phenyl)-2H- 7.87 (d,. / =8,5 Hz, 2H), indazol-2- 7.83 - 7.67 (m, 5H), 6.81 yl)pyrrolidin- (d, J=7.1 Hz, 1H), 6.67 (br l-yl)pyridin-2- d, J=7.9 Hz, 1H), 5.60 - yl)methanol 5.51 (m, 1H), 4.49 (s, 2H),

[1975] 4.13 - 4.06 (m, 1H), 4.05 - 3.98 (m, 1H), 3.95 - 3.89 p (m, 4H), 3.86 - 3.79 (m, HO^ 2H), 2.70 - 2.57 (m, 2H).

[1976] 5- N

[1977] N' *1 (7?)-5-(4-(4- 422.2 E: 1.12 (500 MHz, DMSO-d6) 6 14 methyl-4H- 8.56 (d, J=19.7 Hz, 2H), 1,2,4-triazol-3- 8.09 - 8.04 (m, 2H), 7.88 - o

[1978] yl)phenyl)-2- 7.84 (m, 2H), 7.84 - 7.81 (l-(pyridin-2- (m, 2H), 7.75 - 7.70 (m, ( / yl)pyrrolidin- 1H), 7.68 - 7.62 (m, 1H), 'IT 3-yl)-2H- 7.58 - 7.47 (m, 1H), 6.59 indazole (dd, J=6.6, 5.4 Hz, 1H), 6 6.53 (d,. / =8,5 Hz, 1H),

[1979] 5.52 - 5.44 (m, 1H), 4.06 - o

[1980] 3.97 (m, 1H), 3.96 - 3.89 (m, 1H), 3.78 (s, 3H), 3.76 - 3.69 (m, 1H), 3.65 - 3.60 (m, 1H), 2.68 - 2.56 (m, 2H).

[1981] 5- (7?)-6-(3-(5-(4- 464.1 E: 1.20 (500 MHz, DMSO-d6) 6 15 p

[1982] (1-methyl-1H- 8.58 (s, 1H), 8.14 (s, 1H), imidazol-2- 7.97 (d, J=8.4 Hz, 2H), CyX

[1983] yl)phenyl)-2H- 7.92 (br s, 1H), 7.85 (d, f / indazol-2- J=8.5 Hz, 2H), 7.78 - 7.65 yl)pyrrolidin- (m, 5H), 7.44 (br d, J=1.9 'Nx

[1984] 1- Hz, 1H), 7.26 (d,.7=7.2 Hz, yl)picolinamid 1H), 6.73 (d,.7=8.5 Hz, 6

[1985] e 1H), 5.56 - 5.48 (m, 1H),

[1986] 4.14 - 4.03 (m, 2H), 3.90 (s, 3H), 3.83 - 3.76 (m,

[1987]

[1988] 2H), 2.72 - 2.58 (m, 2H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[1989] RT (min.)

[1990] 5- (7?)-2-(l-(2- 451.1 E: 1.40 (500 MHz, DMSO-d6) 6 16 methoxypyridi 8.59 (s, 1H), 8.15 (s, 1H), n-3- 8.00 (br d, J=8.1 Hz, 2H), o yl)pyrrolidin- 7.87 (br d, J=8.2 Hz, 2H),

[1991] 3-yl)-5-(4-(l- 7.82 (s, 1H), 7.79 - 7.72 o methyl-1H- (m, 2H), 7.68 (br d, J=9.2 -hr imidazol-2- Hz, 1H), 7.58 (d,.7=4.7 Hz, yl)phenyl)-2H- 1H), 5.47 - 5.37 (m, 1H), indazole 3.95 - 3.80 (m, 8H), 3.71 - 3.60 (m, 6H).

[1992] 5- N

[1993] N' (7?)-(6-(3-(5- 452.2 E: 1.12 (500 MHz, DMSO-d6) 6 17 VN (4-(4-methyl- 8.57 (s, 1H), 8.52 (s, 1H),

[1994] 4H- 1,2,4- 8.07 (s, 1H), 7.88 - 7.84 O triazol-3- (m, 2H), 7.83 - 7.80 (m, yl)phenyl)-2H- 2H), 7.74 - 7.70 (m, 1H), O indazol-2- 7.67 - 7.62 (m, 1H), 7.54 - iO

[1995] 'Nxyl)pyrrolidin- 7.48 (m, 1H), 6.69 (br d, l-yl)pyridin-2-.7=7,2 Hz, 1H), 6.39 (br d, yl)methanol J=8.3 Hz, 1H), 5.54 - 5.38 6

[1996] r N (m, 1H), 5.23 (br s, 1H),

[1997] 4.39 (br d, J=2.9 Hz, 2H), \= / OH

[1998] 4.03 - 3.97 (m, 1H), 3.94 - 3.88 (m, 1H), 3.78 (s, 3H), 3.74 - 3.60 (m, 2H), 2.66 - 2.55 (m, 2H).

[1999] 5- (R)-N-methyl- 478.2 E: 1.42 (500 MHz, DMSO-d6) 6 18 p

[2000] 6-(3-(5-(4-(l- 8.53 (s, 1H), 8.51 - 8.46 methyl-1H- (m, 1H), 8.05 (s, 1H), 7.82 p ' imidazol-2- - 7.78 (m, 2H), 7.77 - 7.74 yl)phenyl)-2H- (m, 2H), 7.73 - 7.70 (m, indazol-2- 1H), 7.69 - 7.63 (m, 2H), 'KT yl)pyrrolidin- 7.28 - 7.21 (m, 2H), 6.99

[2001] 1- (s, 1H), 6.72 (d,.7=8.5 Hz, yl)picolinamid 1H), 5.54 - 5.45 (m, 1H), e 4.12 - 4.06 (m, 1H), 3.78 o= / (s, 3H), 3.16 (s, 3 H), 2.79 NH (d,.7=4,9 Hz, 3H), 2.69 - /

[2002]

[2003] 2.59 (m, 2H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[2004] RT (min.)

[2005] 5- (7?)-5-(4-(l- 424.1 E: 1.07 (500 MHz, DMSO-d6) 6 19 methyl-1H- 8.49 (s, 1H), 8.03 (s, 1H), imidazol-2- 7.81 - 7.75 (m, 4H), 7.74 - yl)phenyl)-2- 7.69 (m, 1H), 7.66 - 7.60 (l-(l-methyl- (m, 1H), 7.41 (d, J=2.0 Hz, 1H-pyrazol-3- 1H), 7.26 (s, 1H), 6.99 (s, 'hr yl)pyrrolidin- 1H), 5.55 (d, J=2.1 Hz,

[2006] 3-yl)-2H- 1H), 5.47 - 5.36 (m, 1H), 6 indazole 3.79 (s, 3H), 3.77 - 3.73 1^1 (m, 1H), 3.65 (s, 3H), 3.57 'hr - 3.52 (m, 1H), 3.39 - 3.32 /

[2007] (m, 3H), 2.62 - 2.54 (m, 1H).

[2008] 5- (R)-3-(3-(5-(4- 437.1 E: 1.24 (500 MHz, DMSO-d6) 6 20 (1-methyl-1H- 11.35 - 11.20 (m, 1H), 8.59 imidazol-2- (s, 1H), 8.13 (s, 1H), 7.97 o

[2009] yl)phenyl)-2H- (d, J=8.4 Hz, 2H), 7.85 (d, indazol-2- J=8.5 Hz, 2H), 7.75 (d, o

[2010] yl)pyrrolidin-, / =7.9 Hz, 2H), 7.72 - 7.64 '1ST l-yl)pyridin- (m, 2H), 6.81 (br d, J=6.9

[2011] 2(lH)-one Hz, 1H), 6.46 (d,. / =7,5 Hz, 6 o 1H), 6.12 (t,. / =6,9 Hz,

[2012] 1H), 5.44 - 5.29 (m, 1H), t5H4.04 (br dd, J=10.9, 3.9 Hz,

[2013] 1H), 3.93 - 3.87 (m, 5H), 3.72 - 3.67 (m, 3H).

[2014] 5- (7?)-5-(4-(l- 489.1 E: 1.19 (500 MHz, DMSO-d6) 6 22 LN methyl-1H- 8.73 (s, 1H), 8.37 (s, 1H), imidazol-2- 8.08 (dd, J=5.0, 1.1 Hz, yl)phenyl)-2- 1H), 7.97 (s, 1H), 7.88 - (l-(pyridin-2- 7.82 (m, 2H), 7.82 - 7.77 F3C^ )

[2015] yl)pyrrolidin- (m, 2H), 7.56 - 7.50 (m, IO 3-yl)-7- 1H), 7.27 (d, J=0.9 Hz, " IT

[2016] (trifluoromethy 1H), 7.00 (d, J=l.l Hz, l)-2H-indazole 1H), 6.60 (dd, J=6.7, 5.3 6

[2017] y_ N Hz, 1H), 6.54 (d,. / =8,5 Hz, A 1H), 5.59 - 5.50 (m, 1H),

[2018] 4.06 - 4.01 (m, 1H), 3.98 - 3.92 (m, 1H), 3.79 (s, 3H), 3.76 - 3.68 (m, 1H), 3.66 - 3.59 (m, 1H), 2.71 - 2.59

[2019]

[2020] (m, 2H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2021] RT (min.)

[2022] 5- (7?)-6-(3-(5-(4- 465.0 E: 1.00 (500 MHz, DMSO-d6) 6 23 (1-methyl-1H- 8.52 (s, 1H), 8.04 (s, 1H), imidazol-2- 7.81 - 7.77 (m, 2H), 7.77 - yl)phenyl)-2H- 7.73 (m, 2H), 7.72 - 7.69 indazol-2- (m, 1H), 7.68 - 7.61 (m, yl)pyrrolidin- 2H), 7.28 - 7.23 (m, 2H), 'Nxl-yl)picolinic 6.98 (s, 1H), 6.75 (d, J=8.8 acid Hz, 1H), 5.52 - 5.42 (m, 6

[2023] 1H), 4.10 - 3.98 (m, 3H), 3.79 - 3.76 (m, 5H), 2.68 - 2.57 (m, 2H).

[2024] 4'

[2025] 5- CD3

[2026] D3C— hf (R)-4-(2-(l-(6- 448.2 E: 1.20 (500 MHz, DMSO-d6) 6 24 \=O (hydroxymethy 8.51 (s, 1H), 8.01 (s, 1H), l)pyridin-2- 7.73 (d, J=8.3 Hz, 2H), O yl)pyrrolidin- 7.70 (d, J=9.1 Hz, 1H),

[2027] 3-yl)-2H- 7.60 (dd, J=9.1, 1.6 Hz, indazol-5-yl)- 1H), 7.54 - 7.50 (m, 1H), 'hr N, N- 7.50 - 7.45 (m, 2H), 6.69 6 bis(methyl- (d,. / =7,2 Hz, 1H), 6.38 (d, d3)benzamide J=8.2 Hz, 1H), 5.49 - 5.40

[2028] (m, 1H), 5.22 (brt,. / =5,4 Hz, 1H), 4.39 (br d, J=4A HO— /

[2029] Hz, 2H), 4.03 - 3.97 (m, 1H), 3.95 - 3.87 (m, 1H), 3.75 - 3.67 (m, 1H), 3.65 - 3.59 (m, 1H), 2.66 - 2.55 (m, 2H).

[2030] 5- CD3(7?)-6-(3-(5-(4- 461.2 E: 1.48 (500 MHz, DMSO-d6) 6 25 D3C-h(

[2031] \=O (bis(methyl- 8.54 (s, 1H), 8.02 (s, 1H), d3)carbamoyl) 7.92 (br s, 1H), 7.76 - 7.65 phenyl)-2H- (m, 4H), 7.60 (d, J=9.2 Hz, indazol-2- 1H), 7.48 (d,. / =8,2 Hz, yl)pyrrolidin- 2H), 7.43 (br d, J=2.1 Hz, iO

[2032] 'hr 1- 1H), 7.26 (d,. / =7,2 Hz, 6 yl)picolinamid 1H), 6.73 (d,.7=8.3 Hz, e 1H), 5.55 - 5.44 (m, 1H),

[2033] 4.14 - 4.07 (m, 1H), 4.06 - hr %

[2034] 4.00 (m, 1H), 3.85 - 3.75 H2N— 4 (m, 1H), 3.73 - 3.63 (m,

[2035]

[2036] 1H), 2.71 - 2.57 (m, 2H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2037] RT (min.)

[2038] 5- (R)-3-(3-(5-(4- 463.1 E: 1.27 (500 MHz, DMSO-d6) 6 26 (1-methyl-1H- 8.53 (s, 1H), 8.04 (s, 1H), imidazol-2- 7.88 (br s, 1H), 7.82 - 7.75 yl)phenyl)-2H- (m, 4H), 7.72 (br d, 7=8.8 indazol-2- Hz, 1H), 7.66 - 7.61 (m, IO yl)pyrrolidin- 1H), 7.28 - 7.20 (m, 3H), 'i\r 1- 7.15 (br d, 7=7.4 Hz, 1H), yl)benzamide 7.10 (br s, 1H), 6.99 (s,

[2039] 1H), 6.76 (br d, 7=8.2 Hz, 1H), 5.57 - 5.46 (m, 1H), 3.97 - 3.88 (m, 1H), 3.79 (s, 4H), 3.70 - 3.61 (m, 1H), 3.54 - 3.48 (m, 1H), 2.70 - 2.58 (m, 2H).

[2040] 5- (R)-N-(3- 484.2 E: 1.21 (500 MHz, DMSO-d6) 58.51 27 °w hydroxy-3- (s, 1H), 8.06 (br d, 7=4.1 Hz, methylbutyl)- 1H), 8.01 (s, 1H), 7.77 - 7.67 p L

[2041] N-methyl-4-(2- (m, 3H), 7.59 (dd, 7=9.0, 1.3

[2042] Hz, 1H), 7.54 - 7.49 (m, 1H), (l-(pyridin-2- 7.44 (br d, 7=7.9 Hz, 2H), yl)pyrrolidin- 6.61 - 6.57 (m, 1H), 6.52 (d, 'N 3-yl)-2H- 7=8.5 Hz, 1H), 5.50 - 5.43 indazol-5- (m, 1H), 4.06 - 3.98 (m, 1H), yl)benzamide 3.94 - 3.87 (m, 1H), 3.76 - 3.67 (m, 1H), 3.58 (s, 1H), 3.57 (s, 1H), 2.93 (br s, 3H), 2.67 - 2.55 (m, 2H), 2.54 (s, 1H), 1.67 (brs, 2H), 1.15 (br s, 3H), 0.94 (br s, 3H).

[2043] 5- (R)-N-(2- 456.2 E: 1.24 (500 MHz, DMSO-d6) 58.47 28 p

[2044] methoxyethyl)- (s, 1H), 8.06 - 7.94 (m, 2H), N-methyl-4-(2- 7.76 - 7.65 (m, 3H), 7.63 - o (l-(pyridin-2- 7.58 (m, 1H), 7.55 - 7.48 (m, / 1H), 7.44 (br d, 7=7.4 Hz, yl)pyrrolidin- o 2H), 6.59 (dd, 7=7.0, 5.0 Hz,

[2045] 3-yl)-2H- 1H), 6.53 (br d, 7=8.5 Hz, IO indazol-5- 'hr 1H), 5.55 - 5.34 (m, 1H), 4.02 yl)benzamide - 3.89 (m, 2H), 3.74 - 3.52 (m, 4H), 3.47 - 3.36 (m, 2H), 3.28 (brs, 1H), 3.15 (br s, 2H), 2.96 (s, 3H), 2.66 - 2.52

[2046]

[2047] D (m, 2H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2048] RT (min.)

[2049] 5- (R)-7-methyl- 433.2 E: 1.33 (500 MHz, DMSO-d6) 6 29 V

[2050] _ _ / "0 5-(4- 8.51 (s, 1H), 8.08 (br d, o (m ethyl sulfony, / =3.9 Hz, 1H), 7.99 - 7.90 l)phenyl)-2-(l- (m, 5H), 7.53 - 7.49 (m, (pyridin-2- 1H), 7.42 (s, 1H), 6.59 (dd, yl)pyrrolidin- J=6.4, 5.5 Hz, 1H), 6.53 (d, 'Nx3-yl)-2H- J=8.5 Hz, 1H), 5.50 - 5.43 indazole (m, 1H), 4.05 - 3.99 (m,

[2051] 1H), 3.96 - 3.89 (m, 1H), 3.78 - 3.70 (m, 1H), 3.63 - 3.57 (m, 1H), 3.23 (s, 3H), 2.66 - 2.59 (m, 2H), 2.56 (s, 3H).

[2052] 5- (R)-6-(3-(7- 476.0 E: 1.60 (500 MHz, DMSO-d6) 6 30 u

[2053] methyl-5-(4- 8.52 (s, 1H), 7.98 - 7.90 (m ethyl sulfony (m, 6H), 7.67 (t, J=7.9 Hz, —T\ l)phenyl)-2H- 1H), 7.42 (s, 2H), 7.26 (d, indazol-2-.7=7,2 Hz, 1H), 6.73 (d, hO

[2054] 'NXyl)pyrrolidin- J=8.4 Hz, 1H), 5.48 (quin,

[2055] 1- J=5.7 Hz, 1H), 4.14 - 3.98 6 __ yl)picolinamid (m, 2H), 3.89 - 3.73 (m, e 2H), 3.21 (s, 3H), 2.68 - o 2.61 (m, 2H), 2.55 (s, 3H). o=\

[2056] NH2

[2057] 5- H

[2058] O N (R)-6-(3-(7- 481.1 E: 1.46 (500 MHz, DMSO-d6) 6 31 " N

[2059] k-J? methyl-5-(4- 12.03 (br s, 1H), 8.48 (s, (5-oxo-l,5- 1H), 8.39 (s, 1H), 7.93 (br C5 dihydro-4H- s, 1H), 7.82 - 7.77 (m, 3H), 1,2,4-triazol-4- 7.76 - 7.72 (m, 2H), 7.67 Z~jf yl)phenyl)-2H- (t,.7=7,8 Hz, 1H), 7.43 (br ’i\r

[2060] indazol-2- d,.7=2,0 Hz, 1H), 7.40 - yl)pyrrolidin- 7.37 (m, 1H), 7.26 (d, 1-.7=7,2 Hz, 1H), 6.73 (d, yl)picolinamid J=8.5 Hz, 1H), 5.53 - 5.42 4? e (m, 1H), 4.15 - 4.08 (m,

[2061] 1H), 4.07 - 4.00 (m, 1H), 3.84 - 3.75 (m, 1H), 3.72 - 3.63 (m, 1H), 2.67 - 2.61 (m, 2H), 2.57 - 2.55 (m,

[2062]

[2063] 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2064] RT (min.)

[2065] 5- (R)-2-(1-(6- 453.1 E: 1.68 (500 MHz, DMSO-d6) 6 32 fluoropyridin- 8.50 (s, 1H), 7.94 - 7.87

[2066] 2- (m, 3H), 7.81 (d, 7=8.2 Hz, yl)pyrrolidin- 2H), 7.68 - 7.60 (m, 2H), 3-yl)-7-methyl- 7.54 (s, 1H), 7.44 (s, 1H), 5-(4-(l- 6.41 (dd, 7=8.0, 2.3 Hz, rO

[2067] 'IT methyl-1H- 1H), 6.23 (dd, 7=7.7, 1.7 imidazol-2- Hz, 1H), 5.52 - 5.42 (m, yl)phenyl)-2H- 1H), 4.04 - 3.97 (m, 1H), indazole 3.90 (dd, 7=11.2, 4.2 Hz, p

[2068] 1H), 3.86 (s, 2H), 3.75 - 3.68 (m, 1H), 2.88 (s, 1H), 2.72 (s, 1H), 2.69 - 2.58 (m, 2H), 2.56 (s, 3H). 5- H

[2069] N (R)-4-(4-(2-(1- 468.1 E: 1.14 (500 MHz, DMSO-d6) 6 33

[2070] (6- 12.03 (br s, 1H), 8.50 - (hydroxymethy 8.35 (m, 2H), 7.83 - 7.76 / ?JN

[2071] l)pyridin-2- (m, 3H), 7.76 - 7.71 (m, yl)pyrrolidin- 2H), 7.51 (t, 7=7.9 Hz, 3-yl)-7-methyl- 1H), 7.38 (s, 1H), 6.70 (d, IO 2H-indazol-5- 7=7.2 Hz, 1H), 6.39 (d, 'NX

[2072] yl)phenyl)-2,4- 7=8.0 Hz, 1H), 5.48 - 5.38 dihydro-3H- (m, 1H), 5.21 (t, 7=6.0 Hz, ci

[2073] 1,2,4-triazol-3- 1H), 4.39 (d, 7=5.6 Hz, one 2H), 4.07 - 3.97 (m, 1H),

[2074] 3.91 (dd, 7=11.2, 4.4 Hz, r? 1H), 3.81 - 3.67 (m, 1H),

[2075] 3.61 - 3.57 (m, 1H), 2.65 - 2.58 (m, 2H), 2.56 (s, 3H).

[2076] 5- (R)-6-(3-(7- 478.4 E: 1.25 (500 MHz, DMSO-d6) 6 34 methyl-5-(4- 8.53 (s, 1H), 7.99 - 7.92 (1-methyl-1H- (m, 4H), 7.88 - 7.83 (m, o

[2077] imidazol-2- 2H), 7.82 - 7.79 (m, 1H), _ry yl)phenyl)-2H- 7.79 - 7.74 (m, 1H), 7.70 - indazol-2- 7.65 (m, 1H), 7.48 - 7.40 'Nxyl)pyrrolidin- (m, 2H), 7.27 (d, 7=7.2 Hz,

[2078] 1- 1H), 6.74 (d, 7=8.4 Hz, yl)picolinamid 1H), 5.56 - 5.45 (m, 1H), e 4.18 - 4.09 (m, 1H), 4.07 - 4.01 (m, 1H), 3.91 (s, 3H), 7 3.82 - 3.74 (m, 2H), 2.68 -

[2079]

[2080] NH22.61 (m, 2H), 2.58 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2081] RT (min.)

[2082] 5- — i / (R)-6-(3-(5-(4- 469.2 E: 1.59 (500 MHz, DMSO-d6) 6 35 \=o (dimethylcarba 8.48 (s, 1H), 7.94 (br s, moyl)phenyl)- 1H), 7.82 (s, 1H), 7.72 (d, O 7-methyl-2H-. / =8,2 Hz, 2H), 7.67 (t, indazol-2-. / =7,8 Hz, 1H), 7.46 (d, yl)pyrrolidin-. / =8,2 Hz, 2H), 7.42 (br d, 1- J=0.9 Hz, 1H), 7.38 (s, 'IN yl)picolinamid 1H), 7.26 (d,. / =7,2 Hz, e 1H), 6.73 (d,,7=8.4 Hz,

[2083] 1H), 5.47 (quin,.7=5.8 Hz, 1H), 4.13 - 4.07 (m, 1H), 4.06 - 4.00 (m, 1H), 3.86 - 3.62 (m, 1H), 3.59 - 3.54 NH2

[2084] (m,.7=7,3 Hz, 1H), 3.05 - 2.91 (m, 6H), 2.64 (q, J=6.9 Hz, 2H), 2.55 (s, 3H).

[2085] 5- (R)-6-(3-(7- 450.1 E: 1.08 (500 MHz, DMSO-d6) 6 36 methyl-5-(4- 8.42 (s, 1H), 7.84 (s, 1H),

[2086] (1-methyl-1H- 7.81 - 7.73 (m, 4H), 7.42 o

[2087] imidazol-2- (s, 1H), 7.26 (s, 1H), 7.16 yl)phenyl)-2H- (t, <7=7.9 Hz, 1H), 6.99 (s, indazol-2- 1H), 5.74 (d,.7=7,8 Hz, 'hr

[2088] 6 yl)pyrrolidin- 1H), 5.67 (d,.7=7,9 Hz, l-yl)pyridin-2- 1H), 5.46 (s, 2H), 5.43 - amine 5.35 (m, 1H), 3.98 - 3.90. P (m, 1H), 3.89 - 3.83 (m,

[2089] 1H), 3.78 (s, 3H), 3.69 - 3.62 (m, 1H), 3.56 - 3.52 (m, 1H), 2.61 - 2.55 (m, 5H).

[2090] 5- (R)-N-methyl- 493.1 E: 1.41 (500 MHz, DMSO-d6) 6 37 \=ri

[2091] 6-(3-(7- 8.57 (s, 1H), 8.51 (s, 1H), methyl-5-(4- 8.49 - 8.42 (m, 1H), 7.88 (4-methyl-4H- (s, 1H), 7.86 - 7.83 (m, 1,2,4-triazol-3- 2H), 7.83 - 7.79 (m, 2H), yl)phenyl)-2H- 7.67 (t, <7=7.8 Hz, 1H), 7.44 iO 'i\r indazol-2- (s, 1H), 7.25 (d, <7=7.2 Hz, yl)pyrrolidin- 1H), 6.73 (d, <7=8.5 Hz, 1- 1H), 5.50 (quin, <7=6.0 Hz, yl)picolinamid 1H), 4.20 - 4.09 (m, 1H), p

[2092] e 4.08 - 3.99 (m, 1H), 3.86 - °^lN~ 3.81 (m, 1H), 3.78 (s, 3H),

[2093] 3.72 - 3.57 (m, 1H), 2.79 (d, <7=4.8 Hz, 3H), 2.69 -

[2094]

[2095] 2.61 (m, 2H), 2.57 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[2096] RT (min.)

[2097] 5- (R)-7-methyl- 437.2 E: 1.10 (500 MHz, DMSO-d6) 6 38 5-(4-(4- 8.58 (s, 1H), 8.53 - 8.47 methyl-4H- (m, 2H), 7.90 - 7.87 (m, 1,2,4-triazol-3- 1H), 7.87 - 7.79 (m, 4H), yl)phenyl)-2- 7.44 (br s, 1H), 7.40 - 7.33 (l-(pyridazin- (m, 1H), 7.02 - 6.92 (m, 'N 3- 1H), 5.57 - 5.47 (m, 1H), yl)pyrrolidin- 4.19 - 3.98 (m, 2H), 3.89 - 6 3-yl)-2H- 3.81 (m, 1H), 3.80 - 3.77 indazole (m, 3H), 3.72 - 3.66 (m, 0 1H), 2.73 - 2.61 (m, 2H),

[2098] 2.56 (s, 3H).

[2099] 5- (R)-6-(3-(7- 479.1 E: 1.35 (500 MHz, DMSO-d6) 6 39 \=N

[2100] methyl-5-(4- 8.57 (s, 1H), 8.51 (s, 1H), (4-methyl-4H- 7.93 (br s, 1H), 7.88 (s, 1,2,4-triazol-3- 1H), 7.87 - 7.83 (m, 2H), yl)phenyl)-2H- 7.83 - 7.78 (m, 2H), 7.67 IO

[2101] 'NZindazol-2- (t,. / =7,9 Hz, 1H), 7.44 (s, yl)pyrrolidin- 2H), 7.27 (d,. / =7,2 Hz, d 1- 1H), 6.74 (d,,7=8.4 Hz, yl)picolinamid 1H), 5.55 - 5.43 (m, 1H), e 4.15 - 4.09 (m, 1H), 4.07 - V NH24.00 (m, 1H), 3.83 - 3.79

[2102] (m, 1H), 3.78 (s, 3H), 3.70 - 3.62 (m, 1H), 2.68 - 2.61 (m, 2H), 2.57 (s, 3H). 5- (R)-2-(1-(1H- 425.1 E: 1.17 (500 MHz, DMSO-d6) 6 40 pyrazol-3- 8.87 - 8.71 (m, 1H), 8.51 cS yl)pyrrolidin- (s, 1H), 7.94 (s, 1H), 7.91 - 3-yl)-7-methyl- 7.80 (m, 5H), 7.74 (br s, 5-(4-(4- 1H), 7.44 (s, 1H), 5.86 - methyl-4H- 5.73 (m, 1H), 5.60 - 5.38 'i\r 1,2,4-triazol-3- (m, 1H), 3.89 - 3.84 (m, yl)phenyl)-2H- 2H), 3.82 (s, 4H), 3.79 - 6 indazole 3.74 (m, 2H), 2.67 - 2.59

[2103] (m, 1H), 2.57 (s, 3H). 'NX

[2104]

[2105] HEx Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[2106] RT (min.)

[2107] 5- (R)-(4-(2-(1- 427.0 E: 1.23 (500 MHz, DMSO-d6) 6 41 (1H-pyrazol-3- 12.17 - 11.60 (m, 1H), 8.45 yl)pyrrolidin- (s, 1H), 8.40 (s, 1H), 7.84 - 3-yl)-7-methyl- 7.77 (m, 3H), 7.76 - 7.72 2H-indazol-5- (m, 2H), 7.45 (br s, 1H), yl)phenyl)-2,4- 7.38 (s, 1H), 5.60 (br s, IO dihydro-3H- 1H), 5.48 - 5.35 (m, 1H), 'IT

[2108] 1,2,4-triazol-3- 3.80 - 3.72 (m, 1H), 3.70 - 6 one 3.62 (m, 1H), 3.61 - 3.45

[2109] (m, 3H), 3.35 - 3.20 (m, 2H), 2.59 - 2.55 (m, 3H).

[2110] 5- (R)-4-(2-(1- 415.1 E: 1.29 (500 MHz, DMSO-d6) 6 42 v

[2111] \ (1H-pyrazol-3- 12.09 - 11.69 (m, 1H), 8.45 yl)pyrrolidin- (s, 1H), 7.82 (s, 1H), 7.72 3-yl)-7-methyl- (br d, J=8.2 Hz, 2H), 7.51 - 2H-indazol-5- 7.42 (m, 3H), 7.38 (s, 1H), o yl)-N, N- 5.59 (br s, 1H), 5.47 - 5.36 'i\r dimethylbenza (m, 1H), 3.80 - 3.73 (m, mide 1H), 3.66 (br dd, J=10.1, 6 4.3 Hz, 1H), 3.60 - 3.43 (m, 2H), 3.35 - 3.31 (m, 1H), 3.03 - 2.92 (m, 6H), 2.66 - 2.55 (m, 4H).

[2112] 5- H

[2113] N (R)-4-(4-(2-(1- 453.1 C: 1.19 (500 MHz, DMSO-d6) 6 43

[2114] (6- 11.99 (br s, 1H), 11.80 - aminopyridin- 11.62 (m, 1H), 8.56 (s, o 2- 1H), 8.42 (s, 1H), 7.83 (s, yl)pyrrolidin- 1H), 7.82 - 7.79 (m, 2H), 3-yl)-7-methyl- 7.78 - 7.74 (m, 2H), 7.68 - H

[2115] 'hr 2H-indazol-5- 7.54 (m, 1H), 7.42 (s, 1H), yl)phenyl)-2,4- 7.30 - 7.14 (m, 1H), 6.00 6 dihydro-3H- (br d, J=1.0 Hz, 2H), 5.57 1,2,4-triazol-3- (br s, 1H), 4.16 - 4.05 (m, H2r / one 1H), 3.99 (br d, J=6.8 Hz,

[2116] 1H), 3.88 - 3.74 (m, 1H), 3.72 - 3.64 (m, 1H), 2.74 -

[2117]

[2118] 2.65 (m, 2H), 2.55 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2119] RT (min.)

[2120] 5- (R)-3-(3-(7- 477.1 E: 1.33 (500 MHz, DMSO-d6) 6 45 methyl-5-(4- 8.51 (s, 1H), 7.97 - 7.91 o (1-methyl-1H- (m, 4H), 7.89 (br s, 1H), imidazol-2- 7.84 (d, 7=8.2 Hz, 2H), yl)phenyl)-2H- 7.73 (s, 1H), 7.65 (s, 1H), indazol-2- 7.46 (s, 1H), 7.28 - 7.23 'i\r

[2121] yl)pyrrolidin- (m, 3H), 6.77 (br d, J=9.2 6 1- Hz, 1H), 5.58 - 5.46 (m, yl)benzamide 1H), 3.95 - 3.91 (m, 1H),

[2122] 3.89 (s, 3H), 3.81 (br dd,H2N- P^ 7=10.3, 4.2 Hz, 1H), 3.69 - 3.64 (m, 2H), 2.70 - 2.63 (m, 2H), 2.58 (s, 3H). 5- H

[2123] (R)-N, N- 508.1 E: 1.65 (500 MHz, DMSO-d6) 6 46 °^ZN'N

[2124] dimethyl-3-(3- 12.02 (br d, 7=0.9 Hz, 1H), (7-methyl-5- 8.46 (s, 1H), 8.39 (s, 1H), o (4-(5-oxo-l,5- 7.84 - 7.76 (m, 3H), 7.76 - dihydro-4H- 7.71 (m, 2H), 7.39 (s, 1H), rO 1,2,4-triazol-4- 7.28 - 7.23 (m, 1H), 6.70 - 'hr yl)phenyl)-2H- 6.65 (m, 1H), 6.62 (d, indazol-2- 7=7.8 Hz, 1H), 6.57 (s, yl)pyrrolidin- 1H), 5.55 - 5.43 (m, 1H), 1- 3.92 - 3.85 (m, 1H), 3.81 - yl)benzamide 3.74 (m, 1H), 3.70 - 3.57 > P

[2125] (m, 2H), 3.01 - 2.87 (m, 6H), 2.69 - 2.59 (m, 2H), 2.56 (s, 3H).

[2126] 5- H

[2127] O (R)-4-(3-(7- 481.0 E: 1.10 (500 MHz, DMSO-d6) 6 47N'N

[2128] methyl-5-(4- 8.49 (s, 1H), 8.38 (s, 1H), (5-oxo-l,5- 8.19 - 8.14 (m, 1H), 8.03 - o dihydro-4H- 7.96 (m, 1H), 7.85 - 7.77 1,2,4-triazol-4- (m, 3H), 7.73 (br d, 7=8.5 yl)phenyl)-2H- Hz, 2H), 7.50 - 7.43 (m, 'hr indazol-2- 1H), 7.39 (s, 1H), 7.21 (s, yl)pyrrolidin- 1H), 6.76 - 6.66 (m, 1H), 1- 5.58 - 5.44 (m, 1H), 3.86 - yl)picolinamid 3.70 (m, 5H), 3.16 (s, 3H), e 2.69 - 2.61 (m, 2H).

[2129] H2N^ 0 /

[2130]

[2131] Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2132] RT (min.)

[2133] 5- (R)-2-fluoro-3- 498.2 C: 1.47 (500 MHz, DMSO-d6) 6 48 (3-(7-methyl- 11.98 (br s, 1H), 8.51 (s,

[2134] 5-(4-(5-oxo- 1H), 8.42 (d, 7=1.5 Hz, 1,5-dihydro- 1H), 7.85 - 7.79 (m, 3H), 4H- 1,2,4- 7.78 - 7.73 (m, 2H), 7.64 triazol-4- (br s, 1H), 7.50 (br s, 1H), 'i\r yl)phenyl)-2H- 7.43 - 7.34 (m, 1H), 7.11 - indazol-2- 7.00 (m, 1H), 6.95 - 6.87 ^5Fyl)pyrrolidin- (m, 2H), 5.50 - 5.41 (m, \ / 0

[2135] 1- 1H), 4.00 - 3.93 (m, 1H), VJ / NH2yl)benzamide 3.91 - 3.85 (m, 1H), 3.79 - 3.70 (m, 1H), 3.58 - 3.50 (m, 1H), 2.62 - 2.56 (m, 5H).

[2136] 5- — l / (R)-4-(2-(1-(3- 454.1 E: 1.51 (500 MHz, DMSO-d6) 6 49 )=0 carbamoylphen 8.53 (s, 1H), 8.02 (s, 1H), yl)pyrrolidin- 7.90 (br s, 1H), 7.74 (d, o

[2137] 3-yl)-2H- 7=8.2 Hz, 2H), 7.71 (d, indazol-5-yl)- 7=9.1 Hz, 1H), 7.60 (dd, o

[2138] N, N- 7=9.2, 1.5 Hz, 1H), 7.48 (d, IO

[2139] 'NZdimethylbenza 7=8.3 Hz, 2H), 7.28 - 7.25 mide (m, 1H), 7.24 - 7.20 (m, 6 1H), 7.15 (d, 7=7.5 Hz,

[2140] 1H), 7.09 (s, 1H), 6.79 - 6.73 (m, 1H), 5.55 - 5.47 P

[2141] (m, 1H), 3.95 - 3.87 (m, 1H), 3.79 (dd, 7=10.3, 3.7 Hz, 1H), 3.65 (q, 7=7.5 Hz, 1H), 3.54 - 3.50 (m, 1H), 3.08 - 2.88 (m, 6H), 2.70 - 2.57 (m, 2H).

[2142] 5- o. _ (R)-3-(3-(7- 494.2 C: 1.57 (500 MHz, DMSO-d6) 6 50 V 'N methyl-5-(4- 8.49 (d, 7=11.7 Hz, 2H), (1-methyl-5- 7.90 - 7.84 (m, 1H), 7.83 - oxo-1,5- 7.79 (m, 3H), 7.78 - 7.71 dihydro-4H- (m, 2H), 7.40 (s, 1H), 7.28 1,2,4-triazol-4- - 7.21 (m, 2H), 7.16 (d, 'N^

[2143] yl)phenyl)-2H- 7=7.8 Hz, 1H), 7.12 (d, indazol-2- 7=1.9 Hz, 1H), 6.77 (dd, yl)pyrrolidin- 7=8.1, 1.9 Hz, 1H), 5.54 - 0 1- 5.48 (m, 1H), 3.95 - 3.88 H2N-Z yl)benzamide (m, 1H), 3.81 (dd, 7=10.3,

[2144] 4.5 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.54 - 3.46 (m, 1H), 3.41 (s, 3H), 2.69 -

[2145]

[2146] 2.62 (m, 2H), 2.57 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[2147] RT (min.)

[2148] 5- H (R)-3-fluoro-4- 498.1 E: 1.46 (500 MHz, DMSO-d6) 6 51 O^AN

[2149] (3-(7-methyl- 12.02 (br s, 1H), 8.50 (s, 5-(4-(5-oxo- 1H), 8.39 (s, 1H), 7.85 - 1,5-dihydro- 7.71 (m, 6H), 7.66 - 7.56 4H- 1,2,4- (m, 2H), 7.39 (s, 1H), 7.20 triazol-4- - 7.06 (m, 1H), 6.80 (brt, 'NXyl)phenyl)-2H- J=8.8 Hz, 1H), 5.51 - 5.39 indazol-2- (m, 1H), 4.10 - 4.01 (m, 6Fyl)pyrrolidin- 1H), 3.99 - 3.90 (m, 1H),

[2150] 1- 3.85 - 3.73 (m, 1H), 3.67 - yl)benzamide 3.59 (m, 1H), 2.63 - 2.57 (m, 2H), 2.56 (s, 3H). 5- H

[2151] „N(R)-4-(4-(2-(1- 454.1 E: 1.14 (500 MHz, DMSO-d6) 6 52

[2152] " V (2- 12.04 (br s, 1H), 8.52 (d, aminopyrimidi J=9.8 Hz, 1H), 8.39 (s, n-4- 1H), 7.87 - 7.71 (m, 7H), yl)pyrrolidin- 7.40 (br s, 1H), 6.36 - 6.25 3-yl)-7-methyl- (m, 1H), 5.58 - 5.43 (m, rO

[2153] 'NX2H-indazol-5- 1H), 4.08 (br s, 2H), 4.00 - yl)phenyl)-2,4- 3.66 (m, 3H), 2.73 - 2.55 d dihydro-3H- (m, 2H), 2.55 - 2.52 (m, 1,2,4-triazol-3- 3H).

[2154] H2N one

[2155] 5- H

[2156] N (7?)-2-(3-(7- 481.1 E: 1.05 (500 MHz, DMSO-d6) 6 53

[2157] °%JNmethyl-5-(4- 12.22 - 11.87 (m, 1H), 8.47

[2158] (5-oxo-l,5- (s, 1H), 8.39 (s, 1H), 8.18 dihydro-4H- (d, J=5.1 Hz, 1H), 8.10 (br 1,2,4-triazol-4- s, 1H), 7.84 - 7.77 (m, 3H), yl)phenyl)-2H- 7.76 - 7.70 (m, 2H), 7.54 JO indazol-2- (br s, 1H), 7.39 (s, 1H), 'NXyl)pyrrolidin- 6.97 (d, J=5.3 Hz, 1H),

[2159] 1- 6.93 (s, 1H), 5.55 - 5.42 6

[2160] \ __NH2yl)isonicotina (m, 1H), 4.09 - 4.03 (m, mide 1H), 3.98 (br dd, J=11.3, \=J <3

[2161] 4.2 Hz, 1H), 3.83 - 3.74 (m, 1H), 3.69 - 3.63 (m, 1H), 2.70 - 2.60 (m, 2H),

[2162]

[2163] 2.57 - 2.55 (m, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[2164] RT (min.)

[2165] 5- H

[2166] N_. (R)-5-(3-(7- 481.1 E: 1.15 (500 MHz, DMSO-d6) 6 54

[2167] O==^N JNmethyl-5-(4- 8.49 (s, 1H), 8.39 (s, 1H),

[2168] (5-oxo-l,5- 8.34 (s, 1H), 8.16 - 8.10 dihydro-4H- (m, 1H), 8.07 (br s, 1H), 1,2,4-triazol-4- 7.84 - 7.71 (m, 5H), 7.49 - yl)phenyl)-2H- 7.43 (m, 1H), 7.43 - 7.35 o

[2169] 'i\r indazol-2- (m, 2H), 5.58 - 5.47 (m, yl)pyrrolidin- 1H), 4.00 - 3.91 (m, 1H), NH21- 3.89 - 3.82 (m, 1H), 3.74 - yl)nicotinamid 3.66 (m, 2H), 3.53 - 3.52 e (m, 1H), 2.70 - 2.62 (m,

[2170] 2H), 2.58 - 2.55 (m, 3H).

[2171] 5- H

[2172] NK 1(R)-4-(4-(2-(1- 467.0 E: 1.56 (500 MHz, DMSO-d6) 6 55

[2173] (3- 12.01 (br s, 1H), 8.45 (s, (hydroxymethy 1H), 8.41 (s, 1H), 7.84 - f5 l)phenyl)pyrrol 7.71 (m, 5H), 7.39 (s, 1H), idin-3-yl)-7- 7.13 (brt, 7=7.7 Hz, 1H), / A methyl-2H- 6.66 - 6.57 (m, 2H), 6.50 indazol-5- (br d, 7=8.0 Hz, 1H), 5.54 - 'NZyl)phenyl)-2,4- 5.42 (m, 1H), 5.14 - 5.04 dihydro-3H- (m, 1H), 4.44 (br d, 7=3.4 d 1,2,4-triazol-3- Hz, 2H), 3.91 - 3.83 (m, one 1H), 3.80 - 3.70 (m, 1H),

[2174] 3.68 - 3.57 (m, 1H), 3.49 - HO P^

[2175] 3.46 (m, 1H), 2.69 - 2.60 (m, 2H), 2.57 (s, 3H). 5- — l / (R)-4-(2-(1-(3- 468.0 E: 1.60 (500 MHz, DMSO-d6) 6 56 )=O carbamoylphen 8.47 (s, 1H), 7.89 (br s, yl)pyrrolidin- 1H), 7.82 (s, 1H), 7.72 (d, o

[2176] 3-yl)-7-methyl- 7=8.2 Hz, 2H), 7.47 (d, 2H-indazol-5- 7=8.2 Hz, 2H), 7.39 (s, rO yl)-#^V- 1H), 7.28 - 7.25 (m, 1H), 'Nxdimethylbenza 7.23 (br d, 7=7.9 Hz, 1H), mide 7.15 (d, 7=7.9 Hz, 1H), d

[2177] 7.11 - 7.08 (m, 1H), 6.80 - 6.73 (m, 1H), 5.55 - 5.46 (m, 1H), 3.96 - 3.87 (m, 1H), 3.80 (dd, J=10.2, 4.3 Hz, 1H), 3.72 - 3.62 (m, 2H), 3.05 - 2.92 (m, 6H), 2.69 - 2.60 (m, 2H), 2.56

[2178]

[2179] (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2180] RT (min.)

[2181] 5- (R)-N,N- 479.5 E: 1.24 (500 MHz, DMSO-d6) 6 57 \=KI

[2182] dimethyl-6-(3- 8.57 (s, 1H), 8.46 (s, 1H), (7-methyl-5- 7.92 - 7.78 (m, 5H), 7.43 (4-(4-methyl- (s, 1H), 7.27 (t,,7=8.0 Hz, 4H- 1,2,4- 1H), 5.86 (br d, J=8.2 Hz, iO triazol-3- 1H), 5.74 (br d, J=7.9 Hz, 'Nx

[2183] yl)phenyl)-2H- 1H), 5.51 - 5.38 (m, 1H), indazol-2- 4.00 (br dd, J=11.2, 6.7 Hz, d

[2184] yl)pyrrolidin- 1H), 3.88 (br dd, J=10.9, l-yl)pyridin-2- 4.4 Hz, 1H), 3.79 (s, 3H), P amine 3.74 - 3.65 (m, 1H), 3.62 - \

[2185] 3.55 (m, 1H), 2.95 (s, 6H), 2.64 - 2.55 (m, 5H).

[2186] 5- ■^N^N (R)-3-(3-(7- 478.1 E: 1.37 (500 MHz, DMSO-d6) 6 58 \=ri

[2187] methyl-5-(4- 8.81 (s, 1H), 8.49 (s, 1H), (4-methyl-4H- 7.98 - 7.78 (m, 6H), 7.44 1,2,4-triazol-3- (s, 1H), 7.33 - 7.20 (m, yl)phenyl)-2H- 2H), 7.15 (d,.7=8,0 Hz, H

[2188] 'er indazol-2- 1H), 7.10 (s, 1H), 6.77 (br yl)pyrrolidin- d,,7=8.2 Hz, 1H), 5.55 - 1- 5.45 (m, 1H), 3.91 (dd, yl)benzamide,7=10.4, 6.8 Hz, 1H), 3.84 - 3.78 (m, 4H), 3.71 - 3.64H=N- P% (m, 2H), 2.69 - 2.61 (m,

[2189] 2H), 2.57 (s, 3H).

[2190] 5- "-N^N 465.7 E: 1.18 (500 MHz, DMSO-d6) 6 59 (R)-N-methyl- 8.64 (s, 1H), 8.54 (s, 1H),

[2191] 6-(3-(7- 7.96 - 7.88 (m, 1H), 7.84 (~ 7 methyl-5-(4- (q, J=8.3 Hz, 4H), 7.57 - (4-methyl-4H- 7.49 (m, 1H), 7.45 (s, 1H), ~^C~7 1,2,4-triazol-3- 5.94 (br d,,7=7.2 Hz, 1H), rO

[2192] 'Nxyl)phenyl)-2H- 5.89 (br d,,7=8.0 Hz, 1H), indazol-2- 5.59 - 5.49 (m, 1H), 4.12 - yl)pyrrolidin- 4.04 (m, 1H), 4.01 - 3.93 l-yl)pyridin-2- (m, 1H), 3.83 - 3.75 (m, amine 4H), 3.70 - 3.63 (m, 2H), 0

[2193] HN 2.81 (s, 3H), 2.69 - 2.60 \

[2194]

[2195] (m, 2H), 2.56 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2196] RT (min.)

[2197] 5- (R)-6-(3-(7- 496.3 E: 1.51 (500 MHz, DMSO-d6) 6 60 methyl-5-(4- 8.48 (d,.7=4,8 Hz, 2H), (1-methyl-5- 7.92 (br s, 1H), 7.84 - 7.77 oxo-1,5- (m, 3H), 7.76 - 7.71 (m, dihydro-4H- 2H), 7.67 (t,,7=7.8 Hz, 1,2,4-triazol-4- 1H), 7.43 (br s, 1H), 7.39 yl)phenyl)-2H- (s, 1H), 7.26 (d,.7=7,2 Hz, indazol-2- 1H), 6.73 (d, <7=8.4 Hz, yl)pyrrolidin- 1H), 5.53 - 5.43 (m, 1H), 1- 4.15 - 4.08 (m, 1H), 4.07 - p

[2198] yl)picolinamid 4.00 (m, 1H), 3.85 - 3.74 H2NXO

[2199] e (m, 1H), 3.71 - 3.60 (m,

[2200] 1H), 3.40 (br s, 3H), 2.68 - 2.60 (m, 2H), 2.56 (s, 3H).

[2201] 5- (R)-4-(4-(2-(1- 481.4 E: 1.66 (500 MHz, DMSO-d6) 6 61

[2202] pj (3- 8.45 (d, <7=8.1 Hz, 2H), (hydroxymethy 7.83 - 7.77 (m, 3H), 7.76 - l)phenyl)pyrrol 7.70 (m, 2H), 7.39 (s, 1H), idin-3-yl)-7- 7.13 (t, <7=7.7 Hz, 1H), 6.64 — T? methyl-2H- - 6.57 (m, 2H), 6.50 (br d, iO indazol-5-.7=7,2 Hz, 1H), 5.47 (quin, 'i\r

[2203] yl)phenyl)-2- 7=5.6 Hz, 1H), 5.19 - 5.09 <5 methyl-2,4- (m, 1H), 4.44 (br d, <7=5.6 dihydro-3H- Hz, 2H), 3.90 - 3.83 (m, 1,2,4-triazol-3- 1H), 3.74 (br dd, <7=10.1, HO P—' one 4.1 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.41 - 3.38 (m, 4H), 2.67 - 2.58 (m, 2H), 2.56 (s, 3H).

[2204] 5- (R)-2-fluoro-3- 512.2 C: 1.56 (500 MHz, DMSO-d6) 6 62 (3-(7-methyl- 8.51 (d, <7=3.5 Hz, 2H),

[2205] 5-(4-(l- 7.86 - 7.79 (m, 3H), 7.78 - methyl-5-oxo- 7.73 (m, 2H), 7.64 (br s, 1,5-dihydro- 1H), 7.50 (br s, 1H), 7.40 4H- 1,2,4- (s, 1H), 7.11 - 7.03 (m, triazol-4- 1H), 6.96 - 6.88 (m, 2H), yl)phenyl)-2H- 5.49 - 5.39 (m, 1H), 3.98 - 6 indazol-2- 3.94 (m, 1H), 3.91 - 3.85 yl)pyrrolidin- (m, 1H), 3.77 - 3.70 (m,F-p

[2206] 1- 2H), 3.41 (s, 3H), 2.65 - H2N— \-. yl)benzamide 2.58 (m, 2H), 2.58 - 2.55

[2207]

[2208] (m, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+Method,

[2209] RT (min.)

[2210] 5- (R)-3-fluoro-5- 512.2 C: 1.62 (500 MHz, DMSO-d6) 6 63 (3-(7-methyl- 8.50 (d, 7=8.0 Hz, 2H),

[2211] 5-(4-(l- 7.94 (s, 1H), 7.83 - 7.79 methyl-5-oxo- (m, 3H), 7.78 - 7.74 (m, 1,5-dihydro- 2H), 7.42 - 7.39 (m, 1H), - o 4H- 1,2,4- 7.38 - 7.35 (m, 1H), 6.98 - 'i\r triazol-4- 6.93 (m, 1H), 6.92 - 6.87 yl)phenyl)-2H- (m, 1H), 6.58 (dt, 7=11.9, indazol-2- 2.2 Hz, 1H), 5.54 - 5.49 H-F yl)pyrrolidin- (m, 1H), 3.95 - 3.91 (m,

[2212] 1- 1H), 3.83 (dd, 7=10.5, 4.5 H2N— Z

[2213] yl)benzamide Hz, 1H), 3.70 - 3.63 (m,

[2214] 1H), 3.54 - 3.48 (m, 1H), 3.41 (s, 3H), 2.69 - 2.63 (m, 2H), 2.57 (s, 3H). 5- (R)-2-fluoro-5- 512.3 C: 1.62 (500 MHz, DMSO-d6) 6 64 o 'N

[2215] (3-(7-methyl- 8.49 (d, 7=12.8 Hz, 2H), 5-(4-(l- 7.81 (d, 7=8.9 Hz, 3H), €5 methyl-5-oxo- 7.78 - 7.74 (m, 2H), 7.59 - - / A 1,5-dihydro- 7.51 (m, 2H), 7.43 - 7.38

[2216] 4H- 1,2,4- (m, 1H), 7.11 (dd, 7=10.3, rO 'Nxtriazol-4- 9.1 Hz, 1H), 6.84 (dd, yl)phenyl)-2H- 7=5.9, 3.1 Hz, 1H), 6.74 indazol-2- (dt, 7=8.9, 3.6 Hz, 1H), yl)pyrrolidin- 5.53 - 5.46 (m, 1H), 3.91 - b

[2217] 1- 3.86 (m, 1H), 3.77 (dd, H2N— / F

[2218] yl)benzamide 7=10.1, 4.4 Hz, 1H), 3.67 - 3.60 (m, 1H), 3.52 - 3.47 (m, 3H), 2.69 - 2.64 (m, 2H), 2.57 (s, 3H) (pyrrolidine signals obscured by water signal).

[2219] 5- (R)-4-(4-(2-(1- 467.3 E: 1.31 (500 MHz, DMSO-d6) 6 65 (6- 8.49 (s, 1H), 8.42 (s, 1H), aminopyridin- 7.86 - 7.78 (m, 3H), 7.77 - 2- 7.72 (m, 2H), 7.39 (s, 1H), yl)pyrrolidin- 7.15 (t, 7=7.9 Hz, 1H), 5.74 3-yl)-7-methyl- (d, 7=7.8 Hz, 1H), 5.66 (d, 2H-indazol-5- 7=7.7 Hz, 1H), 5.47 (s, yl)phenyl)-2- 2H), 5.44 - 5.37 (m, 1H), 6 methyl-2,4- 3.98 - 3.91 (m, 1H), 3.89 - dihydro-3H- 3.81 (m, 1H), 3.71 - 3.60 rXb

[2220] 1,2,4-triazol-3- (m, 1H), 3.58 - 3.47 (m, H2N one 2H), 3.41 (s, 3H), 2.62 -

[2221]

[2222] 2.58 (m, 1H), 2.57 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2223] RT (min.)

[2224] 5- o _ (R)-4-(3-(7- 494.2 E: 1.52 (500 MHz, DMSO-d6) 6 66 'V 'N

[2225] iW methyl-5-(4- 8.47 (d, 7=4.3 Hz, 2H), (1-methyl-5- 7.86 - 7.60 (m, 8H), 7.39 oxo-1,5- (s, 1H), 6.95 - 6.82 (m, dihydro-4H- 1H), 6.62 (d, 7=8.7 Hz, 1,2,4-triazol-4- 2H), 5.49 (quin, 7=5.7 Hz, yl)phenyl)-2H- 1H), 3.97 - 3.90 (m, 1H), d> indazol-2- 3.82 (dd, 7=10.4, 4.3 Hz, yl)pyrrolidin- 1H), 3.73 - 3.61 (m, 1H), 1- 3.41 - 3.39 (m, 4H), 2.68 - / =O

[2226] H2N yl)benzamide 2.61 (m, 2H), 2.55 (s, 3H).

[2227] 5- (R)-4-(4-(2-(1- 441.2 E: 1.27 (500 MHz, DMSO-d6) 6 67 0=^ 'N (1H-pyrazol-3- 8.46 (s, 1H), 8.41 (s, 1H), yl)pyrrolidin- 7.83 - 7.75 (m, 3H), 7.74 - 3-yl)-7-methyl- 7.68 (m, 3H), 7.38 (s, 1H), 2H-indazol-5- 5.79 - 5.73 (m, 1H), 5.49 - yl)phenyl)-2- 5.40 (m, 1H), 3.89 - 3.84 methyl-2,4- (m, 4H), 3.46 (br dd, 'hr dihydro-3H- 7=14.5, 7.9 Hz, 2H), 3.40 1,2,4-triazol-3- (s, 3H), 2.67 - 2.56 (m, 6 one 1H), 2.53 (s, 3H). VH

[2228] 5- (R)-2-methyl- 508.2 E: 1.64 (500 MHz, DMSO-d6) 6 68 5-(3-(7- 8.44 (d, 7=10.6 Hz, 2H), methyl-5-(4- 7.84 - 7.76 (m, 3H), 7.75 - d (1-methyl-5- 7.70 (m, 2H), 7.62 (br s, oxo-1,5- 1H), 7.38 (s, 1H), 7.22 (br / A dihydro-4H- s, 1H), 7.03 (br d, 7=8.4 1,2,4-triazol-4- Hz, 1H), 6.65 - 6.56 (m, yl)phenyl)-2H- 2H), 5.49 - 5.43 (m, 1H), indazol-2- 3.87 - 3.82 (m, 1H), 3.74 yl)pyrrolidin- (br dd, 7=10.6, 4.0 Hz, y^s

[2229] 1- 1H), 3.42 - 3.38 (m, 5H),H2N^C. yl)benzamide 2.66 - 2.58 (m, 2H), 2.56

[2230]

[2231] (s, 3H), 2.23 (s, 3H).Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2232] RT (min.)

[2233] 5- (R)-3-methyl- 508.1 E: 1.67 (500 MHz, DMSO-d6) 6 69 oJ-N

[2234] AJ 5-(3-(7- 8.43 (s, 2H), 7.86 (br s, methyl-5-(4- 1H), 7.82 - 7.75 (m, 3H), (1-methyl-5- 7.71 (br d, J=8.3 Hz, 2H), oxo-1,5- 7.38 (s, 1H), 7.16 (br s, —( / dihydro-4H- 1H), 6.98 (s, 1H), 6.89 (s, 1,2,4-triazol-4- 1H), 6.59 (s, 1H), 5.54 - 'NZyl)phenyl)-2H- 5.41 (m, 1H), 3.91 - 3.85 indazol-2- (m, 1H), 3.82 - 3.74 (m, 6 ^ yl)pyrrolidin- 2H), 3.48 - 3.44 (m, 1H),

[2235] 1- 3.40 (s, 3H), 2.68 - 2.58 yl)benzamide (m, 2H), 2.55 (s, 3H), 2.27H2N^4 0 (s, 3H).

[2236] 5- (R)-4-fluoro-3- 512.3 E: 1.69 (500 MHz, DMSO-d6) 6 70 (3-(7-methyl- 8.50 (d, J=14.4 Hz, 2H),

[2237] 5-(4-(l- 7.94 (br s, 1H), 7.84 - 7.79 methyl-5-oxo- (m, 3H), 7.78 - 7.72 (m, 1,5-dihydro- 2H), 7.39 (s, 1H), 7.34 - 4H- 1,2,4- 7.23 (m, 3H), 7.15 (dd, triazol-4- J=13.6, 8.3 Hz, 1H), 5.51 - yl)phenyl)-2H- 5.41 (m, 1H), 4.01 - 3.95 rO 'i\r indazol-2- (m, 1H), 3.92 - 3.85 (m, yl)pyrrolidin- 1H), 3.79 - 3.71 (m, 1H), 6F1- 3.61 - 3.53 (m, 1H), 2.64 - yl)benzamide 2.58 (m, 2H), 2.57 (s, 3H), o 2.54 (s, 3H).

[2238] H2N— /

[2239] 5- (S)-3-(3-(7- 494.3 E: 1.54 (500 MHz, DMSO-d6) 6 71 L

[2240] methyl-5-(4- 8.47 (d, J=2.8 Hz, 2H), (1-methyl-5- 7.89 (br s, 1H), 7.85 - 7.78 oxo-1,5- (m, 3H), 7.74 (br d, J=8.5 dihydro-4H- Hz, 2H), 7.39 (s, 1H), 7.28 1,2,4-triazol-4- - 7.20 (m, 2H), 7.16 (br d, yl)phenyl)-2indazol-2- yl)pyrrolidin- 1- yl)benzamide J=7.2 Hz, 1H), 7.10 (br s, o indazol-2- 1H), 6.77 (br d, J=8.4 Hz, 'NZyl)pyrrolidin- 1H), 5.52 - 5.45 (m, 1H),

[2241] 1- 3.94 - 3.86 (m, 1H), 3.84 - a yl)benzamide 3.76 (m, 1H), 3.73 - 3.61

[2242] (m, 1H), 3.41 - 3.39 (m, 4H), 2.70 - 2.61 (m, 2H), H2N^ PO2.57 (s, 3H).

[2243]

[2244] Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2245] RT (min.)

[2246] 5- / =N

[2247] — N (R)-2-fluoro-3- 496.1 E: 1.40 (500 MHz, DMSO-d6) 6 72 (3-(7-methyl- 8.64 (s, 1H), 8.53 (s, 1H),

[2248] 5-(4-(4- 7.89 (s, 1H), 7.88 - 7.84 0 methyl-4H- (m, 2H), 7.84 - 7.81 (m, 1,2,4-triazol-3- 2H), 7.67 (br s, 1H), 7.57 - yl)phenyl)-2H- 7.48 (m, 1H), 7.47 - 7.41 indazol-2- (m, 1H), 7.09 - 7.05 (m, yl)pyrrolidin- 1H), 6.97 - 6.88 (m, 2H), Y ] 1- 5.50 - 5.39 (m, 1H), 3.99 - yl)benzamide 3.94 (m, 1H), 3.92 - 3.84 H2N\ (m, 1H), 3.80 (s, 3H), 3.77

[2249] - 3.69 (m, 1H), 3.57 - 3.51 (m, 1H), 2.65 - 2.57 (m, 5H).

[2250] 5- O CD,

[2251] V7 (R)-4-(2-(1-(3- 492.2 E: 1.67 (500 MHz, DMSO-d6) 6 73 / = / CD3carbamoyl-4- 8.47 (s, 1H), 7.82 (s, 1H), w fluorophenyl)p 7.72 (d, 7=8.2 Hz, 2H), yrrolidin-3-yl)- 7.56 (br d, 7=18.2 Hz, 2H), 7-methyl-2H- 7.47 (d, 7=7.9 Hz, 2H), io

[2252] 'IT indazol-5-yl)- 7.38 (s, 1H), 7.14 - 7.08 N, N- (m, 1H), 6.83 (dd, J=5.6, 6 bis(methyl- 3.3 Hz, 1H), 6.78 - 6.70 d3)benzamide (m, 1H), 5.54 - 5.43 (m, ft 1H), 3.91 - 3.83 (m, 1H), H2N-^

[2253] 3.75 (dd, 7=10.1, 4.3 Hz, 1H), 3.66 - 3.58 (m, 1H), 2.70 - 2.59 (m, 2H), 2.55 (s, 3H) (one proton obscured by solvent signal).

[2254] 5- o

[2255] y_NH2(R)-3-(3-(5-(4- 508.2 E: 1.58 (500 MHz, DMSO-d6) 6 74 (1,3-dimethyl- 8.47 (s, 1H), 7.91 (br s, M 5-oxo-l,5- 1H), 7.84 (s, 1H), 7.80 (d, dihydro-4H- 7=8.5 Hz, 2H), 7.45 (d, 1,2,4-triazol-4- 7=8.4 Hz, 2H), 7.40 (s, 9

[2256] yl)phenyl)-7- 1H), 7.28 - 7.25 (m, 1H), A methyl-2H- 7.23 (br d, 7=9.4 Hz, 1H), O~ indazol-2- 7.14 (br d, 7=7.5 Hz, 1H), yl)pyrrolidin- 7.09 (s, 1H), 6.77 (br d, 1- 7=8.5 Hz, 1H), 5.49 (quin, ''y- p=o yl)benzamide 7=5.8 Hz, 1H), 3.94 - 3.86 'N (m, 1H), 3.79 (br dd,

[2257] 7=10.6, 4.3 Hz, 1H), 3.71 - 3.63 (m, 2H), 3.34 (s, 3H), 2.70 - 2.60 (m, 2H), 2.56

[2258]

[2259] (s, 3H), 2.10 (s, 3H)Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2260] RT (min.)

[2261] 5- o (R)-2-chloro-5- 528.0 E: 1.66 (500 MHz, DMSO-d6) 6 75 ci VNH2

[2262] (3-(7-methyl- 8.43 (s, 2H), 7.80 (br d, 5-(4-(l-. / =4,6 Hz, 2H), 7.78 (br s, c

[2263] methyl-5-oxo- 2H), 7.72 (d,.7=8.5 Hz, 1,5-dihydro- 2H), 7.47 (br s, 1H), 7.38 7 4H- 1,2,4- (s, 1H), 6.68 - 6.63 (m, triazol-4- 1H), 6.62 (d, 7=2.4 Hz, y / yl)phenyl)-2H- 1H), 5.58 - 5.33 (m, 1H), indazol-2- 3.90 - 3.84 (m, 1H), 3.81 - O yl)pyrrolidin- 3.72 (m, 2H), 3.49 - 3.42

[2264] 1- (m, 2H), 3.40 (s, 3H), 2.69 t! / '" N yl)benzamide - 2.59 (m, 2H), 2.55 (br s,

[2265] 3H)

[2266] 5- O

[2267] ^NH (R)-3-(3-(5-(4- 526.2 E: 1.60 (500 MHz, DMSO-d6) 6 762

[2268] (1,3-dimethyl- 8.50 (s, 1H), 7.84 (s, 1H), 5-oxo-l,5- 7.80 (d, 7=8.4 Hz, 2H), VJT

[2269] dihydro-4H- 7.68 (br s, 1H), 7.50 (br s, 1,2,4-triazol-4- 1H), 7.46 (d, 7=8.4 Hz, 7 yl)phenyl)-7- 2H), 7.40 (s, 1H), 7.09 - methyl-2H- 7.02 (m, 1H), 6.95 - 6.87 A

[2270] y# indazol-2- (m, 2H), 5.49 - 5.39 (m, yl)pyrrolidin- 1H), 3.99 - 3.91 (m, 1H), o l-yl)-2- 3.89 - 3.82 (m, 1H), 3.79 - fluorobenzami 3.69 (m, 1H), 3.50 - 3.47 'rJ””

[2271] 'N )=o de (m, 2H), 3.34 (s, 3H), 2.64

[2272] - 2.58 (m, 1H), 2.56 (s, 3H), 2.10 (s, 3H)

[2273] 5- O

[2274] y_NH2(R)-2-methyl- 507.9 E: 1.52 (500 MHz, DMSO-d6) 6 77 3-(3-(7- 8.54 (s, 1H), 8.47 (s, 1H),

[2275] Q" methyl-5-(4- 7.86 - 7.78 (m, 3H), 7.78 - (1-methyl-5- 7.71 (m, 2H), 7.65 (br s, oxo-1,5- 1H), 7.39 (s, 1H), 7.31 (br?

[2276] dihydro-4H- s, 1H), 7.19 - 7.12 (m, 1H), 1,2,4-triazol-4- 7.11 - 7.05 (m, 1H), 6.95 O- yl)phenyl)-2H- (d, 7=7.6 Hz, 1H), 5.51 - indazol-2- 5.33 (m, 1H), 3.67 - 3.61 o yl)pyrrolidin- (m, 1H), 3.59 - 3.50 (m,

[2277] 1- 3H), 3.41 (s, 3H), 3.27 - 'N yl)benzamide 3.18 (m, 1H), 2.69 - 2.60 I

[2278] (m, 1H), 2.58 (s, 3H), 2.27

[2279]

[2280] (s, 3H)Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2281] RT (min.)

[2282] 5- o

[2283] ^NH2(R)-4-(3-(7- 533.1 E: 1.52 (500 MHz, DMSO-d6) 6 78 methyl-5-(4- 11.20 (br s, 1H), 8.50 (s,

[2284] / A

[2285] HN(1-methyl-5- 1H), 8.47 (s, 1H), 7.85 - U- / N— < oxo-1,5- 7.77 (m, 4H), 7.77 - 7.71 dihydro-4H- (m, 2H), 7.39 (br d, J=5.9 7 1,2,4-triazol-4- Hz, 2H), 7.28 (d,. / =2,7 Hz, yl)phenyl)-2H- 1H), 7.01 (br d, J=0.8 Hz, A indazol-2- 1H), 6.69 (br s, 1H), 6.64 C / yl)pyrrolidin- (s, 1H), 5.55 - 5.45 (m, l-yl)-lH- 1H), 4.19 - 4.11 (m, 1H), o indole-6- 4.10 - 4.01 (m, 1H), 3.99 - carb oxami de 3.90 (m, 1H), 3.83 - 3.76 (m, 1H), 3.40 (s, 3H), 2.69 \ - 2.63 (m, 2H), 2.58 (s, 3H) 5- o

[2286] ^NH2(R)-4- 524.1 E: 1.47 (500 MHz, DMSO-d6) 6 79 methoxy-3-(3- 8.52 (s, 1H), 8.48 (s, 1H),

[2287] (7-methyl-5- 7.87 - 7.78 (m, 4H), 7.77 - (4-(l-methyl- 7.71 (m, 2H), 7.44 - 7.37 5-oxo-l,5- (m, 2H), 7.28 (s, 1H), 7.10 dihydro-4H- (br s, 1H), 6.96 (d, J=8.5 1,2,4-triazol-4- Hz, 1H), 5.39 (quin, J=6.1 A yl)phenyl)-2H- Hz, 1H), 3.85 - 3.80 (m, indazol-2- 5H), 3.68 - 3.57 (m, 1H), yl)pyrrolidin- 3.41 - 3.40 (m, 5H), 2.61 - o 1- 2.56 (m, 4H)

[2288] yl)benzamide

[2289] ^=o

[2290] 'N

[2291] 1

[2292] 5- ^CN (R)-2-(3-(3-(7- 490.1 E: 1.95 (500 MHz, DMSO-d6) 6 80 methyl-5-(4- 8.47 (d, J=7.9 Hz, 2H), o (1-methyl-5- 7.85 - 7.78 (m, 3H), 7.77 - oxo-1,5- 7.70 (m, 2H), 7.39 (s, 1H), dihydro-4H- 7.21 - 7.17 (m, 1H), 6.66 - 1,2,4-triazol-4- 6.53 (m, 3H), 5.52 - 5.44 yl)phenyl)-2H- (m, 1H), 3.93 - 3.91 (m, indazol-2- 6H), 3.42 - 3.42 (m, 2H), yl)pyrrolidin- 2.72 - 2.60 (m, 3H), 2.57 1- (s, 3H) yl)phenyl)acet

[2293] •TN^0

[2294]

[2295] onitrileEx Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2296] RT (min.)

[2297] 5- NH2(R)-2-(3-(3-(7- 508.3 E: 1.60 (500 MHz, DMSO-d6) 6 81 methyl-5-(4- 8.44 - 8.40 (m, 2H), 7.84 - (1-methyl-5- 7.75 (m, 3H), 7.70 (d, o

[2298] oxo-1,5- 7=8.5 Hz, 2H), 7.38 (s, dihydro-4H- 1H), 7.25 - 7.07 (m, 3H), " Y 1,2,4-triazol-4- 6.87 - 6.78 (m, 1H), 6.63 - yl)phenyl)-2H- 6.58 (m, 1H), 6.58 - 6.52 C# indazol-2- (m, 1H), 6.49 (br d, 7=7.6 yl)pyrrolidin- Hz, 1H), 5.49 - 5.39 (m, o 1- 1H), 3.91 - 3.82 (m, 2H), yl)phenyl)aceta 3.47 - 3.38 (m, 6H), 2.67 - f ^=0

[2299] 'N mide 2.57 (m, 2H), 2.55 (s, 3H) 5- O

[2300] ^OH (R)-3-(3-(7- 495.2 E: 1.77 (500 MHz, DMSO-d6) 6 82 methyl-5-(4- 8.47 (s, 2H), 7.84 - 7.78 d (1-methyl-5- (m, 3H), 7.77 - 7.71 (m, oxo-1,5- 2H), 7.39 (s, 1H), 7.34 - dihydro-4H- 7.28 (m, 1H), 7.24 (br d, Y'

[2301] 1,2,4-triazol-4- 7=6.9 Hz, 1H), 7.16 (br s, yl)phenyl)-2H- 1H), 6.92 - 6.83 (m, 1H), indazol-2- 5.57 - 5.45 (m, 1H), 3.96 - yl)pyrrolidin- 3.89 (m, 1H), 3.85 - 3.77 o l-yl)benzoic (m, 2H), 3.69 - 3.63 (m, acid 3H), 2.70 - 2.60 (m, 3H), f >=O

[2302] 'N 2.56 (s, 3H) (one proton i obscured)

[2303] 5- 0 H (R)-N-ethyl-3- 522.2 E: 1.76 (500 MHz, DMSO-d6) 6 83 (3-(7-methyl- 8.47 (d, 7=4.7 Hz, 2H), A?

[2304] 5-(4-(l- 8.41 - 8.30 (m, 1H), 7.84 - MXN— A methyl-5-oxo- 7.77 (m, 3H), 7.76 - 7.70

[2305] 1,5-dihydro- (m, 2H), 7.39 (s, 1H), 7.29 V 4H- 1,2,4- - 7.22 (m, 1H), 7.11 (br d, triazol-4- 7=7.5 Hz, 1H), 7.05 (br s, yl)phenyl)-2H- 1H), 6.75 (br d, 7=8.2 Hz, JA indazol-2- 1H), 5.58 - 5.45 (m, 1H), yl)pyrrolidin- 3.94 - 3.88 (m, 1H), 3.80 1- (br dd, 7=10.1, 4.3 Hz, yl)benzamide 1H), 3.72 - 3.64 (m, 1H), > TN>O3.59 - 3.45 (m, 2H), 3.37 - 3.22 (m, 4H), 2.69 - 2.61 (m, 2H), 2.57 (s, 3H), 1.10

[2306]

[2307] (t, 7=7.2 Hz, 3H)Ex Structure Name LCMS HPLC1H NMR (δ ppm) # (M+H)+ Method,

[2308] RT (min.)

[2309] 5- O H (R)-N-methyl- 508.2 E: 1.67 (500 MHz, DMSO-d6) 6 84 r \ 3-(3-(7- 8.46 (s, 2H), 8.35 - 8.29 methyl-5-(4- (m, 1H), 7.85 - 7.77 (m, M (1-methyl-5- 3H), 7.73 (br d, J=8.6 Hz, oxo-1,5- 2H), 7.39 (s, 1H), 7.28 - 9 dihydro-4H- 7.20 (m, 1H), 7.10 (br d, 1,2,4-triazol-4- J=7.1 Hz, 1H), 7.04 (s, PL yl)phenyl)-2H- 1H), 6.75 (br d, J=8.1 Hz, indazol-2- 1H), 5.54 - 5.44 (m, 1H), yl)pyrrolidin- 3.94 - 3.87 (m, 1H), 3.83 - o 1- 3.76 (m, 1H), 3.69 - 3.62 yl)benzamide (m, 1H), 3.60 - 3.55 (m,

[2310] 1H), 3.40 (s, 3H), 2.76 (d, J=4.5 Hz, 3H), 2.68 - 2.62 (m, 2H), 2.57 - 2.55 (m, 3H)

[2311] 5- 0 H (R)-N- 536.2 E: 1.86 (500 MHz, DMSO-d6) 6 85 isopropyl-3-(3- 8.46 (s, 2H), 8.09 (br d, (7-methyl-5-.7=7,8 Hz, 1H), 7.84 - 7.77 (4-(l-methyl- (m, 3H), 7.73 (br d, J=7.9 5-oxo-l,5- Hz, 2H), 7.39 (s, 1H), 7.28 9 dihydro-4H- - 7.22 (m, 1H), 7.11 (br d, 1,2,4-triazol-4- J=7.1 Hz, 1H), 7.03 (br s, A yl)phenyl)-2H- 1H), 6.75 (br d, J=7.8 Hz, indazol-2- 1H), 5.56 - 5.43 (m, 1H), yl)pyrrolidin- 4.11 - 4.03 (m, 1H), 3.94 - p 1- 3.88 (m, 1H), 3.84 - 3.76 yl)benzamide (m, 1H), 3.72 - 3.61 (m,

[2312] 1H), 3.41 - 3.37 (m, 4H), C<Xo

[2313] 2.70 - 2.60 (m, 2H), 2.56 (s, 3H), 1.14 (br d, J=6.6 Hz, 6H)

[2314] 5- 0 H

[2315] 'pN (R)-N- 534.1 E: 1.78 (500 MHz, DMSO-d6) 6 86 cyclopropyl-3- 8.47 (d, J=5.0 Hz, 2H), (3-(7-methyl- 8.32 (br d, J=3.8 Hz, 1H), N—A5-(4-(l- 7.84 - 7.78 (m, 3H), 7.74 methyl-5-oxo- (br d,.7=8,7 Hz, 2H), 7.39 9 1,5-dihydro- (s, 1H), 7.29 - 7.20 (m,

[2316] 4H- 1,2,4- 1H), 7.09 (br d, J=7.2 Hz, triazol-4- 1H), 7.02 (br s, 1H), 6.75 yl)phenyl)-2H- (br...

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I) or salt thereof:wherein, independently for each occurrence:R1isRlais H, D, OH, halo, C1-3alkyl, or C1-3alkoxy substituted with 0-1 -OH, OCH3, or halo; or 2 R1aon the same or adjacent carbon atoms may join to form a 3-5 membered cycloalkyl substituted with 0-1 of -OH, halo, or -OCH3;one of R2and R5is phenyl or a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, the phenyl or the heterocycle being substituted with R7and are further substituted with 0-2 R11and 0-1 R10;the other of R2and R5is H, F, Cl, CH3, OCH3, CHF2or CF3;R3is -H, Cl, F, C1-3 alkyl, C1-3 alkoxy, -CN, -CF3, -CHF2, or cyclopropyl;R4is -H, -CH3, -OCH3, -F, -Cl, or -CHF2;R6is -H or -F;R7is -H, halo, -NH2, -CHF2, -C1-6 alkyl substituted with 0-3 R7d, cyclopropyl substituted with 0-2 R7d, -S(O)-Ci-6 alkyl, -S(O)2-C1-6alkyl, -NHC(O)C1-3alkyl, -NHS(O)2C 1-3 alkyl, -CON(R7b)(R7c), or -S(O)2-azetidinyl;or R7is a 4-6 membered heterocycle having 1-4 heteroatoms selected from N, O, and S, wherein the heterocycle is substituted with 0-3 R7a;R7ais H, halo, -OH, =0, C1-3 alkyl, C1-3 deuteroalkyl, C1-5 alkoxy C3-6 cycloalkyl, -CH2OH, -CH2OCH3, -CHF2, -CF3, -OCH3, -NHCH3, -N(CH3)2, -NH2, or -C(0)NH2 or a 3-6 membered heterocycle having 1-2 heteroatoms selected from N, O, or S;R7band R7care independently H, C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 alkoxyalkyl, or C1-5 deuteroalkyl;alternatively, R7band R7c, together with the N to which they are are attached, join to form a 3-6 membered ring substituted with 0-1 substituents selected from H, F, -OH, or -CH3;R7dis F, OH, or C1-3 alkoxy;R9is phenyl, or a 5 or 10 membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, any of which are substituted with 0-4 R9a;R9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)P-NR12R12, -(CH2)P-NR12R17, -COOH, C1-3 alkyl, C1-3 alkoxy, C1-3hydroxyalkyl, -(CH2)P-NR12COOR12, -(CH2)p-NR12CONR17R12,-(CH2)P-OCONR17R12, -(CH2)P-NR12(CO)-R12, -(CH2)P-SO2NH2,-(CH2)p-C(O)N(R12)(R17), -(CH2)P-C(O)R14, -(CH2)P-S(O2)N(R12)(R17), -(CH2)P-S(O)(NH)-R12, -(CH2)P-SO2C1-3 alkyl, or a 5-6 membered heterocycle or heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein alkyl, heterocycle or heteroaryl are substituted with 0-2R7a;R10is -H orR11is -H, -CH3, -F, -Cl, -CN, -OCH3, orR12is H, C1-3 alkyl, C1-3 dueteroalkyl, C1-3 haloalkyl or alkoxyalkyl;R14is H, -Ci-6 alkyl, C1-3 deuteroalkyl, -NRaRa, methyl-piperazinyl, morpholinyl, pyrrolidinyl, or piperidinyl;R17is -H, Ci-6 alkyl, -(CH2)-C(O)N(R12)(R12), -(CH2)P-C3-6 cycloalkyl, -(CH2)P-phenyl, or a -(CH2)P-4 to 10 membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, the alkyl, cycloalkyl, phenyl, or heterocycle are substituted with 0-3 R17a;or R12and R17, together with the N to which they are attached, join to form a 4-10 membered heterocycle or bicyclic heterocycle having an additional 0-2 heteroatoms selected from N, O, or S, substituted with 0-3 R17a;R17ais H, D, halo, -OH, Ci-4 alkyl substituted with 0-3 Re, Ci-6 hydroxyalkyl, Ci-6 alkoxy, =0, Ci-3 fluoroalkyl, or C3-6 cycloalkyl substituted with 0-3 Re, -(CH2)n-CO2-C1-3alkyl, -(CH2)n-N(R7b)(R7c), -(CH2)n-C(O)N(R7b)(R7c), -(CH2)n-N(R7b)C(O)-R7b, -(CH2)n-NR7bC(O)N(R7b)(R7c), -(CH2)n-OC(O)N(R7b)(R7c),(CH2)n-OC(O)N(R7b)(R7c), -(CH2)n-NR7bC(O)O(R7b), -(CH2)n-pyridyl, -(CH2)n-piperazinyl, or -(CH2)n-cyclopropyl;R19is -H, -NH2, or -OH;Rais H, or C1-6 alkyl;Reis H, F, Cl, -OH, -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamine, C1-6 dialkylamine, morpholino, pyrrolidino, S(O)2Ci-6 alkyl, or C3-6 cycloalkyl;n is 0, 1 or 2;m is 0, 1, 2, 3 or 4;p is 0 or 1; andq is 1, 2, or 3.

2. The compound according to Claim 1, or salt thereof, whereinR2is phenyl or a 5-6 membered heterocycle having 1-3 heteroatoms selected from N, O, and S, the phenyl or the heterocycle being substituted with R7and are further substituted with 0-2 R11and 0-1 R10; andR5is H, F, Cl, CH3, OCH3, CHF2or CF3.

3. The compound according to Claims 1 or 2, or salt thereof, wherein:R1is4. The compound according to Claims 1 - 3, or salt thereof, wherein: R2isv / X / X / X / Xz v / X / X / Xz ux / xrR75. The compound according to Claims 1-4, or salt thereof, wherein:R7is -H, halo, -NH2, -CHF2, -S(O)-Ci-6 alkyl, -CON(CH3)2, NHS(O)2CH3, -CON(R7b)(R7c), or -NHS(O)2CH3;or R7is H, cyclopropyl, oxazolyl, oxetanyl, oxadiazolyl, thiazolyl, imidazolyl, triazolyl, oxoimidazolidinyl, tetrazolyl, 2-oxo-2,3-dihydro-1H-imidazol-l-yl, piperidinyl, pyrrolidinyl, morpholinyl, oxomorpholinyl, dioxoimidazolidinyl, piperazinyl, oxopiperazinyl, pyrazolyl, or oxopyrrolidinyl, any of which are substituted with 0- 2 R7a;or R7isR7ais H, C1-3alkyl, =O, -NH2, or -OH;R7band R7care independently H, C1-5 alkyl, C1-5 alkoxy, C1-5 hydroxyalkyl, or C1-5 deuteroalkyl;R8is H, C1-3alkyl, or cyclopropyl;R8ais H, halo, C1-3alkyl, CH2OH, or CHF2; andR19is H, OH, NH2, OMe, NHCH3, N(CH3)2, CH2OH, CH2OCH3, or CH3.

6. The compound according to Claims 1-5, or salt thereof, wherein:R1isR9is phenyl, thiazolyl, pyrazinyl, pyridazinyl, dihydropyridinyl, pyrimidinyl, pyridinyl, dihydroisoquinolinyl, indolyl, pyrazolyl, or isoindolinyl, any of which are substituted with 0-3 R9a; andR9ais -H, -halo, =0, -OH, -(CH2)P-CN, -(CH2)p-NR12R12, -COOH, -(CH2)P-CONHCH3, -(CH2)p-C(O)NH2, C1-3alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, -(CH2)p-SO2NH2, -(CH2)p-C(O)NH-R17, or -(CH2)p-C(O)N(R12)(R17).

7. The compound according to claims 1-6, or salt thereof, wherein:R9is phenyl or pyridinyl substituted with 0-3 R9a.

8. The compound according to Claims 1-7, or salt thereof, wherein:R17is -H, methyl, ethyl, cyclopropylmethyl, oxanyl, pyrazolyl, l-methyl-2-oxo-l,2- dihy dropyri din-3 -yl,9. The compound according to Claims 1-8, or salt thereof, wherein:NHR9isr17; andR9bis H, orF.

10. The compound according to Claims 1-9, or salt thereof, wherein:R17is -H, methyl, ethyl, cyclopropylmethyl, oxanyl, pyrazolyl, l-methyl-2-oxo-l,2- dihy dropyri din-3 -yl, any of which are substituted with 0-1 R17a, or R17is R32R31R32is -H, Ci-3 alkyl substituted with 0-3 Re, C1-3 fluoroalkyl, C4-6 cycloalkyl substituted with 0-3 Re, -(CH2)q-C(O)N(R7b)(R7c), -(CH2)n-pyridyl, or -(CH2)n-cyclopropyl.

11. The compound according to Claims 1-8, or salt thereof, wherein: / "‘R12R9isr17; and R9bis H, orF.

12. The compound according to Claims 1-8, or salt thereof, wherein: R9ais -H, -NH2, -NR12R17, -NR12(CO)-R12, -(CH2)P-C(O)R14, -NR12CONR17R12, or -(CH2)P-S(O)(NH)-R12,alkyl, or C1-3 alkoxy, N(Ra)2, or -CH2-C(O)N(Ra)2.

13. The compound according to Claims 1-12, or salt thereof, wherein the compound of (I) is (la):

14. A compound of claim 1, wherein the compound is selected from the examples.

15. A pharmaceutical composition comprising one or more compounds of claims 1-14, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A method of inhibiting STAT6 activity in a patient, comprising administering to the patient in need thereof, a therapeutically effective amount of one or more compounds according to claims 1-14.

17. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one of claims 1-14, wherein the disease is selected from chronic obstructive pulmonary disease (COPD), asthma, idiopathic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, atopic dermatitis (AtD), prurigo nodularis (PN), bullous pemphigoid, eosinophilic esophagitis (EoE), allergic eosinophilic gastroenteritis, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), food allergy, hypereosinophilic syndrome, urticaria, systemic mastocytosis with eosinophilia, breast cancer, colorectal cancer, melanoma, hematological cancers such as B cell lymphomas.

18. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of claim 14, wherein the disease is selected from chronic obstructive pulmonary disease (COPD), asthma, atopic dermatitis (AtD), prurigo nodularis (PN), eosinophilic esophagitis (EoE), urticaria, and cancer.

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