TW201607930A - 5-amino-4-carbamoyl-pyrazole compounds as selective and irreversible T790M over WT EGFR kinase inhibitors and the use thereof - Google Patents

Abstract

The present application provides at least one compound selected from compounds of Formula (I) stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein the variables R1, R2, R3, R4, L, W, R7, Y, Z, R', R'' and * are as defined herein. These compounds have good selectivity of T790M vs WT EGFR inhibition and are useful for treating disorders mediated thereby. The present application also provides pharmaceutical compositions comprising the same, processes for the preparation thereof, and the use thereof in therapy.

Description

5-amino-4-carbamyl-pyrazole compound as a selective and irreversible kinase inhibitor of T790M/WT-EGFR and use thereof

The present invention discloses 5-amino-4-carbamimido-pyrazole compounds, pharmaceutical compositions containing the same, processes for their preparation and their use in therapy. The present invention discloses certain 5-amino-4-carbamyl-pyrazole compounds that have good selectivity for T790M relative to WT EGFR and are useful in the treatment of conditions mediated thereby.

Lung cancer continues to be the leading cause of cancer-related mortality, suggesting that traditional cytotoxic therapies have limited efficacy in patients with this disease (Bedano PM, Hanna NH. J Thorac Oncol. 2006; 1:582-587. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. CA Cancer J Clin. 2006; 56:106-130.). The development of novel and effective therapies for patients with advanced lung cancer still has extremely urgent health needs, and targeted therapies can provide well-tolerated disease-modulating treatment options in a population of patients defined by the relevant oncogene mutational state. Based on observed patterns of EGFR and HER2 oncogene mutations, members of the ERBB receptor tyrosine family (including epidermal growth factor receptor (EGFR), HER2, HER3, and HER4) target therapy for patients with NSCLC Presented as an attractive option (Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. N Engl J Med. 2004; 350:2129-2139.; Paez JG, Janne PA , Lee JC, Tracy S, Greulich H, Gabriel S, et al. Science. 2004;304:1497-1500.; Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. Proc Natl Acad Sci USA. 2004;101:13306-13311.; Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Nature. 2004;431:525-526.; Shigematsu H, Takahashi T , Nomura M, Majmudar K, Suzuki M, Lee H, et al. Cancer Res. 2005;65:1642-1646.; Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, et al. Cancer Res. 2006;66:6487-6491.; Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S, et al. Cancer Cell. 2006; 10:25-38.).

The first generation of small molecule EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, are shown to be effective against lung tumor cells that have mutations in the EGFR kinase domain, most Common is the small in-frame deletion in exon 19 or the L858R missense mutation in exon 21 (Janne PA, Engelman JA, Johnson BE. J Clin Oncol. 2005; 23:3227-3234. ). However, despite initial response, patients almost inevitably become resistant to these inhibitors and relapse after a few months (Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES, et al. Clin Cancer Res. 2006;12:839-844.).

Patients with non-small cell lung cancer (NSCLC) with activated EGFR mutations initially responded well to EGFR tyrosine kinase inhibitor (TKI) erlotinib and gefitinib. However, clinical efficacy is limited by resistance. The most common resistance mechanism is the second point mutation (T790M) in EGFR exon 20 observed in about 50% of cases (Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG) , et al. Cancer Res. 2005b; 65:7096-7101.; Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. PLoS Med. 2005a; 2:e73.). In combination with the major changes in exon 19 or 21 alone, T790M EGFR exhibits elevated enzymatic activity and transforming activity (Mulloy R, Ferrand A, Kim Y, Sordella R, Bell DW, Haber DA, et al. Cancer Res. 2007;67:2325-2330.; Schiffer HH, Reding EC, Fuhs SR, Lu Q, Piu F, Wong S, et al. Mol Pharmacol. 2007;71:508-518.; Vikis H, Sato M, James M, Wang D, Wang Y, Wang M, et al. Cancer Res. 2007;67:4665-4670; Yuza Y, Glatt KA, Jiang J, Greulich H, Minami Y, Woo MS, et al. Cancer Biol Ther 2007; 6: 661-667.), indicating the need to improve the therapeutic efficacy of the next generation of EGFR inhibitors.

In cell-based assays, irreversible inhibitors of covalently modified EGFR exhibit enhanced potency against resistant mutants of gefitinib and erlotinib (Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV) , Zappaterra M, et al. PLoS Med. 2005; 2:e313.; Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, et al. Proc Natl Acad Sci USA. 2005;102: 7665-7670.; Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. N Engl J Med. 2005a;352:786-792.; Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, et al. Cancer Res. 2005b; 65:7096-7101; Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, et al. Cancer Res. 2006;66: 6487-6491.; Yuza Y, Glatt KA, Jiang J, Greulich H, Minami Y, Woo MS, et al. Cancer Biol Ther. 2007; 6: 661-667.). Preclinical and early clinical trials have also shown that new types of panHER inhibitors have potential efficacy in overcoming acquired resistance relative to T790M. One such inhibitor, BIBW2992 or afatinib, is a novel irreversible dual-specific EGFR/HER2 inhibitor derived from the anilino-quinazoline chemical series, designed to be Cys 773 with EGFR and Cys 805 with HER2 Covalent combination. Although showing clinical benefits, afatinib has only recently been approved for the treatment of non-small cell lung cancer (NSCLC). However, an indirect comparison of phase III trials with erlotinib or gefitinib showed a higher incidence of diarrhea, rash and stomatitis with afatinib (Mok TS, Wu YL, Thongprasert S, et al. N Engl J Med 2009; 361: 947-57; Rosell R, Carcereny E, Gervais R, et al. Lancet Oncol 2012; 13: 239-46; Han JY, Park K, Kim SW, et al. J Clin Oncol 2012; 1122-8.). It should be considered that all of these data indicate that the toxicity of the second generation covalent inhibitor may be higher than that observed with the first generation of compounds. For the first and second generation therapies in the clinic, wild-type EGFR inhibition is thought to drive the observed dose-limiting toxicity (such as rash and diarrhea).

To further improve the efficacy of second-generation EGFR inhibitors such as afatinib, dacomitinib and neratinib and overcome their side effects, third-generation irreversible EGFR inhibitors have been reported and Enter the clinical trial. These novel EGFR inhibitors have good selectivity for T790M relative to WT EGFR inhibitors. For example, CO-1686 and AZD9291 are mutant forms of irreversible kinase inhibitors that target EGFR by inhibiting common activating mutations (L858R, delE746-A750) and gated mutations (T790M) rather than wild-type receptors. Thus, CO-1686 and AZD9291 have the potential to effectively treat first- and second-line NSCLC patients with EGFR mutations without causing dose-limiting toxicity associated with approved EGFR kinase inhibitors.

Certain other T790M EGFR kinase inhibitors have also been identified. International Patent Application Publication No. WO 2011/162515, International Patent Application Publication No. WO 2013/184757, International Patent Application Publication No. WO 2013/184766, International Patent Application Publication No. WO 2013/014448, International Patent Application Publication No. WO 2013/042006, International Patent Application Publication No. WO 2013/118817, International Patent Application Publication No. WO 2013/125709, and International Patent Application Publication No. WO 2014/025486.

The object of the present invention is to provide a novel 5-amino-4-carbamyl-pyrazole compound which inhibits mutant EGFR kinase.

The present invention discloses 5-amino-4-carbamimido-pyrazole compounds that selectively inhibit T790M EGFR kinase relative to WT-EGFR kinase.

The present invention provides at least one 5-amino-4-carbamimidyl-pyrazole compound selected from the group consisting of a compound of formula (I), a stereoisomer of a compound of formula (I), and a pharmaceutically acceptable salt of a compound of formula (I) , ( I ) wherein: R ₁ , R ₂ and R _{3 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _{1 -6} haloalkyl; L is a linking group, which is selected from a _{bond, - (CR 5 R 6)} n-, S, -O- , and -NR ₈ -, wherein n is an integer of 1, 2 or 3; W is selected from An aryl or heteroaryl group optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R'',NR'COR'',NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl; or W and R ₄ together with the nitrogen to which they are attached form optionally another hetero atom selected from NR ₈ , O and S a 4- or 5- or 6-membered heterocyclic ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R '', NR'COR'', NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne group, C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl; R _7, at each occurrence, is independently selected from hydrogen, halo , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy; and wherein p is an integer 2, 3 or 4; Y is selected from - CR ₅ R ₆ - and -O-; Z is selected from -(CR ₅ R ₆ ) _m -, -CR ₅ R ₆ -O-, -O- and -NR'-, wherein m is an integer of 1 or 2; R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; R' and R '', at each occurrence, is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; and * is a chiral center pair.

In some embodiments, R ₁ , R ₂ and R ₃ are hydrogen.

In some embodiments, R ₄ is hydrogen.

In some embodiments, L is a bond and W is an aryl or heteroaryl group.

In other embodiments, L is a bond and W is phenyl or pyridyl.

In some embodiments, L is -(CR ₅ R ₆ ) _n -, and W is aryl or heteroaryl, wherein n is an integer 1, 2 or 3, and R ₅ and R _{6 are} independently selected from hydrogen, Halogen, C _1-6 alkyl and C _1-6 haloalkyl. In other embodiments, L is -(CR ₅ R ₆ ) _n -, and W is phenyl or pyridyl, wherein n is an integer 1, 2 or 3, and R ₅ and R _{6 are} independently selected from hydrogen, Halogen, C _1-6 alkyl and C _1-6 haloalkyl. In other embodiments, L is -CH ₂ -, and W is phenyl or pyridyl.

In some embodiments, L is a bond or -(CR ₅ R ₆ ) _n -, and W and R ₄ together with the nitrogen to which they are attached form a 4 member containing another heteroatom selected from NR ₈ , O, and S Or a 5- or 6-membered heterocyclic ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R'', NR'COR'', NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, heterocyclic, aryl and heteroaryl, wherein R ₅ , R ₆ , R ₈ , R′, R′′ and n are as defined above. In other embodiments, L is a bond or -(CR ₅ R ₆ ) _n -, and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of nitrogen: Heterocyclic butyl (such as azetidin-2-yl (ie And azetidin-3-yl (ie )), pyrrolidinyl (such as pyrrolidin-2-yl (ie And pyrrolidin-3-yl (ie )), acridinyl (such as acridin-2-yl (ie ), acridine-3-yl ( And acridin-4-yl (ie )) and morpholinyl (such as morpholin-2-yl (ie And morpholin-3-yl (ie And wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; and n is an integer 1, 2 or 3, and wherein the wavy line indicates a linker The point of attachment of group L, and the acryl group on the nitrogen atom has been omitted. In other embodiments, L is a bond, and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of azacyclobutyl (such as azetidine) -2- base (ie And azetidin-3-yl (ie )), pyrrolidinyl (such as pyrrolidin-2-yl (ie And pyrrolidin-3-yl (ie )), acridinyl (such as acridin-2-yl (ie ), acridine-3-yl ( And acridin-4-yl (ie )) and morpholinyl (such as morpholin-2-yl (ie And morpholin-3-yl (ie )), and wherein the wavy line indicates the point of attachment to the linking group L, and the acryl group on the nitrogen atom has been omitted. In other embodiments, L is -CH ₂ -, and W is selected from and R ₄ form a 4-membered or 5-membered or 6-membered heterocyclic ring together with the nitrogen to which they are attached: azetidinyl (such as nitrogen Heterocyclic but-2-yl (ie And azetidin-3-yl (ie )), pyrrolidinyl (such as pyrrolidin-2-yl (ie And pyrrolidin-3-yl (ie )), acridinyl (such as acridin-2-yl (ie ), acridine-3-yl ( And acridin-4-yl (ie )) and morpholinyl (such as morpholin-2-yl (ie And morpholin-3-yl (ie )), and wherein the wavy line indicates the point of attachment to the linking group L, and the acryl group on the nitrogen atom has been omitted.

In some embodiments, Y is -O- and Z is -O-. In some embodiments, Y is -O- and Z is -NR'-, wherein R' is independently selected from the group consisting of hydrogen, _C1-6 alkyl, and _C1-6 haloalkyl. In some embodiments, Y is -CR ₅ R ₆ -, and Z is -NR'-, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _1-6 haloalkyl And R' is independently selected from the group consisting of hydrogen, _C1-6 alkyl and _C1-6 haloalkyl. In some embodiments, Y is -CR ₅ R ₆ -, and Z is -CR ₅ R ₆ -, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _1-6 Haloalkyl. In some embodiments, Y is -CR ₅ R ₆ -, and Z is -O-, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _1-6 haloalkyl. In some embodiments, Y is -CR ₅ R ₆ -, and Z is -(CR ₅ R ₆ ) ₂ -, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _{1 -6} haloalkyl. In some embodiments, Y is -CR ₅ R ₆ -, and Z is -CR ₅ R ₆ O-, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _{1- 6} haloalkyl.

The present invention provides at least one 5-amino-4-carbamimidyl-pyrazole compound of the formula (I), wherein the formula (I) is a stereoisomer of the formula ( I-1 ), the formula ( I-1 ) and Medicinal salt of formula ( I-1 ): ( I-1 ) wherein: R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; L is a linking group selected from a bond or -CH ₂ -; W is selected from phenyl or pyridine Or R ₇ , at each occurrence, independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; And wherein p is an integer of 0, 1, 2, 3 or 4; Y is selected from -CH ₂ - and -O-; Z is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -O -and-NMe-; and * is the center of the palm.

The present invention provides at least one 5-amino-4-carbamimidyl-pyrazole compound of the formula (I), wherein the formula (I) is a stereoisomer of the formula ( I-2 ), the formula ( I-2 ) and Medicinal salt of formula ( I-2 ): ( I-2 ) wherein: L is a bond or -CH ₂ -; W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of azacyclobutyl and pyrrole An alkyl group, an acridinyl group, and a morpholinyl group, which are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R'',NR'COR'',NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl; R ₇ , at each occurrence, independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy and C _1-6 haloalkoxy; and wherein p is an integer of 0, 1, 2, 3 or 4; R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkane R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; R' and R'', at each occurrence, are independently selected from hydrogen, C _1-6 alkyl and C _{1 -6} haloalkyl; Y is selected from -CH ₂ - and -O-; Z is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -O- and -NMe-; and * is a pair Palm center.

In some embodiments, at least one 5-amino-4-carbamimidyl-pyrazole compound of Formula 1-2, wherein: L is a bond or -CH ₂ -, and W and R ₄ are taken together with the nitrogen to which they are attached Forming a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of: with Azacyclobutyl; selected from with Pyrrolidinyl group; , with Acridine group, and selected from with Morpholinyl, and wherein the wavy line indicates the point of attachment to the linking group L, and the acryloyl group on the nitrogen atom has been omitted; R ₇ , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, C _{1 a -6} alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, and a C _1-6 haloalkoxy group; and wherein p is an integer of 0, 1, 2, 3 or 4; Y is selected from -CH ₂ - And -O-; Z are selected from the group consisting of -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -O-, and -NMe-; and * is the palm center.

In some embodiments, at least one 5-amino-4-carbamimidyl-pyrazole compound of Formula 1-2, via which the linking group L is attached to a 4 member formed by W and R ₄ together with a nitrogen atom or The carbon atom of the 5- or 6-membered heterocyclic ring is in the (R) or (S) configuration.

The present invention provides at least one 5-amino-4-carbamimidyl-pyrazole compound of the formula (I), wherein the formula (I) is a stereoisomer of the formula (I-3), the formula (I-3) and Medicinal salt of formula (I-3): ( I-3 ) wherein: R ₇ , independently at each occurrence, is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 Haloalkoxy; and wherein p is an integer of 0, 1, 2, 3 or 4; Y is selected from -CH ₂ - and -O-; Z is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O -, -O- and -NMe-; and * is the center of the palm. R _{9 is} selected from the group consisting of F, Cl, Br, OR ₈ , NR'R'', O-(CH ₂ )n-NR'R''; n = 1, 2, 3; R _{8 is} selected from hydrogen, C _{1- 6} alkyl and C _1-6 haloalkyl; R' and R'', each occurrence, are independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl;

The present invention also provides the following compounds, stereoisomers thereof and pharmaceutically acceptable salts thereof:

The invention also provides at least one compound selected from the group consisting of the following stereochemistry:

The present invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of compounds of formula (I), formula (I-1) or formula (I-2).

The present invention also provides at least one compound selected from the group consisting of a compound of the formula (I), the formula (I-1) or the formula (I-2), a stereoisomer thereof and a pharmaceutically acceptable salt thereof for preparation for inhibiting EGFR-T790M kinase Use of the drug.

The invention also provides the use of at least one compound selected from the group consisting of a compound of formula (I), a stereoisomer thereof and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, including but not limited to ovarian cancer, Cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer (including non-small cell lung cancer) ), hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma , melanoma and mesothelioma.

The following words, phrases and symbols used in the present invention are generally intended to have the following meaning unless the context in which they are used is the contrary. The following abbreviations and terms have the specified meanings throughout the text:

The term "C _1-6 alkyl" in the present invention means a hydrocarbon group selected from linear and branched saturated hydrocarbon groups having 1 to 6 carbon atoms. Examples of the alkyl group may be selected from methyl, ethyl, 1-propyl or n-propyl (n-Pr), 2-propyl or isopropyl (i-Pr), 1-butyl or n-butyl ( n-Bu), 2-methyl-1-propyl or isobutyl (i-Bu), 1-methylpropyl or sec-butyl (s-Bu) and 1,1-dimethylethyl or Tert-butyl (t-Bu).

The term "C _2-6 alkenyl" in the present invention means a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 6 carbon atoms. Examples of alkenyl groups may be selected from ethenyl or vinyl (--CH=CH ₂ ), prop-1-enyl (--CH=CHCH ₃ ), prop-2-enyl (- -CH ₂ CH=CH ₂ ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, butan-1,3-dienyl , 2-methylbuty-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexadiene base.

The term "C _2-6 alkynyl" in the present invention means a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl (--C≡CH), 1-propynyl (-C≡CCH ₃ ), 2-propynyl (propargyl, -CH ₂ C≡CH), 1-butyne Base, 2-butynyl and 3-butynyl.

The term "C _3-8 cycloalkyl" as used in the present invention means a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. The group also contains 3-8 carbon atoms, such as 3-6, 3-5 or 3-4 carbon atoms. By way of further example, the C _3-8 cycloalkyl group can be selected from the group consisting of 3-8 (such as 3-6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, Cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl and cyclooctyl.

The term "aryl" as used in the present invention means a group selected from a 5- or 6-membered carbocyclic aromatic ring, for example, a phenyl group; a bicyclic ring system such as a 7-12 membered bicyclic ring system, wherein at least One ring is a carbocyclic ring and an aromatic ring, for example selected from the group consisting of naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring system, such as a 10-15 membered three-ring ring system, at least one of which The ring is a carbocyclic ring and an aromatic ring, such as hydrazine.

The term "halogen" or "halo" in the present invention means F, Cl, Br or I.

The term "heteroaryl" in the present invention means a group selected from the group consisting of a 5-7 membered aromatic monocyclic ring containing at least one hetero atom selected from N, O and S, for example, 1 to 4, or In some embodiments, there are 1-3, the remaining ring atoms are carbon; 8-12 membered bicyclic rings comprising at least one heteroatom selected from N, O and S, for example 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2, the remaining ring atoms are carbon, and at least one of the rings is aromatic and at least one heteroatom is present in the aromatic ring; and 11-14 yuan a tricyclic ring comprising at least one heteroatom selected from N, O and S, for example from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2, remaining The ring atoms are carbon, and at least one of the rings is aromatic and at least one hetero atom is present in the aromatic ring.

For example, the heteroaryl group includes a 5-7 membered heterocyclic aromatic ring fused to a 5-7 membered cycloalkyl ring. For the above fused bicyclic heteroaryl ring system in which only one ring contains at least one hetero atom, the linked bit points may be in the heteroaryl ring or in the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, the hetero atoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is at most 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is at most one.

Examples of heteroaryl groups include, but are not limited to, (numbered starting from the position of the linkage designated as priority 1), pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), porphyrinyl, pyridyl Azinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, Tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isodecyl, indanyl, pyridazinyl, pyrazine , pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolidinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), Pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazole-6-yl), pteridinyl, Sulfhydryl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazole, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4 -diazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazole, 1-thia-2,5-diazolyl, 1-thia-3 , 4-oxazolyl, furazinyl, benzofurazyl, benzothiophene , benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, diaza naphthyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazole-6-yl) , carbazolyl (such as 1H-carbazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

The term "heterocyclic" or "heterocyclic" or "heterocyclyl" as used in the present invention means selected from 4-12 members (such as 4, 5 or 6) monocyclic, bicyclic and tricyclic saturated and partially a ring of an unsaturated ring, the ring comprising at least one other than at least one (such as 1-4, again such as 1-3 or further such as 1 or 2) heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen carbon atom.

Examples of heterocycles include, but are not limited to, (numbered starting from the position specified as priority 1), 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 1- Pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1-acridinyl, 2-acridinyl, 3-acridinyl , 4-acridinyl, 2,5-pyridazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxacyclopropyl, azacyclopropyl, thiopropyl, nitrogen Heterocyclic butyl, oxetanyl, thioheterobutyl, 1,2-dithiot-butyl, 1,3-dithiot-butyl, dihydropyridyl, tetrahydropyridyl, sulfur Morpholinyl, oxathiolanyl, pyridazinyl, oxazinyl, homoacridinyl, azepanyl, oxetanyl, thiaheptyl, 1,4-oxothio Hexyl, 1,4-dioxanyl, 1,4-oxathiaheptyl, 1,4-oxazacycloheptyl, 1,4-dithiaheptyl, 1,4- Thiazepane and 1,4-diazepanyl, 1,4-dithiaalkyl, 1,4-azetidinyl, oxazepine, diazepine, sulphur Azaindole, dihydrothienyl, dihydropyranyl, dihydrogen Cyclol, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrroline, 2-pyrroline, 3-pyrrolyl, indanyl, 2H-pyridyl Cyclol, 4H-pyranyl, 1,4-dioxyl, 1,3-dioxolyl, pyrazolinyl, pyrazolidinyl, dithiaalkyl, dithiacyclopentyl , pyrazolidinyl, imidazolinyl, pyrimidinone, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0 Cycloheptyl and azabicyclo[2.2.2]cyclohexyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties such as acridinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1 , 1-dioxo-1-thiomorpholinyl.

Used in the present invention, "C _1-6 haloalkyl" means wherein one or more hydrogen atoms are replaced by halogen, C _1-6 alkyl (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. The C _1-6 haloalkyl group may be substituted or unsubstituted.

The "C _1-6 alkoxy group" used in the present invention means a formula -OR wherein R is a C _1-6 alkyl group. A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy And tert-butoxy. The C _1-6 alkoxy group may be substituted or unsubstituted.

Used in the present invention, "C _1-6 haloalkoxy" means a group wherein one or more hydrogen atoms are replaced by halogen C _1-6 alkoxy group (e.g., mono-haloalkoxy, di- haloalkoxy and tri-haloalkoxy base). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. The C _1-6 haloalkoxy group may be substituted or unsubstituted.

The compounds of the invention may contain asymmetric centers and may thus exist as enantiomers. When the compounds of the invention have two or more asymmetric centers, they may also exist as diastereomers. Both enantiomers and diastereomers fall into a wider variety of stereoisomers. The invention is intended to include all possible stereoisomers, such as substantially pure analytical enantiomers, their racemic mixtures, and mixtures of diastereomers. The invention is intended to include all stereoisomers of the compounds of the invention and/or pharmaceutically acceptable salts thereof. Unless otherwise specified, reference to one isomer applies to any possible isomer. Wherever the composition of the isomer is not specified, all possible isomers are included.

The term "substantially pure" as used herein means that the target stereoisomer contains up to 35% by weight, such as up to 30% by weight, such as up to 25% by weight, and further such as up to 20% by weight of any one or more other solid forms. isomer. In some embodiments, the term "substantially pure" means that the target stereoisomer contains up to 10% by weight, such as up to 5% by weight, such as up to 1% by weight, of any one or more other stereoisomers.

The reaction products can advantageously be separated from each other and/or from the starting materials. The desired product of each step or series of steps is separated and/or purified (hereinafter referred to as separation) to the desired degree of homogenization by the general techniques in the art. Typically the above separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography can involve a number of methods including, for example, reversed phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium and low pressure liquid chromatography methods and apparatus; small analytical chromatography; simulated moving bed (SMB) chromatography and Preparation of thin-layer or thick-layer chromatography and techniques for small-volume thin layers and flash chromatography. Those of ordinary skill in the art should use techniques that are most likely to achieve the desired separation.

The diastereomeric mixtures can be separated into their individual non-pairs by methods well known to those of ordinary skill in the art, such as chromatography and/or fractional crystallization, based on physicochemical differences in diastereomers. Isomer. Enantiomers can be separated by converting the enantiomeric mixture to a non-pair by reacting with a suitably optically active compound (for example, a palmitic adjuvant such as palmitic alcohol or Mosher's ruthenium chloride). The mixture is imaged, the diastereomers are separated, and the individual diastereomers are then converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Separation of the enantiomers can also be carried out using a palmar HPLC column.

A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by resolution of the racemic with an optically active resolving agent using methods such as the formation of diastereomers. Mixture (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr. , 113(3) (1975): pp. 283-302). The racemic mixture of the palmitic compound of the present invention can be separated and isolated by any suitable method, which comprises: (1) forming an ionic diastereomeric salt with a palmitic compound, followed by fractional crystallization Or by other methods, (2) forming a diastereomeric compound with a palmitic derivatizing reagent, isolating the diastereomer, and then converting into a pure stereoisomer, (3) in the palm The substantially pure or enriched stereoisomers are directly isolated under the conditions of the species. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

"Pharmaceutically acceptable salt" includes, but is not limited to, salts formed with inorganic acids, for example, salts selected from the group consisting of hydrochlorides, phosphates, dihydrogen phosphates, hydrobromides, sulfates, sulfites, and nitrates; a salt formed with an organic acid, for example, selected from the group consisting of malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, a 2-hydroxyethanesulfonate, a benzoate, a salicylate, a stearate, an alkanoate such as an acetate and a salt formed with HOOC-(CH ₂ ) _n -COOH, wherein n is selected from 0-4) salt. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Further, if the compound of the present invention is obtained in the form of an acid addition salt, the free base can be obtained by a solution of an alkalized acid salt. Conversely, if the product is the free base, an addition salt (such as a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and then following the preparation of the acid addition salt from the base compound. The solution is generally treated with an acid. Those of ordinary skill in the art will be aware of a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

As used herein, "pharmaceutically acceptable salts thereof" includes at least one salt of a compound of formula I, and at least one salt of a stereoisomer of a compound of formula I and II, such as a salt of an enantiomer and/or a diastereomer. The salt of the body.

"Treatment," "treating," or "disposing" or "alleviating" is the administration of at least one compound of the present invention and/or at least one of its stereoisomers to a subject considered to have such a need (with, for example, cancer). A construct and/or at least one pharmaceutically acceptable salt thereof.

The term "effective amount" refers to at least one compound of the invention and/or at least one stereoisomer thereof and/or at least one thereof, which is effective to "treat" (as defined above) a disease or condition in a subject. The amount of medicinal salt.

The compounds of the present invention and/or their pharmaceutically acceptable salts can be synthesized from commercially available starting materials using the teachings of the present invention. The following schemes detail the preparation of some of the compounds of the invention. Option I R = different warheads Pg = protecting groups such as t-Bocyl groups (t-Boc) R ₇ , p, Y are as defined above.

In this scheme, a commercially available starting material (3,4-dihydro-1(2H)-naphthalenone or 6,7,8,9-tetrahydro-5H-benzo[7]cyclopentene-5- The ketone is reacted with dimethyl carbonate under basic conditions to form the formula 2, and the formula 2 is reduced to give the ester 3 in the presence of acidic conditions. The ester 3 is then hydrolyzed to give the acid 4, which is coupled to malononitrile and then reacted with trimethoxymethane to give the formula 6. The hydrazine ring is then used to obtain the key pyrazole 7. The compound of formula 7 is alkylated using a protected palmitic prolinol and then the cyano group is hydrolyzed under acidic conditions to form the guanamine 9. The compound of formula 9 is deprotected (for example, by treatment with trifluoroacetic acid, the BOC protecting group can be removed). The amine 10 is reacted with different warheads to provide a compound of formula I.

The invention also provides a method of treating a cancer responsive to inhibition of EGFR kinase comprising administering to a subject in need of treatment, such as a mammal or a human, an effective amount of a compound of the invention selected from formula (I) At least one compound, a stereoisomer thereof, and a pharmaceutically acceptable salt of the compound.

The at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, may be used alone or in combination with at least one other therapeutic agent for treatment. In some embodiments, the at least one compound selected from the compounds of formula (I), stereoisomers thereof, and pharmaceutically acceptable salts thereof, can be used in combination with at least one other therapeutic agent. The at least one other therapeutic agent may, for example, be selected from the group consisting of anti-hyperproliferative drugs, anticancer drugs, and chemotherapeutic drugs. The at least one compound and/or at least one pharmaceutically acceptable salt of the invention may be administered in a single dose or in separate dosage forms with at least one other therapeutic agent. When administered in a separate dosage form, the at least one additional therapeutic agent can be administered prior to, concurrently with, or subsequent to administration of at least one compound and/or at least one pharmaceutically acceptable salt of the invention. A "chemotherapeutic drug" is a chemical compound used to treat cancer, regardless of the mechanism of action. Chemotherapeutic drugs include "targeted therapies" and compounds used in general chemotherapy. Suitable chemotherapeutic agents may, for example, be selected from the group consisting of: drugs that induce apoptosis; polynucleotides (eg, ribozymes); polypeptides (eg, enzymes); drugs; biological analogs; alkaloids; alkylating agents; Antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated to anticancer drugs, toxins and/or radionuclides; biological response modifiers (eg, interferons, such as IFN-[alpha], and interleukins, such as IL-2); adoptive immunotherapy; hematopoietic growth factor; drugs that induce tumor cell differentiation (eg, all-trans retinoic acid); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; Inhibitor.

Examples of chemotherapeutic drugs include erlotinib (TARCEVA®, Genentech/OSI Pharm.); Bortezomib (VELCADE®, Millennium Pharm.); fulvestrant (FASLODEX®, AstraZeneca); Sunitinib (SUTENT®, Pfizer); Letrozole (FEMARA®, Novartis); Imatinib mesylate (GLEEVEC®, Novartis); PTK787/ZK 222584 (Novartis); Oxaliplatin ( Eloxatin®, Sanofi); 5-FU (5-fluorouracil); formazan tetrahydrofolate (Leucovorin); rapamycin (Sirolimus, RAPAMUNE®, Wyeth); Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline); Lonafarnib (SCH 66336); Sorafenib (NEXAVAR, Bayer); Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (IRESSA®, AstraZeneca); AG1478, AG1571 ( SU 5271, Sugen); alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and guanidine Piposulfan; aziridine such as benzodopa, carboquone, meturedopa and uredopa; ethylenimine Mine) and methylamelamine, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; Acetogenin (such as bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin (bryostatin); callystatin; CC-1065 and its adozelesin, carzelesin and bizelesin synthetic analogues; cryptophycins (such as cryptophycin 1 and cryptophycin 8); Dolastatin; duocarmycin and synthetic analogues such as KW-2189 and CB1-TM1; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard such as chlorambucil, naphthalene Chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, hydrochloric acid Mechlorethamine oxide hydrochloride, melphalan, novembibin, phenesterine, prednimustine, trofosfamide, uracil nitrogen Mustard mustard; nitrourea such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and Ranimustine; antibiotics such as enediyne antibiotics (eg, calicheamicin, such as calicheamicin γ1I and calicheamicin ωI1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); an antibiotic (dynemicin) such as dynemicin A; a bisphosphonate such as clodronate; esperamicin; Neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophore, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin (bleomycin), actinomycetes C (cactinomycin), carabincin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, tow ratio Detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-multi Roubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxonol), epirubicin, esorubicin , idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olive mold Olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptomycin (streptonigrin), streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate呤(met Hotrexate) and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-nitrogen 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluoride Fluoxuridine; and rhon such as calutosterone, dromostanolone propionate, epitiostolol, mepitiostane, testosterone (testolactone) ; anti-adrenal such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; Acetaldehyde lactone (aceglatone); aldophosphamide glycosides (aldophosphami De glycoside); aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine ;; demecolcine; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea (hydroxyurea); lentinan; lonidainine; maytansinoid such as maytansine and ansamitocin; mitoguazone; mitoxantrone Mit (mitoxantrone); mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic Acid); 2-ethyl hydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran ); spirogermanium; fine oxysporum (tenuazonic acid); triaziquone; 2,2',2"-trichlorotriethylamine; trichothecene (such as T-2 toxin, verracurin A, bacillus A ( Roridine A) and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitophorol ); pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoid, for example TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor-free), paclitaxel-assisted nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; Mercaptopurine); methotrexate; platinum analogues Cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine ; NAVELBINE® (vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; Capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoid Retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

The "chemotherapeutic agent" may also, for example, be selected from the group consisting of: (i) an anti-hormone drug for regulating or inhibiting the action of a hormone on a tumor, such as an anti-estrogen and a selective estrogen receptor modulator (selective Estrogen receptor modulator (SERM), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen , trioxifene, keoxifene, LY117018, onapristone and FARESTON® (toremifine citrate); (ii) inhibition of aromatase Aromatase inhibitors of estrogen production in the adrenal gland, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane) Exemestane); Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis) and ARIMIDEX® (anastrozole; AstraZeneca); Iii) anti-androgen drugs, such as flutamide, nilutamide (nilutamide), bicalutamide, leuprolide and goserelin; and troxacitabine (1,3-dioxolan nucleoside cytosine) (iv) a protein kinase inhibitor; (v) a lipid kinase inhibitor; (vi) an antisense oligonucleotide, such as a gene that inhibits gene expression in a signal transduction pathway involved in abnormal cell proliferation Oligonucleotides, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (eg, ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, such as ALLOVECTIN ®, LEUVECTIN® and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic drugs such as bevacizumab (AVASTIN®, Genentech) And (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.

"Chemotherapeutic agents" may also, for example, be selected from therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (cetuximab) (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®) , 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia) and antibody drug conjugate olikittuzumab (gemtuzumab ozogamicin ) (MYLOTARG®, Wyeth).

A humanized monoclonal antibody having at least one compound selected from the group consisting of a compound of formula (I) (such as formula (II)), a stereoisomer thereof and a pharmaceutically acceptable salt thereof, for example, optionally having therapeutic potential as a chemotherapeutic drug From: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, mobivuzumab (bivatuzumab) Mertansine), cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab (eculizumab), efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, omeji Gemuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepo Meclizumab, movizumab, mo Tovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, paclizumab (pascolizumab ), pefdusutuzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, roslizumab (reslizumab) ), resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sotuzumab, taciluzumab Tetraxetan), tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, west Mucotin ( tucotuzumab celmoleukin), tucusituzumab, umavizumab, urtoxazumab, visilizumab, Nivolumab and Lambrolizumab.

The invention also provides compositions comprising at least one compound selected from the group consisting of compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

Although the most appropriate route in any given case will depend on the nature and severity of the disease to which the particular subject, the active ingredient is to be administered, comprises at least one compound selected from the compounds of formula (I), its stereoisomers and Compositions of pharmaceutically acceptable salts can be administered in a variety of known manners, such as oral, topical, rectal, parenteral, by inhalation spray or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions of the present invention are conveniently presented in unit dosage form and may be prepared by any methods known in the art.

The at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof can be administered in the form of solid dosage forms such as capsules, tablets, troches, dragées. , granules and powders; or liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. The at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, may also be administered parenterally in the form of sterile liquid dosage forms such as dispersions, suspensions or solutions. . It may also be used for the administration of at least one compound selected from the compounds of the formula (I), other stereoisomers and pharmaceutically acceptable salts thereof, such as ointments, creams, drops for topical administration, a transdermal patch or powder; such as an ophthalmic solution or suspension formulation for ocular administration, that is, an eye drop; such as an aerosol spray or powder composition for inhalation or intranasal administration; or A cream, ointment, spray or suppository for rectal or vaginal administration.

Gelatin capsules may also be employed which comprise at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof, and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. A similar diluent can be used to prepare the compressed tablet. Both tablets and capsules can be prepared as sustained release products to provide sustained release of the drug over a period of time. The compressed tablet can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from atmospheric damage, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may also include at least one agent selected from the group consisting of coloring agents and flavoring agents for improving patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol can be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may comprise at least one compound of the invention, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts and sodium EDTA can also be used as examples of suitable stabilizers. Furthermore, the parenteral solution may also comprise at least one preservative, for example selected from the group consisting of benzalkonium chloride, methyl and hydroxybenzoic acid and chlorobutanol.

Pharmaceutically acceptable carriers are, for example, selected from carriers which are compatible with the active ingredients of the compositions (and in some embodiments, are capable of stabilizing the active ingredient) and are not deleterious to the subject to be treated. For example, a solubilizing agent, such as a cyclodextrin (which can form a specific more soluble complex with at least one compound and/or at least one pharmaceutically acceptable salt of the invention), can be used as a pharmaceutical excipient for delivery of the active ingredient. . Examples of other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and a pigment such as D&C Yellow #10. Suitable pharmaceutical carriers are described in standard reference texts in the art, Remington's Pharmaceutical Sciences, A. Osol.

The efficacy of at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, in the treatment of cancer can also be examined by in vivo assays. For example, at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof can be administered to an animal having cancer (for example, a mouse model) and a therapeutic effect thereof can be obtained. A positive result in one or more of the above tests is sufficient to increase the scientific knowledge base and thus sufficient to demonstrate the practical utility of the tested compounds and/or salts. Based on the results, an appropriate dosage range and route of administration for an animal, such as a human, can also be determined.

For administration by inhalation, at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, may conveniently be presented in the form of an aerosol spray from a pressure pack or nebulizer. Delivered. The at least one compound selected from the compounds of the formula (I), the stereoisomers thereof and the pharmaceutically acceptable salts thereof may also be delivered in the form of a powder, which may be formulated and then passed through a powder inhalation powder (insufflation powder) Inhaler device) Inhalable powder composition. An exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol that can be formulated into at least one compound selected from the group consisting of compounds of formula (I) as described herein. A suspension or solvent of the construct and the pharmaceutically acceptable salt in at least one suitable propellant, such as selected from the group consisting of fluorocarbons and hydrocarbons.

For ophthalmic administration, the ophthalmic preparation may be in an appropriate ophthalmic vehicle with an appropriate weight percentage of at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, as described herein. The solution or suspension is formulated such that at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, are contacted with the surface of the eye for a sufficient period of time to allow penetration of the compound The cornea and inner area of the eye.

Useful pharmaceutical dosage forms for the administration of at least one compound, stereoisomers and pharmaceutically acceptable salts thereof, selected from the compounds of formula (I) according to the invention include, but are not limited to, hard and soft gelatin capsules, tablets, gastrointestinal External injections and oral suspensions.

The dosage administered will depend on a number of factors, such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment, (if any) the frequency of treatment and the nature of the desired effect. Generally, the daily dose of the active ingredient can vary, for example, from 0.1 to 2000 mg per day. For example, one or more times of 10-500 mg per day can effectively achieve the desired effect.

In some embodiments, a plurality of unit capsules can be prepared by using standard two-piece hard gelatin capsules, for example, at least one of the compounds of formula (I) according to the invention, in the form of, for example, 100 mg in powder form. The compound, its stereoisomers and pharmaceutically acceptable salts, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate were loaded.

In some embodiments, a mixture of at least one compound selected from the group consisting of a compound of formula (I), a stereoisomer thereof and a pharmaceutically acceptable salt thereof, and an edible oil such as soybean oil, cottonseed oil or olive oil may be prepared. Then, it is injected into gelatin by means of a positive displacement pump to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsules are washed and then dried.

In some embodiments, a plurality of tablets may be prepared by ordinary procedures such that the dosage unit comprises, for example, 100 mg of at least one compound selected from the group consisting of compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, 0.2 mg colloid Ceria, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Appropriate coatings can be used to increase palatability or delay absorption.

In some embodiments, a parenteral composition suitable for administration by injection can be prepared by subjecting 1.5% by weight of at least one compound of the invention and/or at least one enantiomer, non-pair The conjugate or a pharmaceutically acceptable salt thereof was stirred in 10% by volume of propylene glycol. The solution was adjusted to the desired volume with water for injection and then sterilized.

In some embodiments, an aqueous suspension for oral administration can be prepared. For example, the following aqueous suspensions may be employed: each 5 ml of the aqueous suspension comprises 100 mg of very fine at least one compound selected from the compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof, 100 mg of carboxymethylcellulose Sodium, 5 mg sodium benzoate, 1.0 g sorbitol solution USP and 0.025 ml vanillin.

The same dosage form is usually employed when at least one compound selected from the compounds of formula (I), its stereoisomers and pharmaceutically acceptable salts are administered stepwise or in combination with at least one other therapeutic agent. When the drug is administered in a physical combination, the dosage form and administration route are selected depending on the compatibility of the combined drug. Thus, the term "co-administered" is understood to include the administration of at least two drugs simultaneously or sequentially or in a fixed dose combination of at least two active ingredients.

The at least one compound selected from the compounds of the formula (I), the stereoisomers thereof and the pharmaceutically acceptable salts thereof may be administered as the sole active ingredient or with at least one second active ingredient, for example, the second active ingredient is selected Other active ingredients known to be used in the treatment of cancer in patients.

The following examples are intended to be purely exemplary and should not be considered as limiting in any way. While it has been tried to ensure the accuracy of the numbers/quantities used (eg, amounts, temperatures, etc.), there are still some experimental errors and deviations. Temperatures are in degrees Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar or TCI and were used without further purification unless otherwise stated.

Unless otherwise stated, the reactions described below are carried out under a positive pressure of nitrogen or argon or with a drying tube in an anhydrous solvent; the reaction flask is equipped with a rubber gasket for introducing a substrate and a reagent via a syringe; and the glass instrument is Dryed by oven and/or dried by heating.

Unless otherwise stated, column chromatography purification was performed on a Biotage system (manufacturer: Dyax Corporation) with a silica gel column or on a SepPak column (Waters), or on a Teledyne Isco Combiflash purification system using a pre-packed cartridge column. get on.

¹ H NMR spectra were recorded on a 400 MHz operated Varian instrument. Use CDCl ₃ , CD ₂ Cl ₂ , CD ₃ OD, D ₂ O, d ₆ -DMSO, d ₆ -acetone or (CD ₃ ) ₂ CO as solvent and use tetramethylnonane (0.00 ppm) or residual solvent (CDCl) ₃ : 7.25 ppm; CD ₃ OD: 3.31 ppm; D ₂ O: 4.79 ppm; d ₆ -DMSO: 2.50 ppm; d ₆ -acetone: 2.05; (CD ₃ ) ₂ CO: 2.05) ¹ H- as a reference standard NMR spectrum. When reporting peak multiplicity, the following abbreviations are used: s (single peak), d (double peak), t (triplet), q (quadruple), qn (qupentet), sx (sixth peak), m (multiple peak), br (widened), dd (double doublet), dt (double triplet). When given, the coupling constant is reported in Hertz (Hz). All compound nomenclature except reagents were generated by ChemDraw version 12.0.

The following abbreviations are used in the following examples: Example 1: Synthesis of Compounds 1.1 to 1.67 BL-1: tert-butyl (S)-3-(toluenesulfonyloxy) acridine-1-carboxylate

To a solution of (S)-3-hydroxyacridine-1-carboxylic acid tert-butyl ester (168 g, 0.836 mol, 1.0 eq.) in pyridine (1000 mL) was slowly added toluene sulfonium chloride (TsCl, 176 g, 0.92 mol, 1.1 eq.); the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove the pyridine; the residue was dissolved in ethanol / H ₂ O 1000 ml / 600 ml, stirred for 30 min and then separated. The EA layer was washed with water (500 ml x 3), brine (500 ml x 2), dried over Na ₂ SO ₄ and concentrated to remove about 800 ml of EA. After adding PE (1.5 L) and stirring overnight, a white solid was collected and dried in vacuo to give the desired product (228 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79-8.81 (d, J = 8.0 Hz, 2H), 7.48-7.50 (d, J = 8.0 Hz, 2H), 4.47 (s, 1H), 3.38- 3.65 (m, 2H), 2.93-3.06 (m, 1H), 2.42 (s, 3H), 1.50-1.76 (m, 3H), 1.35 (s, 11 H) BL-2: (S)-2-( (toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

To (S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (20 g, 99.2 mmol) was in CH ₂ Cl ₂ (200 mL) was added a stirred solution of Et ₃ N (20 g, 0.198 mol), DMAP (1.23 g, 9.92 mmol), then the reaction mixture was cooled to 0 ° C and toluenesulfonium chloride (TsCl, 28.4 g, 0.149 mol). After the addition, the reaction mixture was stirred overnight. The reaction mixture was acidified to pH = with aqueous HCl (1.0 M) 4 ~ 5 , then extracted with brine, dried Na ₂ SO _4, concentrated and purified by silica gel chromatography (silica gel by weight: 30 g, petroleum ether / EtOAc = 10: 1 ~2:1) Purification gave the desired product (33 g, 93.7%) as a yellow syrup which solidified after one day. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 4.11 - 4.05 (m, 1H), 3.94 (br.s, 2H), 3.29 (dd, J = 13.2, 6.0 Hz, 2H), 2.45 (s, 3H), 2.02 - 1.74 (m, 4H), 1.41 (s, 9H). MS:M/e 356 (M+1 ⁺ compound 1.1: 1-((R)-1-propenyloxaridin-3-yl)-5-amino-3-(2,3-dihydrobenzo[b][1,4]dioxo Heterocyclohexen-2-yl)-1H-pyrazole-4-carboxamide Step A: 2-((2,3-Dihydrobenzo[b][1,4]dioxe-2-yl)(hydroxy)methylene)malononitrile

Adding grass to a solution of 2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid (20.0 g, 111 mmol) in DCM (200 mL) at 0 °C Oxalyl dichloride (30.0 g, 238 mmol) and 0.5 ml DMF. The solution was stirred at 0 ° C for 1 hour, at ambient temperature for 2 h then concentrated to dryness. The resulting oil was diluted in THF (200 mL). Malononitrile (11.0 g, 167 mmol) and TEA (24.6 g, 167 mmol) were added sequentially at 0 °C. The final solution was stirred at ambient temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth, 200 mL H ₂ O was added to the filtrate, and extracted with EA (200 mL x 3). The combined extracts were washed with EtOAc EtOAc EtOAc. MS: M/e 229 (M + 1) ⁺ Step B: 2-((2,3-dihydrobenzo[b][1,4]dioxen-2-yl) (methoxy) Methylene)malononitrile

To a solution of the product from step A (25.5 g, 111 <RTI ID=0.0> The layers were separated, the organics dried over Na ₂ SO _4, concentrated, and the resulting oil was dissolved in trimethoxymethane (200 mL) and heated at 100 ℃ 2 hours. The mixture was concentrated, and the residue was crystalljjjjlilililililili ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.02 - 6.87 (m, 4H), 5.47 (dd, J = 7.6, 2.8 Hz, 1H), 4.64 (dd, J = 12.0, 2.8 Hz, 1H), 4.32 (s, 3H), 4.10 (dd, J = 12.0, 7.6 Hz, 1H). Step C: 5-Amino-3-(2,3-dihydrobenzo[b][1,4]dioxan-2-yl)-1H-pyrazole-4-carbonitrile

To a stirred solution of the product of Step B (17.0 g, 70.2 mmol) in EtOH (10 mL), EtOAc (5 g, 90 mmol), and then the mixture was stirred at room temperature. 1 hour. The mixture was concentrated, dried with EtOAc EtOAc EtOAc. The resulting solid was purified by EtOAc EtOAc EtOAc: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.79 (s, 1H), 6.97 - 6.82 (m, 4H), 6.44 (s, 2H), 5.17 (dd, J = 8.0, 2.4 Hz, 1H), 4.47 (dd, J = 11.6, 2.4 Hz, 1H), 4.27 (dd, J = 11.6, 8.0 Hz, 1H). MS: M/e 243 (M+1) ⁺ . Step D: (3R)-3-(5-Amino-4-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxan-2-yl)- 1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product of Step C (500 mg, 2.05 mmol), ( S )-3-(toluenesulfonyloxy) acridine-1-carboxylic acid tert-butyl ester (BL-1, 944 mg, 2.66 mmol) and Cs _{2 CO 3 (1.34 g, 4.1 mmol} ) was stirred for 24 hours at 70 deg.] C in a mixture (10 mL) of DMF. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHH . MS: M/e 426 (M+1) ⁺ Step E: (3R) -3- (5-amino-4-carbamoyl-3-(2,3-dihydrobenzo[b][1, 4]dioxine-2-yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product of Step D (600 mg, 1.41 mmol) solution in EtOH (5 mL) is added successively DMSO (2 mL), aqueous 5N NaOH (2 mL) and _{H 2 O 2 (1 mL)} . The solution was stirred at 70 ° C for 1 hour. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc (EtOAc m. Oily. MS: M/e 444 (M+1) ⁺ Step F: 5-amino-3-(2,3-dihydrobenzo[b][1,4]dioxe-2-yl)- 1-((R)-acridin-3-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step E (400 mg, 0.90 mmol) The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (md. MS: M/e 344 (M+1) ⁺ step G: 1-((R)-1-propenyl acridine-3-yl)-5-amino-3-(2,3-dihydrobenzo [b][1,4] Dioxe-2-yl)-1H-pyrazole-4-carboxamide

The product of Step F (310 mg, 0.90 mmol) and _{NaHCO 3 (454 mg, 5.40 mmol} ) / H mixture (7 mL / 7 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (81 mg, 0.90 mmol) was added dropwise at 0 °C. The final solution was stirred at 0 °C for 5 minutes, quenched with water and then extracted with EA (10 mL x 3). The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHH . ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.00 - 6.79 (m, 4H), 6.77 - 6.54 (m, 3H), 6.35 (s, 2H), 6.05 (d, J = 17.2 Hz, 1H), 5.63 (d, J = 9.2 Hz, 1H), 5.35 (d, J = 8.0 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.41-4.32 (m, 1H), 4.31- 3.87 (m, 3H), 3.28-3.18 (m, 1H), 3.02-3.01 (m, 1H), 2.04-1.77 (m, 3H), 1.60-1.40 (m, 1H) ppm. MS: M/e 398 (M+1) ⁺ compound 1.2: 1-(((S)-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-(2,3- Dihydrobenzo[b][1,4]dioxine-2-yl)-1H-pyrazole-4-carboxamide

Compound 1.2 is prepared according to the procedure described for compound 1.1 under suitable conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 6.98 - 6.78 (m, 4H), 6.65 (s, 2H), 6.61 - 6.46 (m, 1H), 6.25 (s, 2H), 6.22 - 5.95 (m, 1H), 5.75-5.68 (m, 1H), 5.37 (d, J = 8 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.31 - 4.17 (m, 1H), 4.15 - 4.02 (m, 1H), 4.01 - 3.83 (m, 1H), 3.61 - 3.30 (m, 2H), 2.06 - 1.61 (m, 4H) ppm. MS: M/e 398 (M + 1) ⁺ compound 1.3: 1-((())-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-(6,7- Dichloro-2,3-dihydrobenzo[b][1,4]dioxine-2-yl)-1H-pyrazole-4-carboxamide Step A: 4,5-dichlorobenzene-1,2-diol

SO ₂ Cl ₂ (27.2 g, 0.2 mmol) was added dropwise to a stirred solution of pyrocatechol (10 g, 91 mmol) in Et ₂ O (100 mL) at 0 ° C under N ₂ . After the addition, the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated to give a residue which was taken from petroleum ether and then filtered. The filter cake was collected to give the title compound (11.6 g, 71.2%) as white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98 (s, 2H), 5.13 (s, 2H) ppm. Step B: Ethyl 6,7-dichloro-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylate

K ₂ CO ₃ (19.8 g, 0.14 mol) and 2,3-dibromopropionate (19 g) were added to the stirred solution of the product from step A (11.6 g, 61.4 mmol) in EtOAc (100 mL) , 73.6 mmol). After the addition, the reaction mixture was stirred at 60 ° C for 5 hours. The reaction mixture was filtered and washed with EtOAc (EtOAc) The filtrate was then concentrated to give a crystals crystals crystals eluted elute . MS: M/e 277 (M+1) ⁺ step C: 6,7-dichloro-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid

The product of Step B (13.8 g, 49.8 mmol) was added _{LiOH.H 2 O (4.2 g, 99.6} mmol) was stirred in a mixture of THF / H (50 mL / 20 mL) over ₂ O in the. After the addition, the reaction mixture was stirred overnight. Most of the THF was removed in vacuo and the aqueous layer was acidified to pH = 4 - 5 with aqueous EtOAc then extracted with EtOAc (20 <RTIgt; The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the desired product (10 g, 80.6%), as a pale yellow solid. MS: M/e 248 (M-1) ^- Step D: 2-(6,7-Dichloro-2,3-dihydrobenzo[b][1,4]dioxan-2- Carbonyl)malononitrile

Add HOBT (3.2 g, 24 mmol) and Et ₃ N (4.0 g, 40 mmol) to a stirred solution of the product from step C (5.0 g, 20.1 mmol) in CH ₂ Cl ₂ (50 mL) EDCI (4.6 g, 24 mmol) and malononitrile (1.3 g, 20.1 mmol). After the addition, the reaction mixture was stirred for 3 hours. The reaction mixture was poured into H ₂ O (200 mL), and then (50 mL x 3) and extracted with CH ₂ Cl _2. The combined organic layers were washed with brine, dried over Na ₂ SO _4, and concentrated to give a residue, which was dissolved in EtOAc (150 mL) and stirred for 2 hours with aqueous HCl (6.0 M, 50 mL) , then separated. The EtOAc layer was washed with brine, dried over Na ₂ SO _4, then concentrated to give the desired compound which was used directly in the next step. MS: M/e 297 (M+1) ⁺ Step E: 2-((6,7-dichloro-2,3-dihydrobenzo[b][1,4]dioxetene-2 -yl)(methoxy)methylene)malononitrile

A solution of the product from Step D (5.97 g, 20.1 mmol) in trimethoxymethane (50 mL) was stirred at <RTIgt; The resulting solution was concentrated to give a residue, which was washed with EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc EtOAc m. ), which is a white solid. MS: M/e 311 (M+1) ⁺ step F: 5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

A solution of the product from Step E (2.2 g, 7.07 mmol) and EtOAc (5 mL) EtOAc. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (s, 1H), 7.23 (d, J = 6.8 Hz, 2H), 6.51 (s, 2H), 5.28 (d, J = 5.2 Hz, 1H) , 4.52 (dd, J = 11.6, 2.4 Hz, 1H), 4.34 (dd, J = 9.2, 5.2 Hz, 1H) ppm. MS: M/e 311 (M+1) ⁺ Step G: 5-amino-3 -(6,7-Dichloro-2,3-dihydrobenzo[b][1,4]dioxine-2-yl)-1H-pyrazole-4-carboxamide

A mixture of the product of Step F (300 mg, 0.964 mmol) in M. The reaction mixture was poured into H ₂ O (30 mL) and treated with aqueous NaOH to pH = 9 ~ 10, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO _4, concentrated in vacuo, to give the desired product (307 mg, 96.8%), as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.94 (s, 1H), 7.24 (d, J = 4.4 Hz, 2H), 6.72 (br.s, 2H), 6.04 (s, 2H), 5.54 ( s, 1H), 4.60 (dd, J = 11.6, 2.4 Hz, 1H), 4.46 - 4.32 (m, 1H) ppm. MS: M/e 329 (M+1) ⁺ step H: (2S)-2-((5-amino-4-carbamoyl-3-(6,7-dichloro-2,3-dihydro) Benzo[b][1,4]dioxan-2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of step H (100 mg, 0.304 mmol), (S)-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (BL-2, 129 mg. 0.364 mmol A mixture of Cs ₂ CO ₃ (198 mg, 0.608 mmol) in DMF (3 mL) was stirred at 70 ° C for 2 h. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO _4, concentrated, and then purified by column chromatography (petroleum ether / EtOAc = 1: 1) to obtain the desired product (90 mg, 57.8%), as a white solid . MS: M/e 512 (M+1) ⁺ Step I: 5-amino-3-(6,7-dichloro-2,3-dihydrobenzo[b][1,4]dioxine Alk-2-yl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazole-4-carboxamide

To a solution of the product from EtOAc (EtOAc,EtOAc. The solution was stirred at room temperature overnight. The resulting solution was concentrated to give a crude material, which was taken in the next step. MS: M/e 412 (M+1) ⁺ Step J: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6,7- Dichloro-2,3-dihydrobenzo[b][1,4]dioxine-2-yl)-1H-pyrazole-4-carboxamide

The product of step I (0.176 mmol) and _{NaHCO 3 (29 mg, 0.352 mmol} ) mixture (3 mL / 3 mL) was stirred in CH ₃ CN / H ₂ O at 0 ℃ 5 minutes. Propylene hydrazine chloride (15.9 mg, 0.176 mmol) was added dropwise at 0 °C. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.25 - 7.15 (m, 2H), 6.73 (br.s, 2H), 6.55 (m, 1H), 6.33 (br.s, 1H), 6.20 - 5.93 (m, 2H), 5.68 (dd, J = 10.4 Hz, 1H), 5.53 - 5.43 (m, 1H), 4.53 (t, J = 12.8 Hz, 1H), 4.35 (dd, J = 11.5, 8.4 Hz, 1H), 4.15 (s, 1H ), 4.05 (d, J = 14.2 Hz, 1H), 3.96 - 3.82 (m, 2H), 1.81 (m, 5H) ppm. MS: M/e 466 (M+1) ⁺ Compound 1.4: 1-((R)-1-propenylindazin-3-yl)-5-amino-3-(6,7-dichloro-2 ,3-dihydrobenzo[b][1,4]dioxine-2-yl)-1H-pyrazole-4-carboxamide

Compound 1.4 was prepared according to the procedure described for compound 1.3 under appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.30 - 7.22 (m, 2H), 6.94 - 6.33 (m, 5H), 6.18 - 6.03 (m, 1H), 5.69 - 5.56 (m, 1H), 5.49 (d, J = 6.4 Hz, 1H), 4.64 - 4.53 (m, 1H), 4.46 - 4.34 (m, 1H), 4.29 - 4.12 (m, 2H), 4.09 - 3.96 (m, 1H), 3.16 - 2.95 (m, 1H), 2.07 - 1.73 (m, 4H), 1.57 - 1.36 (m, 1H) ppm. MS: M/e 466 (M+1) ⁺ Compound 1.5: 1-((R)-1-propenyl acridine-3-yl)-5-amino-3-(4-methyl-3,4 -dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1H-pyrazole-4-carboxamide Step A: 2-Aminophenol

A mixture of 2-nitrophenol (20 g, 215.66 mmol) and stannous chloride (II) dihydrate (223 g, 1.08 mol) in EtOH (500 mL) was stirred at <RTIgt; The resulting solution was concentrated. The residue was poured into ice water (500 mL), basified to pH = 8 with 5N aqueous NaOH and then extracted with EA (200 mL). The suspension was filtered through a pad of celite. The filtrate was extracted with EA (200 mL x 3). The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 110 (M+1) ⁺ Step B: 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid ethyl ester

The product of Step A (20 g, 183.24 mmol), ethyl 2,3-dibromopropionate (57.16 g, 219.92 mmol) and K ₂ CO ₃ (70.80 g, 513.08 mmol) in acetone (80 mL) The mixture was stirred at reflux for 5 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAcq EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Brown oil. MS: M/e 208 (M+1) ⁺ step C: ethyl 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

To a solution of the product from Step B (26 g, 125.46 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 10 minutes. The mixture was then cooled to 0 ° C and sodium cyanoborohydride (15.77 g, 250.92 mmol) was added in portions over 15 min. The final solution was stirred at room temperature for 30 minutes. The resulting mixture was poured into ice water (100 mL), neutralized with 5N aqueous NaOH to pH = 7 and then extracted with EA (200 mL x 3). The combined organic layers were washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Oily. MS: M/e 222 (M+1) ⁺ Step D: 4-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid

A solution of 6N NaOH (17.8 g, 445.20 mmol) was added to a solution of the product from step C (19.7 g, 89.04 mmol) in EtOH (40 mL). The solution was stirred at room temperature for 1 hour. The resulting solution was neutralized to pH = 6 with 2N aqueous HCl. The title compound was obtained as a white solid, which was taken directly to the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.83 - 6.52 (m, 4H), 4.78 (t, J = 4.0 Hz, 1H), 3.32 (d, J = 4.0 Hz, 2H), 2.78 (s, 3H) ppm. MS: M/e 194 (M+1) ⁺ Step E: 2-(hydroxy(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl) Methylene)malononitrile

HOBT (14.42 g, 106.83 mmol), Et ₃ N (25.69 mL, 178.04 mmol) and EDCI (20.48 g, 106.83 mmol) were added to the solution of the product from Step D (17.20 g, 89.02 mmol) in DCM (50 mL). ). The solution was stirred at room temperature for 30 minutes. Add malononitrile (7.06 g, 106.83 mmol). The final solution was stirred at room temperature for 2-3 hours. The resulting solution was concentrated, the residue was diluted in EA (100 mL), washed successively with saturated aqueous NaHCO ₃ and saturated aqueous NH ₄ Cl. The organic layer was washed with 6N aqueous HCl. The organic layer was separated and concentrated to give a crystallite. MS: M / e 242 (M + 1) + Step F: 2- (methoxy (4-methyl-3,4-dihydro -2H- benzo [b] [1,4] oxazin-2 -based) methylene)malononitrile

A solution of the product of Step E (21.48 g, 89.04 mmol) in trimethoxymethane (30 mL) was stirred at <RTIgt; The resulting solution was concentrated and purified by EtOAc EtOAc elut elut elut elut MS: M/e 256 (M+1) ⁺ step G: 5-amino-3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2 -yl)-1H-pyrazole-4-carbonitrile

A solution of the product from Step F (5 g, 19.59 mmol) and EtOAc (2 mL) The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAcq EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It is a yellow solid. MS: M/e 256 (M+1) ⁺ step H: (3R)-3-(5-amino-4-cyano-3-(4-methyl-3,4-dihydro-2H-benzo [b][1,4]oxazol-2-yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product of Step G (581 mg, 2.28 mmol), (S)-3-(toluenesulfonyloxy) acridine-1-carboxylic acid tert-butyl ester (BL-1, 970 mg, 2.73 mmol) and Cs _{2 CO 3 (1.49 g, 4.56 mmol} ) was stirred for 24 hours at 70 deg.] C in a mixture (10 mL) of DMF. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHH Oily. MS: M/e 439 (M+1) ⁺ Step I: (3R) -3-(5-amino-4-carbamoyl-3-(4-methyl-3,4-dihydro-2H- Benzo[b][1,4]oxazol-2-yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product from Step H (654 mg, 1.49 mmol) in a solution (5 mL) in EtOH was added sequentially DMSO (2 mL), aqueous 5N NaOH (2 mL) and _{H 2 O 2 (1 mL)} . The solution was stirred at 70 ° C for 1 hour. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAcq EtOAcqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Oily. MS: M/e 457 (M+1) ⁺ Step J: 5-amino-3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2 -yl)-1-((R)-acridin-3-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from EtOAc (EtOAc m. The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (yield: 238 mg, 100%). MS: M/e 357 (M+1) ⁺ step K: 1-((R)-1-propenyl acridine-3-yl)-5-amino-3-(4-methyl-3,4 -dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1H-pyrazole-4-carboxamide

The product of step J (238 mg, 0.67 mmol) and _{NaHCO 3 (337 mg, 4.02 mmol} ) was stirred in a mixture (5 mL / 5 mL) in CH ₃ CN / H ₂ O at 0 ℃ 5 minutes. Propylene hydrazine chloride (60 mg, 0.67 mmol) was added dropwise at 0 °C. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHH solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 6.84 (t, J = 7.6 Hz, 1H), 6.79 - 6.71 (m, 3H), 6.69 (s, 2H), 6.57 (t, J = 7.6 Hz, 1H), 6.34 (s, 2H), 6.12 - 5.99 (m, 1H), 5.69 - 5.57 (m, 1H), 5.23 (dd, J = 8.8, 2.6 Hz, 1H), 4.28 - 3.98 (m , 3,,,,,, (m, 3H), 1.60 - 1.40 (m, 1H) ppm. MS: M/e 411 (M+1) ⁺

Compound 1.6 was prepared according to the procedure described for compound 1.5 under suitable conditions known to those of ordinary skill in the art. Compound 1.6: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(4-methyl-3,4-dihydro-2H-benzo [b][1,4]oxazin-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.00 - 6.79 (m, 2H), 6.81 - 6.72 (m, 2H), 6.67 - 6.55 (m, 2H), 6.30 - 5.98 (m, 1H), 5.79 - 5.42 (m, 1H), 5.33 - 5.21 (m, 1H), 4.45 - 4.16 (m, 1H), 4.13 - 3.88 (m, 2H), 3.65 - 3.34 (m, 4H), 2.89 (s , 3H) , 1.98 - 1.71 (m , 4H). MS: M/e 411 (M+1) ⁺ Compound 1.7: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6-fluoro- 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazol-2-yl)-1H-pyrazole-4-carboxamide Step A: Ethyl 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

To a suspension of 2-amino-4-fluorophenol (12.7 g, 100 mmol) and K ₂ CO ₃ (34 g, 250 mmol) in acetone (200 mL), ethyl 2,3-dibromopropionate (28.6 g, 110 mmol). The resulting mixture was stirred at reflux temperature for 4 hours. The mixture was cooled to room temperature and then concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc. To the oil was added PE/EA (30/1, 60 mL) and mixture was stirred at room temperature for 30 min. A solid was formed, which was filtered and dried to give the desired product ( 3.6 g, 16%) as a brown solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.71 (dd, J = 8.8, 5.6 Hz, 1H), 6.36 (dd, J = 10.8, 3.2 Hz, 1H), 6.31 - 6.26 (m, 1H), 6.15 (s, 1H), 4.90 (t, J = 4.0 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.41 - 3.39 (m, 2H), 1.17 (t, J = 6.8 Hz, 3H ). ppm. MS: M/e 226 (M+1) ⁺ Step B: 6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid ester

To a solution of the product from Step A (3.6 g, 16 mmol) in EtOH (40 mL The reaction mixture was stirred at room temperature under H ₂ (balloon) for 16 h. The mixture was then filtered through a pad of Celite and washed with EtOH (40 mL). The filtrate was concentrated to give the desired product (5 g, crude material). MS: M/e 240 (M+1) ⁺ step C: 6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid

A solution of sodium hydroxide (2.56 g, 64 mmol) in water (20 mL). The solution was stirred at room temperature for 3 hours. The mixture was concentrated. The resulting residue was neutralized to pH = 6 with 2N aqueous HCl. A solid was formed which was then filtered to give the desired product (1,3 g, 38. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.60 (dd, J = 8.4, 5.6 Hz, 1H), 6.41 (dd, J = 12, 3.2 Hz, 1H), 6.28-6.23 (m, 1H), 4.14-4.11 (m, 1H), 3.45-3.39 (m, 1H), 3.14-3.09 (m, 1H), 2.78 (s, 3H) ppm. MS: M/e 212 (M+1) ⁺ Step D: 2-((6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine- 2-yl)(hydroxy)methylene)malononitrile

HOBT (1 g, 7.39 mmol), Et ₃ N (1.26 g, 12.5 mmol) and EDCI (1.4 g, 7.39) were added to the solution of the product from step C (1.3 g, 6.16 mmol) in DCM (20 mL). Mm). The solution was stirred at room temperature for 30 minutes. Add malononitrile (0.4 g, 6.16 mmol). The final solution was stirred at room temperature for 16 hours. The resulting solution was concentrated, the residue was diluted in EA (100 mL), washed with saturated aqueous NaHCO ₃ and saturated aqueous NH ₄ Cl. The organic layer was washed with 10% H ₂ SO ₄ solution. The organic layer was separated and concentrated to give a crude material (l. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.66 - 6.64 (m, 1H), 6.50 (dd, J = 11.6, 3.2 Hz, 1H), 6.34-6.29 (m, 1H), 4.67 (dd, J = 7.6, 2.8 Hz, 1H), 3.29-3.26 (m, 1H), 3.20-3.15 (m, 1H), 2.82 (s, 3H) ppm. MS: M/e 260 (M+1) ⁺ Step E: 2-((6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine- 2-yl)(methoxy)methylene)malononitrile

A solution of the product of Step D (1.5 g, 5.8 mmol) in trimethoxymethane (30 mL) was stirred at 70 ° C for 3 hr. The resulting solution was concentrated and purified by EtOAc EtOAc elut elut elut elut MS: M/e 274 (M+1) ⁺ step F: 5-amino-3-(6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4] Oxazin-2-yl)-1H-pyrazole-4-carbonitrile

A solution of the product from Step E (0.25 g, 0.91 mmol) and EtOAc (2 mL) The resulting solution was concentrated. The residue was washed with water and extracted with EA (30 mL The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 274 (M+1) ⁺ step G: (2S)-2-((5-amino-4-cyano-3-(6-fluoro-4-methyl-3,4-dihydro) -2H-benzo[b][1,4]oxazol-2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product from step F (245 mg, 0.9 mmol), (S)-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (BL-2, 383 mg, 1.08 mmol A mixture of Cs ₂ CO ₃ (585 mg, 1.8 mmol) in DMF (5 mL) was stirred at 70 ° C for 5 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EA (30 mL The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 457 (M+1) ⁺ step H: (2S)-2-((5-amino-4-carbamoyl-3-(6-fluoro-4-methyl-3,4- Dihydro-2H-benzo[b][1,4]oxazol-2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step G (400 mg, crude) in a solution (5 mL) in EtOH was added sequentially DMSO (2 mL), aqueous 5N NaOH (2 mL) and _{H 2 O 2 (2 mL)} . The solution was stirred at 50 ° C for 2 hours. The resulting solution was concentrated. The residue was washed with water and EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc (EtOAc m. It is a yellow oil. MS: M/e 475 (M+1) ⁺ Step I: 5-amino-3-(6-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4] Oxazin-2-yl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazole-4-carboxamide

To a solution of the product from EtOAc (EtOAc (EtOAc). The solution was stirred at room temperature for 3 hours. The resulting solution was treated with saturated aqueous Na ₂ CO ₃ to pH = 8, and extracted with DCM (30 mL x 2). The combined organic layers were washed with EtOAc EtOAc EtOAc. MS: M/e 375 (M+1) ⁺ Step J: 1-(((S)-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-(6-fluoro- 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazol-2-yl)-1H-pyrazole-4-carboxamide

Saturated aqueous NaHCO ₃ (1 mL) solution of the product of step I (100 mg, 0.267 mmol) in a mixture (4 mL) of the ₃ CN CH. The resulting solution was cooled to 0 ℃, then added dropwise chloro-Bing Xixi (24 mg, 0.267 mmol) solution (1 mL) in the CH ₃ CN. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (30 <RTIgt; The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAc. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.83 (br.s, 2H), 6.74-6.70 (m, 1H), 6.64 - 6.51 (m, 2H), 6.45 - 6.40 (m, 2H), 6.35 - 6.30 (m, 1H), 6.24 - 6.18 (m, 1H), 6.05 - 5.71 (m, 1H), 5.25 - 5.21 (m, 1H), 4.21 - 3.90 (m, 3H), 3.65 - 3.40 (m, 4H), 2.90 (s, 3H), 2.00 - 1.74 (m, 4H), ppm. MS: M/e 429 (M + 1) ⁺ Compound 1.8: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6,7- Difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1H-pyrazole-4-carboxamide Step A: 4,5-difluoro-2-nitrophenol

A solution of fuming HNO ₃ (10 mL) in AcOH (80 mL) was added dropwise to a solution of 3,4-difluorophenol (37 g, 0.28 mol) in AcOH (200 mL) over EtOAc. Keep the temperature below 40 °C. The mixture was slowly poured into ice water (300 mL). A red solid was formed, which was filtered, then washed with water (1L) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.46 (s, 1H), 8.19 - 8.12 (m, 1H), 7.19 - 7.13 (m, 1H). ppm. Step B: 2-Amino-4,5-difluorophenol

To a solution of the product from Step A (40 g, 228 mmol) in Et. The reaction mixture was stirred at room temperature under H ₂ (balloon) for 3 days. The mixture was then filtered through a pad of celite and washed with EtOAc (EtOAc). The filtrate was concentrated and the residue was taken &lt;RTI ID=0.0&gt;&gt; The suspension was stirred at room temperature for 0.5 hours. The solid was filtered, washed with EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.39 (br.s, 1H), 6.62 - 6.42 (m, 2H), 4.68 (br.s, 2H). ppm. MS: M/e 146 (M+1) ⁺ step C: 6,7-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid ethyl ester

Add 2,3-dibromopropionate ethyl ester to a suspension of 2-amino-4-fluorophenol (10 g, 69 mmol) and K ₂ CO ₃ (23.6 g, 172.5 mmol) in acetone (80 mL) (19.7 g, 76 mmol). The resulting mixture was stirred at reflux temperature overnight. The mixture was cooled to room temperature and then concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc. PE/EA (30/1, 60 mL) was added to the oil and the mixture was stirred at room temperature for 30 min. Solid formed, filtered and dried to give the desired product (4.5 g, 26.8%) as a brown solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.87 (dd, J = 8.4, 3.6 Hz, 1H), 6.56 (dd, J = 8.4, 3.6 Hz, 1H), 5.99 (s, 1H), 4.96 ( t, J = 3.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.40 - 3.34 (m, 2H), 1.17 (t, J = 6.8 Hz, 3H). ppm. MS: M/e 244 (M+1) ⁺ Step D: 6,7-difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2 -ethyl formate

To a solution of the product from Step C (4.5 g, 18.5 mmol) in EtOH (40 mL), 40% EtOAc (20 mL) The reaction mixture was stirred for 36 hours at ambient H ₂ (balloon) at room temperature. The mixture was then filtered through a pad of Celite and washed with EtOH (40 mL). The filtrate was concentrated to give the desired material (jjjjjj, MS: M/e 258 (M+1) ⁺ Step E: 6,7-difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2 -formic acid

To a solution of the product from step D (8 g, EtOAc)EtOAc. The solution was stirred at room temperature for 4 hours. The mixture was concentrated. The resulting residue was neutralized to pH = 6 with 2N aqueous HCl. A solid formed which was filtered to give the desired product (2 g) as a brown solid. The filtrate was washed with EA (30 mL x 2), washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give a red solid (0.6 g). A total of 2.6 g of product was obtained (63% yield in 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.87 (dd, J = 8.0, 3.6 Hz, 1H), 6.76 (dd, J = 8.0, 5.2 Hz, 1H), 4.96 (t, J = 3.2 Hz, 1H), 3.42 - 3.27 (m, 2H), 2.78 (s, 3H). ppm. MS: M/e 230 (M+1) ⁺ step F: 2-((6,7-difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4] Oxazin-2-yl)(hydroxy)methylene)malononitrile

HOBT (1.83 g, 13.6 mmol), Et ₃ N (2.3 g, 22.7 mmol) and EDCI (2.6 g, 13.6) were added to a solution of the product from step E (2.6 g, 11.35 mmol) in DCM (40 mL). Mm). The solution was stirred at room temperature for 30 minutes. Add malononitrile (0.74 g, 11.35 mmol). The final solution was stirred at room temperature for 3 hours. The resulting solution was concentrated, the residue is diluted in EA (100 mL), washed with saturated aqueous NaHCO ₃ and saturated aqueous NH ₄ Cl. The organic layer was washed with 10% H ₂ SO ₄ aqueous solution and brine. The organic layer was separated and concentrated to give a crude material (3 g, 95%). MS: M/e 278 (M+1) ⁺ step G: 2-((6,7-difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4] Oxazin-2-yl)(methoxy)methylene)malononitrile

A solution of the product from Step F (3 g, 10.8 mmol) eluting The resulting solution was concentrated and purified by EtOAc EtOAc EtOAc:EtOAc MS: M/e 292 (M+1) ⁺ step H: 5-amino-3-(6,7-difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-2-yl)-1H-pyrazole-4-carbonitrile

A solution of the product from Step G (0.5 g, 1.7 mmol) and EtOAc (2 mL) The resulting solution was concentrated. DCM (4 mL) was added to a residue. The solid was filtered and dried then purified to give crystals crystals. MS: M/e 292 (M+1) ⁺ Step I: (2S)-2-((5-amino-4-cyano-3-(6,7-difluoro-4-methyl-3,4) -Dihydro-2H-benzo[b][1,4]oxazol-2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of step H (0.3 g, 1 mmol), (S)-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (BL-2, 426 mg, 1.2 mmol A mixture of Cs ₂ CO ₃ (650 mg, 2 mmol) in DMF (5 mL) was stirred at 70 ° C for 6 h. The resulting solution was concentrated. The residue was washed with water and extracted with EA (30 mL The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 475 (M+1) ⁺ step J: (2S)-2-((5-amino-4-carbamoyl-3-(6,7-difluoro-4-methyl-3) , 4-dihydro-2H-benzo[b][1,4]oxazol-2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Of the product of step I (600 mg, crude) in a solution (6 mL) in EtOH was added sequentially DMSO (2 mL), aqueous 5N NaOH (2 mL) and _{H 2 O 2 (2 mL)} . The solution was stirred at 50 ° C for 3 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc (EtOAc m. It is a white solid. MS: M/e 493 (M + 1) ⁺ Step K: 1-((())-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-(6,7- Difluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step H (230 mg, EtOAc. The solution was stirred at room temperature for 4 hours. The resulting solution was concentrated to dryness, and the residue was dissolved in CH ₃ CN (5 mL). After cooling to 0 ℃, was added saturated aqueous NaHCO ₃ (2 mL). Bing Xixi chloride was then added dropwise (24 mg, 0.267 mmol) solution in CH ₃ CN (1 mL) is. The final solution was stirred at 0 &lt;0&gt;C for 30 min, quenched with water then EtOAc (EtOAc) The organic layer was washed with EtOAc (EtOAc m. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 6.90 (t, J = 10.0 Hz, 1H), 6.84 - 6.68 (m, 3H), 6.66 - 6.54 (m, 1H), 6.37 (s, 2H), 6.20 (dd, J = 16.8, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 5.36 - 5.28 (m, 1H), 4.40 - 4.20 (m, 1H), 4.09 - 3.85 ( m, 2H), 3.65 - 3.38 (m, 4H), 2.87 (s, 3H), 2.00 - 1.70 (m, 4H), ppm. MS: M/e 447 (M+1) ⁺ Compound 1.9: 1-((())-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-(1-methyl -1,2,3,4-tetrahydroquinolin-3-yl)-1H-pyrazole-4-carboxamide Step A: Quinoline-3-carboxylic acid ethyl ester

Sulfuric acid dichloride (25.6 mL, 0.36 mol) was added to a stirred solution of quinoline-3-carboxylic acid (20 g, 0.12 mol) in EtOH (500 mL). The mixture was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA (500 mL). The organic phase was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue (yellow solid, 22 g, 96%) was used directly in the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.32 (s, 1H), 8.99 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H) , 7.94 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H) ppm. MS: M/e 202 (M+1) ⁺ Step B: ethyl 1-methyl-1,2,3,4-tetrahydroquinoline-3-carboxylate

Sodium cyanoborohydride (15.7 g, 0.25) was carefully added to the stirred solution of the product from step A (10 g, 0.05 mol) and paraformaldehyde (14.9 g, 0.5 mol) in acetic acid (200 mL). Mol). The reaction mixture was concentrated under reduced pressure. The residue was washed with a saturated _aqueous ethylenically NaHCO, and then (100 mL x 2) and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue (yellow solid, 7.5 g, 69%) was used directly in the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.00 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.62 - 6.52 (m, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.45 - 3.30 (m, 1H), 3.29 - 3.17 (m, 1H), 3.00 - 2.86 (m, 3H), 2.82 (s, 3H), 1.20 (t, J = 7.2 Hz , 3H)ppm. MS: M/e 220 (M+1) ⁺ Step C: 1-Methyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid

A solution of the product from Step B (7.5 g, 0.03 mol) in MeOH (150 mL) The solution was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The resulting solution was neutralized to pH = 6 with 2N aqueous HCl. A white solid precipitated from the mixture. The mixture was filtered and the solid was dried in a 60 ° C infrared oven. The solid (4.8 g, 72.7%) was used directly in the next step. MS: M/e 192 (M + 1) ⁺ Step D: 2-(hydroxy(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)methylene)malononitrile

Triethylamine (5.1 g, 50 mmol) was added to a stirred solution of EtOAc (EtOAc, EtOAc). EDCI (5.8 g, 30 mmol) and malononitrile (1.7 g, 26 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (40 mL). The mixture was extracted with DCM (40 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was diluted with HCl / EA (6 N). The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure. The residue (crude) was used directly in the next step. MS: M/e 240 (M+1) ⁺ Step E: 2-(Methoxy(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)methylene)propane Nitrile

A solution of the product of Step D (4.5 g, 18.8 mmol) in trimethoxymethane (100 mL) was stirred at 100 ° C for 2 hr. The resulting solution was concentrated under reduced pressure. The residue was diluted with water (100 mL) then extracted with EA (100 mL The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc (EtOAc) MS: M/e 254 (M+1) ⁺ step F: 5-amino-3-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)-1H-pyrazole- 4-carbonitrile

A solution of the product from Step E (280 mg, 1.1 mmol) and EtOAc (1 mL) The resulting solution was concentrated under reduced pressure. The residue was diluted with water (10 mL) then extracted with EA (10 mL EtOAc). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS: M/e 254 (M+1) ⁺ step G: (2S)-2-((5-amino-4-cyano-3-(1-methyl-1,2,3,4-tetrahydro) Benzyl-3-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product from step F (250 mg, 0.1 mmol), (S)-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (BL-2, 421 mg, 0.12 mmol A mixture of Cs ₂ CO ₃ (644 mg, 0.2 mmol) in DMF (10 mL) was stirred at 70 ° C overnight. The resulting solution was concentrated under reduced pressure. The residue was diluted with water (20 mL) then extracted with EtOAc (20 mL The combined organic layers were washed with brine, dried over anhydrous sodium sulfate A yellow oil (200 mg, 45.9%) was used directly in the next step. MS: M/e 437 (M+1) ⁺ step H: (2S)-2-((5-amino-4-carbamoyl-3-(1-methyl-1,2,3,4- Tetrahydroquinolin-3-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step G (200 mg, 0.46 mmol) in EtOH (3 mL) was added successively DMSO (0.5 mL), aqueous 5N NaOH (0.5 mL) and _{H 2 O 2 (0.5 mL)} . The solution was stirred at 60 ° C for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was diluted with water (5 mL) then extracted with EA (10 mL The combined organic phases were washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAcEtOAcEtOAc ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.00 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.68 - 6.57 (m, 3H), 6.53 (t, J = 7.2 Hz, 1H), 6.02 (s, 2H), 3.98 - 3.88 (m, 2H), 3.66 - 3.52 (m, 1H), 3.42 - 3.35 (m, 1H), 3.25 - 3.10 (m, 3H) , 2.91 (d, J = 8.1 Hz, 2H), 2.85 (s, 3H), 2.54 (s, 2H), 1.82 - 1.64 (m, 3H), 1.42 (s, 9H). MS: M/e 455 (M+1) ⁺ Step I: 5-amino-3-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)-1-((S) )-pyrrolidin-2-ylmethyl)-1H-pyrazole-4-carboxamide

To a solution of the product from EtOAc (EtOAc,EtOAc. The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (jjjj, MS: M/e 355 (M+1) ⁺ Step J: 1-((())-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-(1-methyl -1,2,3,4-tetrahydroquinolin-3-yl)-1H-pyrazole-4-carboxamide

The product of step I (146 mg, 0.42 mmol) was stirred at 0 ℃ 5 min the mixture (5 mL) in ₃ CN CH and saturated aqueous NaHCO ₃ (5 mL). Propylene hydrazine chloride (37 mg, 0.41 mmol) was added dropwise at 0 °C. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then EtOAc (EtOAc &lt The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.00 (t, J = 7.6 Hz, 1H), 6.96 - 6.90 (m, J = 7.2 Hz, 1H), 6.70 - 6.48 (m, 5H), 6.26 - 6.16 (m, 1H), 6.15 - 5.98 (m, 2H), 5.76 - 5.44 (m, 1H), 4.43 - 4.14 (m, 1H), 4.07 - 3.87 (m, 2H), 3.64 - 3.36 (m, 4H ), 3.24 - 3.10 (m, 1H), 2.95 - 2.87 (m, 2H), 2.85 (t, J = 3.2 Hz, 3H), 1.95 - 1.68 (m, 4H). MS: M/e 409 (M+1) ⁺ Compound 1.10: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: Methyl 6-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate

Add 6-fluoro-3,4-dihydronaphthalen-1(2H)-one (5 g, 30.45 mmol) to a solution of NaH (2.7 g, 67 mmol) in dimethyl carbonate (25 mL). A solution in dimethyl ester (25 mL). The mixture was stirred at room temperature for 30 minutes and then at 90 ° C for 1 hour. The reaction mixture changes from a suspension to a solid state. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 - 7.70 (m, 1H), 7.10 - 6.77 (m, 2H), 3.76 (s, 3H), 3.59 (dd, J = 10.0, 4.8 Hz, 1H), 3.11 - 2.90 (m, 1H), 2.78 (t, J = 7.8 Hz, 1H), 2.78 - 2.52 (m, 1H), 2.52 - 2.30 (m, 1H). MS: M/e 223 (M+1) ⁺ step B: 6-fluoro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester

A mixture of the product of Step A (6.8 g, 30.5 mmol), EtOAc ( ₄ mL), EtOAc (EtOAc) The reaction suspension was filtered through a pad of celite. The filtrate was concentrated. The residue was diluted with EtOAc (EtOAc EtOAc EtOAc. In one step. MS: M/e 209 (M+1) ⁺ step C: 6-fluoro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

The product of Step B (6.5 g, 30.5 mmol) and NaOH (4.9 g, 122 mmol) and H ₂ O was stirred for 1 hour at room temperature in MeOH (20 mL). The mixture was concentrated. The residue (20 mL) diluted with H ₂ O, 2N HCl and then adjusted to pH = 5-6. The precipitate was collected, then filtered to give the desired product (jjjj, ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.19 - 7.04 (m, 1H), 6.97 - 6.80 (m, 2H), 2.96 - 2.64 (m, 4H), 2.60 - 2.51 (m, 1H), 2.09 - 1.98 (m, 1H), 1.74 - 1.56 (m, 1H). MS: M/e 195 (M+1) ⁺ Step D: 2-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(hydroxy)methylene)malononitrile

A solution of the product from Step C (3.9 g, 20 mmol) in DCM (20 mL) The solution was stirred at room temperature for 2 h then concentrated. The residue was diluted in THF (20 mL). Add malononitrile (2.0 g, 30 mmol). Cool to 0 ° C and add TEA (6 mL, 40 mmol). The final solution was stirred at 0 ° C for 1 hour. The resulting solution was washed with water (30 mL) andEtOAc. The organic layer was washed with EtOAc EtOAc EtOAc EtOAc. in. MS: M/e 243 (M+1) ⁺ step E: 2-((6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(methoxy)methylene)propane Nitrile

A solution of the product from Step D (5 g, 20.60 mmol) elute The resulting solution was concentrated. The residue was diluted with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. 2.2 g, after 2 steps of 43%), it is a yellow oil. MS: M/e 257 (M+1) ⁺ step F: 5-amino-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4- Nitrile

A solution of the product from Step E (2.2 g, 8.6 mmol) and EtOAc (2 mL) The resulting solution was concentrated. The residue was diluted with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. in. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.66 (s, 1H), 7.19 - 7.05 (m, ,1H), 7.03 - 6.80 (m, 2H), 6.27 (s, 2H), 3.10 - 2.61 ( m, 5H), 2.16 - 2.02 (m, 1H), 1.93 - 1.76 (m, 1H). MS: M/e 257 (M+1) ⁺ step G: (2S)-2-((5-amino-4-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalene) -2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of step F (1.0 g, 3.9 mmol), (R)-2-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (BL-2, 1.5 g, 4.2 mmol) and Cs ₂ CO ₃ (2.5 g, 7.6 mmol) was stirred in DMF (10 mL) at 70 ° C for 5 h. The mixture was diluted with EA (50 mL), then brine (20 mL x 3), dried, concentrated and purified by using CH ₂ Cl ₂ / MeOH elution was purified (100: 1: 1 to 40) column chromatography, The desired product (1.02 g, 58%) was obtained as a yellow oil. MS: M/e 440 (M+1) ⁺ . Step H: (2S)-2-((5-Amino-4-carbamoyl-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole Tert-butyl ester of -1-ylmethyl)pyrrolidine-1-carboxylate

The product from Step G at room temperature (1.02 g, 2.3 mmol) was added aqueous 5N NaOH (1 mL) and H ₂ O ₂ (1 mL) in a solution (1 mL) in EtOH (20 mL) and DMSO. The mixture was stirred at 50 ° C for 30 minutes. After removal of EtOH, the residue was diluted with EA (500 mL), washed with NaHSO ₃ (10 mL) and brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and then with CH ₂ Cl ₂ / MeOH ( 100:1 ~ 40:1) Purification of the eluted silica gel column chromatography gave the desired product (950 mg, 90%) as a brown oil.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.17 - 7.06 (m, 1H), 6.98 - 6.86 (m, 2H), 6.59 (s, 2H), 6.05 (br.s, 2H), 4.07 - 3.86 (m, 3H), 3.51 - 3.31 (m, 2H), 3.27 - 3.13 (m, 2H), 2.98 - 2.75 (m, 4H), 2.17 - 2.04 (m, 1H), 1.88 - 1.55 (m, 5H) , 1.41 (s, 9H). MS: M/e 458 (M+1) ⁺ . Step I: 5-Amino-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1-((S)-pyrrolidin-2-ylmethyl)-1H- Pyrazole-4-carboxamide

TFA (5 mL) was added to a solution of EtOAc (EtOAc,EtOAc. The mixture was concentrated to give a crude material (yield: 880 mg) as a brown oil. MS: M / e 358 (M + 1) +. Step J: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6-fluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-1H-pyrazole-4-carboxamide

To a solution of product of step I (880 mg, crude) and _{NaHCO 3 (400 mg, 4.76 mmol} ) was added dropwise Bing Xixi chloride mixture (10 mL / 10 mL) in ₂ O MeCN / H in (160 mg , 1.78 mmol) in MeCN (1 mL), then the mixture was stirred for 1 hour. The resulting mixture was extracted with EA (10 mL×3). The combined extracts were washed with brine (20 mL EtOAc EtOAc EtOAc. Recrystallization was carried out in (2:1, 40 mL) to give the desired product (425 mg, 50% over 2 steps) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.13 - 7.04 (m, 1H), 6.91 - 6.80 (m, 2H), 6.54 (br.s, 1H), 6.36 (s, 2H), 6.16 (d, J = 16.4 Hz, 1H), 5.99 (s, 2H), 5.75 - 5.35 (m, 1H), 4.45 - 4.12 (m, 1H), 4.11 - 3.81 (m, 2H), 3.47 (br. s, 2H), 3.39 - 3.26 (m, 1H), 3.01 - 2.75 (m, 4H), 2.18-2.03 (m, 1H), 1.91 - 1.65 (m, 5H). MS: M/e 412 (M+1) ⁺ . Compound 1.10a or 1.10b: ( R or S ) 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6-fluoro-1,2 ,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (R or S) (2S)-2-((5-Amino-4-carbamoyl-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

DMSO (20 mL), aqueous NaOH (5.0 N, 20 mL) and H were added to a stirred solution of the product from Step G (20 g, 46 mmol) in EtOH (200 mL). ₂ O ₂ (20 mL). After the addition, the reaction mixture was stirred at 50 ° C for 30 minutes. The reaction mixture was concentrated to give a residue, which was diluted with EtOAc (500 mL), washed with brine (200 mL x 3), dried Na ₂ SO _4, then concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) And peak 2 (6.35 g). Peak 1: ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.10 (s, 1H), 6.97 - 6.85 (m, 2 H), 6.59 (s, 2H), 6.04 (s, 2H), 4.10-3.80 ( m, 3H), 3.40 - 3.34 (m, 1H), 3.23 - 3.12 (m, 2 H), 3.02 - 2.75 (m, 4H), 2.10 (d, J = 12.0 Hz, 1H), 1.81 - 1.55 (m , 5H), 1.40 (s, 9 H) ppm. Peak 2: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.17 - 7.05 (m, 1H), 6.98 - 6.85 (m, 2H), 6.59 (s, 2H), 6.06 (s, 2H), 4.09 - 3.78 (m, 3H), 3.40 - 3.35 (m, 1H), 3.23 - 3.11 (m, 2H), 3.0 - 2.78 (m, 4H), 2.11 (d, J = 10.6 Hz, 1H), 1.81 - 1.54 ( m, 5H), 1.41 (s, 9H) ppm. MS: M/e 458 (M+1) ⁺

The conditions for palm separation are as follows: Step B: (R or S) 5-amino-1-((S)-pyrrolidin-2-ylmethyl)-3-(6-fluoro-1,2,3,4-tetrahydronaphthalene-2- -1H-pyrazole-4-carboxamide

To a solution of the product of Step A (1.0 mg, 2.2 mmol) in EtOAc (EtOAc)EtOAc. The mixture was concentrated to give a crude material (1 g). MS: M/e 358 (M+1) ⁺ Step C: (R or S) 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3- (6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

Add propylene chloride to the mixture of the product of Step B (1 g, crude product, 2.2 mmol) and NaHCO ₃ (739 mg, 8.8 mmol) in MeCN/H ₂ O (25 mL / 25 mL) at 0 ° C (200 mg, 2.2 mmol) in a solution of MeCN (2 mL), then the mixture was stirred at 0 ° C for 10 min. The mixture was extracted with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. The product (650 mg, 79% over 2 steps) was obtained as a white solid. Peak 1 (compound 1.10a, retention time: 5.219 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.19 - 7.08 (m, J = 8.9 Hz, 1H), 6.99 - 6.85 (m, J = 8.0 Hz, 2H), 6.72 - 6.52 (m, 2H), 6.28 - 5.98 (m, 3H), 5.78 - 5.42 (m, 1H), 4.41 - 4.13 (m, 1H), 4.07 - 3.84 (m, 2H), 3.60 - 3.35 (m, 3H), 3.06 - 2.74 (m, 4H), 2.13 - 2.04 (m, 1H), 1.96 - 1.62 (m, 5H) ppm. Peak 2 (compound 1.10b, retention time: 6.182 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.19 - 7.06 (m, 1H), 6.98 - 6.85 (m, 2H), 6.68 - 6.47 (m , 2H), 6.30 - 6.00 (m, 3H), 5.79 - 5.44 (m, 1H), 4.42 - 4.15 (m, 1H), 4.09 - 3.82 (m, 2H), 3.59 - 3.36 (m, 3H), 3.02 - 2.75 (m, 4H), 2.11 (d, J = 11.2 Hz, 1H), 1.93 - 1.62 (m, 5H) ppm. MS: M/e 412 (M+1) ⁺

The conditions for palm analysis are as follows: Compound 1.11:1-((R)-1-Prodecylacridin-3-yl)-5-amino-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazole-4-carboxamide Step A: (3R)-3-(5-Amino-4-cyano-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-1- Acridine-1-carboxylic acid tert-butyl ester

5-Amino-3-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile (product of step F in the synthesis of compound 1.10, 1.0 g, 4 mmol), (S)-3-(toluenesulfonyloxy)acridine-1-carboxylic acid tert-butyl ester (BL-1, 2.1 g, 6 mmol) and Cs ₂ CO ₃ (2.6 g, 8 The mixture of mmol) in DMF (20 mL) was stirred at 70 ° C for 24 hours. The resulting solution was concentrated. The residue was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. (700 mg), which was used directly in the next step. MS: M/e 440 (M+1) ⁺ step B: (3R)-3-(5-amino-4-carbamoyl-3-(6-fluoro-1,2,3,4-tetrahydro) Naphthalen-2-yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product from Step A at room temperature (700 mg, crude product, 1.6 mmol) in a solution (2 mL) in EtOH (10 mL) is added successively DMSO and aqueous 6N NaOH (2 mL) and H ₂ O _{2 (2} mL). The mixture was stirred at 50 ° C for 30 minutes. The residue was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude product (130 mg, 8% over 2) was obtained as a yellow solid. Step C: 5-Amino-3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1-((R)-acridin-3-yl)-1H-pyrazole -4-carboxamide

To a solution of the product from Step B (130 mg, 0.3 mmol) The solution was stirred at 0 ° C for 0.5 hours. The resulting solution was concentrated to give a crude material (150 mg, 100%). MS: M/e 358 (M+1) ⁺ Step D: 1-((R)-1-propenylindazin-3-yl)-5-amino-3-(6-fluoro-1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

And _{NaHCO 3 (94 mg, 1.4 mmol} ) was added dropwise Bing Xixi chloride in a mixture of CH ₃ CN (10 mL / 10 mL) is / H ₂ O at 0 ℃ the product of step I (150 mg, 0.28 mmol) ( 25 mg, 0.28 mmol). The mixture was stirred at 0 ° C for 10 minutes. The mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc) 35%), which is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.18 - 7.06 (m, 1H), 6.98 - 6.72 (m, 3H), 6.59 (s, 2H), 6.34 - 6.16 (m, 2H), 6.16 - 6.01 (m, 1H), 5.76 - 5.59 (m, 1H), 4.45 - 3.94 (m, 3H), 3.50 - 3.30 (m, 2H), 3.15 - 2.76 (m, 5H), 2.18 - 2.04 (m, 1H) , 1.99 - 1.76 (m, 3H), 1.75 - 1.59 (m, 1H), 1.55 - 1.39 (m, 1H). MS: M/e 412 (M+1) ⁺

Compounds 1.12 and 1.13 were prepared according to the procedure described for compound 1.11 under the appropriate conditions known to those of ordinary skill in the art. Compound 1.12: 1-((R)-1-Prodecylacridin-3-yl)-5-amino-3-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.14 - 7.02 (m, 1H), 6.92 - 6.81 (m, J = 8.4 Hz, 2H), 6.77 - 6.64 (m, 1H), 6.45 - 6.29 (m , 2H), 6.15 - 5.96 (m, 3H), 5.68 - 5.59 (m, 1H), 4.22 - 3.93 (m, 3H), 3.40 - 3.25 (m, 2H), 3.01 - 2.91 (m, 3H), 2.86 - 2.76 (m, 2H), 2.17 - 2.05 (m, 1H), 1.98 - 1.77 (m, 3H), 1.78 - 1.66 (m, 1H), 1.56 - 1.38 (m, 1H). MS: M/e 412 (M+1) ⁺ compound 1.13: 1-((())-propenylpyridylpyrrolidin-2-yl)methyl)-5-amino-3-(7-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.12 - 7.05 (m, 1H), 6.92 - 6.80 (m, 2H), 6.61 - 6.46 (m, 1H), 6.43 - 6.26 (m, 2H), 6.21 - 5.90 (m, 3H), 5.74 - 5.43 (m, 1H), 4.41 - 4.16 (m, 1H), 4.11 - 3.84 (m, 2H), 3.54 - 3.30 (m, 3H), 3.00 - 2.94 (m, 2H), 2.85 - 2.77 (m, 2H), 2.18 - 2.05 (m, 1H), 1.90 - 1.70 (m, 5H). MS: M/e 412 (M + 1) ⁺ Compound 1.14: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: Methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate

To a solution of NaH (6.0 g, 150.68 mmol) in dimethyl carbonate (50 mL) was added 3,4-dihydronaphthalene-1 (2H)-one (10 g, 68.50 mmol) in dimethyl carbonate ( Solution in 25 mL). The mixture was stirred at room temperature for 30 minutes and then at 85 ° C for 2 hours. The reaction mixture changes from a suspension to a solid state. The reaction mixture was quenched with water (100 mL)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 205 (M+1) ⁺ Step B: 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester

A mixture of the product of Step A (13.23 g, 64.78 mmol), HClO ₄ (1 mL) and Pd/C (1.3 g, 0.1 eq.) in HOAc (50 mL) was stirred at room temperature under 4 atmospheres of hydrogen. hour. The mixture suspension was filtered through a pad of celite. The filtrate was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 191 (M+1) ⁺ Step C: 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

A solution of 6N NaOH (10.51 g, 262.83 mmol) was added to a solution of EtOAc (EtOAc). The solution was stirred at room temperature for 2 hours. The resulting solution was neutralized to pH = 6 with 2N aqueous HCl. The title compound was obtained as a white solid, which was taken directly to the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.13 - 7.01 (m, 4H), 2.98 - 2.82 (m, 2H), 2.81 - 2.73 (m, 2H), 2.70 - 2.59 (m, 1H), 2.13 - 2.03 (m, 1H), 1.79 - 1.67 (m, 1H) ppm. MS: M/e 177 (M+1) ⁺ Step D: 2-(hydroxy(1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile

To a solution of the product of Step C (18 g, 102.15 mmol) in DCM (40 mL) The solution was stirred at room temperature for 30 minutes and then concentrated. The residue was diluted in THF (50 mL). Add malononitrile (10.11 g, 153.22 mmol). Cool to 0 ° C and add TEA (29 mL, 204.30 mmol) dropwise. The final solution was stirred at 0 ° C for 1 hour. The resulting solution was washed with water and extracted with EA (50 mL EtOAc). The organic layer was washed with 6N aqueous HCl. The organic layer was separated and concentrated to give a crude material (2. MS: M/e 225 (M+1) ⁺ step E: 2-(methoxy (1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile

A solution of the product of Step D (22.8 g, 101.66 mmol) in trimethoxymethane (40 mL) was stirred at 70 ° C for 4-5 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHH solid. MS: M/e 239 (M+1) ⁺ step F: 5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

A solution of the product from Step E (13 g, 54.56 mmol) and EtOAc (2 mL) The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHH solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.64 (br.s, 1H), 7.09-7.02 (m, 4H), 6.27 (br.s, 2H), 3.03 - 2.90 (m, 3H), 2.88 - 2.79 (m, 2H), 2.15 - 2.04 (m, 1H), 1.86 (s, 1H) ppm. MS: M/e 239 (M+1) ⁺ step G: (2S)-2-((5-amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Product of Step F (200 mg, 0.84 mmol), (S)-2-((Tosylsulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (BL-2, 328 mg, 0.92 mmol A mixture of Cs ₂ CO ₃ (548 mg, 1.68 mmol) in DMF (15 mL) was stirred at 70 ° C for 2 h. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 422 (M+1) ⁺ step H: (2S)-2-((5-amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalene-2) -yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step G (354 mg, 0.84 mmol) solution in EtOH (5 mL) is added successively DMSO (2 mL), aqueous 5N NaOH (2 mL) and _{H 2 O 2 (1 mL)} . The solution was stirred at 60 ° C for 2 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid. MS: M/e 440 (M+1) ⁺ Step I: 5-amino-1-((S)-pyrrolidin-2-ylmethyl)-3-(1,2,3,4-tetrahydronaphthalene -2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step H (254 mg, 0.5 <RTIgt; The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (m. MS: M/e 340 (M + 1) ⁺ Step J: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of step I (196 mg, 0.58 mmol) and _{NaHCO 3 (291 mg, 3.47 mmol} ) was stirred in a mixture (5 mL / 5 mL) in CH ₃ CN / H ₂ O at 0 ℃ 5 minutes. Propylene hydrazine chloride (51 mg, 0.58 mmol) was added dropwise at 0 °C. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHH solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.07-7.05 (m, 4H), 6.66-6.52 (m, 1H), 6.34 (s, 2H), 6.18-6.14 (m,1H), 5.99 (s, 2H), 5.57-5.30 (m, 1H), 4.40-4.22 (m, 1H), 4.06-4.04 (m, 1H), 3.95-3.81 (m, 1H), 3.54-3.40 (m, 2H) ), 3.35-3.25 (m, 1H), 3.02 - 2.71 (m, 4H), 2.20-2.00 (m, 1H), 1.90-1.75 (m, 5H) ppm. MS: M/e 394 (M+1) ⁺ compound 1.14a or 1.14b: ( R or S ) 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5- Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (R or S)(2S)-2-((5-Amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridyl Tert-butyl ester of oxazol-1-ylmethyl)pyrrolidine-1-carboxylate

Add H ₂ O ₂ (2 mL), NaOH aqueous solution (5.0 N, 2 mL), DMSO to a stirred solution of the product of Step G (2.0 g, 4.46 mmol) in EtOH (50 mL). 2 mL). After the addition, the reaction mixture was stirred at 50 ° C for 2 hours. The reaction mixture was concentrated to give EtOAc m. The combined organic layers were washed with brine, dried over Na ₂ SO _4, concentrated, and then purified by column chromatography (petroleum ether / EtOAc = 5: 1: 1 ~ 1) to afford the desired product (2.23 g, 100%), It was a yellow solid which was isolated by palm chromatography to give peak 1 (0.93 g, prior peak) and peak 2 (0.89 g, after peak).

The conditions for palm separation are as follows:

Peak 1: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.58 (s, 2H), 6.04 (s, 2H), 4.57 - 3.80 (m, 4H), 3.17 (s, 2H), 3.03 - 2.75 (m, 4H), 2.12 (d, J = 14.4 Hz, 1H), 1.82-1.58 (m, 5H), 1.40 (s, 9H) ppm.

Peak 2: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.58 (s, 2H), 6.06 (s, 2H), 4.51 - 3.81 (m, 4H), 3.18 (s, 2H), 3.01 - 2.75 (m, 4H), 2.13 (d, J = 11.6 Hz, 1H), 1.81 - 1.53 (m, 5H), 1.41 (s, 9H) ppm. MS: M/e 440.5 (M + 1) ⁺ Step B: (R or S) 5-amino-1-((S)-pyrrolidin-2-ylmethyl)-3-(1,2,3, 4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step A (0.93 g, 2.12 mmol) was added to a _{CH 2 Cl 2 (10 mL)} , then added TFA (2 mL). After the addition, the reaction mixture was stirred overnight. Most of the solvent was removed to give a residue which was basified to pH = 9 - 10 with aqueous NaOH and then extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the desired product (538 mg, 74.8%) as a white solid. MS: M/e 340.5 (M + 1) ⁺ Step C: (R or S) 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3- (1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The NaHCO (267 mg, 3.18 mmol) was added to the product of Step B ₃ (538 mg, 1.59 mmol) was in _{CH 3 CN / H 2 O (} 10 mL / 10 mL) stirred mixture. The mixture was then cooled to 0 ℃, Bing Xixi added dropwise chloro (143.6 mg, 1.59 mmol) solution (3 mL) in the CH ₃ CN. After the addition, the reaction mixture was stirred for 10 minutes. The reaction mixture was extracted with EtOAc (40 mLEtOAc). The combined organic layers were washed with brine, dried over Na ₂ SO _4, and concentrated to give a residue, which was purified by column chromatography (petroleum ether / EtOAc = 3: 1 ~ 100 % EtOAc) to afford the desired product (440 mg, 70.4%), which is a pale yellow solid.

Peak 1 (compound 1.14a, retention time: 4.756 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.74 - 6.44 (m, 2H), 6.28 - 5.97 (m, 4H) ), 5.82 - 5.36 (m, 1H), 4.45 - 4.11 (m, 1H), 4.09 - 3.83 (m, 2H), 3.60 - 3.35 (m, 3H), 3.08 - 2.70 (m, 4H), 2.10 (d , J = 11.2 Hz, 1H), 2.02 - 1.61 (m, 5H) ppm.

Peak 2 (compound 1.14b, retention time: 5.347 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.67 - 6.49 (m, 2H), 6.28 - 5.97 (m, 4H) ), 5.76 - 5.43 (m, 1H), 4.42 - 4.14 (m, 1H), 4.11 - 3.82 (m, 2H), 3.59 - 3.36 (m, 3H), 3.05 - 2.72 (m, 4H), 2.13 (d , J = 12.0 Hz, 1H), 1.95 - 1.64 (m, 5H) ppm. MS: M/e 394.5 (M+1) ⁺

The analysis conditions for palmity are as follows. The palmar synthesis of compound 1.14a: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-((R)-1,2,3, 4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (R)-4-benzyl-3-(3-phenylpropenyl)oxazolidin-2-one

To (R)-4-benzyloxazolidin-2-one (16.7 g, 94.3 mmol), Et ₃ N (19 g, 0.188 mol) and DMAP (1.1 g, 9.43 mmol) in CH ₂ Cl at 0 °C _A solution of 3-phenylpropionyl chloride (17.4 g, 10.3 mmol) in CH ₂ Cl ₂ (50 mL) was added dropwise. After the addition, the reaction mixture was stirred for 2 hours. The reaction mixture was washed with H ₂ O (200 mL), aqueous HCl (2.0 M, 200 mL) , washed with aqueous NaHCO ₃ and brine, then dried Na ₂ SO _4, and concentrated to give a residue, which was treated with THF / hexane (100 mL / 100 mL) wash and filter. The filter cake was collected and dried to give title product (24 g, 82.3%) as white solid. MS: M/e 310 (M+1) ⁺ Step B: (S)-3-benzyl-4-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4 -tert-butyl oxobutanoate

Lithium diisopropylamide (LDA, 2.0 M, 46.6 mL, 93.24 mmol) was added dropwise to a stirred solution of the product from step A (24 g, 77.7 mmol) in anhydrous THF (200 mL). A solution of tert-butyl 2-bromoacetate (16.7 g, 85.4 mmol) in THF (20 mL). After the addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ₄ Cl NH, then extracted with EtOAc (50 mL x 3). The dried organic layers were washed with brine to Na ₂ SO _4, then concentrated to give a residue, which was stirred at -5 ℃ with IPA / hexane (50 mL / 50 mL) for, then filtered. The filter cake was collected to give the title product (16 g, 48.6%) as white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.38 - 7.17 (m, 10H), 4.65 - 4.52 (m, 1H), 4.32 - 4.18 (m, 2H), 4.14 (dd, J = 8.8, 2.4 Hz , 1H), 2.97 (dd, J = 13.2, 4.0 Hz, 2H), 2.89 (dd, J = 13.6, 7.6 Hz, 1H), 2.69 (dd, J = 16.8, 10.8 Hz, 1H), 2.57 (dd, J = 13.2, 9.2 Hz, 1H), 2.25 (dd, J = 16.8, 4.0 Hz, 1H) ppm. MS: M/e 368 (M- t -Bu+1) ⁺ Step C: (S)-3-benzyl-4-((R)-4-benzyl-2-oxooxazolidine-3- 4-oxobutyric acid

The product from Step B (16 g, 37.8 mmol) was added TFA (20 mL) was stirred in CH ₂ Cl ₂ (200 mL) in the. After the addition, the reaction mixture was stirred for 2 days. The reaction mixture was concentrated to give a residue, which was treated with aqueous NH ₄ Cl (50 mL), then extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the desired product (12.9 g, 92.4%), as a white solid. MS: M/e 368 (M+1) ⁺ Step D: (S)-2-benzylsuccinic acid

An aqueous solution of H ₂ O ₂ (30%, 15 mL) and LiOH (2.5 g, 104 mmol) were added dropwise to a stirred solution of the product from step C (12.9 g, 34.96 mmol) in THF (50 mL). ) A solution in H ₂ O (20 mL). After the addition, the reaction mixture was stirred overnight. The reaction mixture was washed with aqueous Na ₂ SO ₃ (50 mL) quenched to remove most of THF, to give aqueous layer was then extracted with EtOAc (50 mL x 3). The aqueous layer was acidified with aq. EtOAc (EtOAc) (EtOAc) (EtOAc) The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the title compound (7 g, 100%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.22 (s, 2H), 7.35 - 7.13 (m, 5H), 2.98 - 2.84 (m, 2H), 2.81 - 2.67 (m, 1H), 2.42 (dd , J = 16.8, 8.8 Hz, 1H), 2.24 (dd, J = 16.8, 4.4 Hz, 1H) ppm. MS: M/e 207 (M-1) ^- Step E: (S)-4-Oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

The product of Step D (7 g, 33.6 mmol) was stirred in a mixture (20 mL) in concentrated H ₂ SO ₄ at 60 ℃ 20 minutes. The reaction mixture was poured into ice water (ice-H ₂ O, 150 mL) and thenEtOAc. The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the title compound (6.3 g, 100%), as a white solid which was used directly in the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.48 (s, 1H), 7.85 (dd, J = 7.6, 1.2 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.37 (dd, J = 16.0 , 8.0 Hz, 2H), 3.28 - 3.12 (m, 3H), 2.79 (d, J = 8.8 Hz, 2H) ppm. MS: M/e 191 (M +1) ⁺ step F: (R)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

The product of Step E (6.3 g, 33.6 mmol) was dissolved in AcOH (40 mL) was added HClO ₄ (0.5 mL) and Pd / C (500 mg). The reaction mixture was stirred under H ₂ (1 atm) overnight. The reaction mixture was filtered, then the filtrate was concentrated to give a residue, which was stirred for half an hour with H ₂ O (50 mL), then filtered. The filter cake was collected and dried to give the title compound (3 g, 50.7%) as white solid. MS: M/e 177 (M+1) ⁺ Step G: (R)-2-(hydroxy(1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile

The product of Step F (3 g, 17 mmol) in a solution of CH ₂ Cl ₂ (30 mL) are successively added HOBT (2.7 g, 20.4 mmol) , Et 3 N (4.4 g, 34 mmol) and EDCI (3.9 g, 20.4 mmol). After stirring for 20 min, malononitrile (1.12 g, 17 mmol) was added. The reaction mixture was then stirred for 2 hours. Washed with brine, the mixture was dried with H ₂ O (30 mL), to Na ₂ SO _4, then concentrated to give a residue, which was dissolved in EtOAc (50 mL), treated with H ₂ SO ₄ aqueous solution (4 M, 40 mL), washed with brine, dried Na ₂ SO _4, then concentrated to give the desired product (3.8 g, 99.7%), as a tan solid. MS: M/e 225 (M+1) ⁺ step H: (R)-2-(methoxy (1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile

A solution of the product of Step G (3.8 g, 16.96 mmol) in trimethoxymethane (20 mL) was stirred at 70 ° C for 4-5 hours. The resulting solution was concentrated. The residue was washed with EtOH / hexane (5 mL / 10 mL) then filtered. The filter cake was collected to give the title product (2.2 g, 54.5%) as white solid. MS: M/e 239 (M+1) ⁺ Step I: (R)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4- Nitrile

A solution of the product of Step H (2.2 g, 9.24 mmol) and EtOAc (2 mL) The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the desired product (2.3 g, 100%), as a white solid. MS: M/e 239 (M+1) ⁺ Step J: (R)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4- Formamide

A mixture of the product of step 1 (1.0 g, EtOAc, m. The reaction mixture was poured into H ₂ O (20 mL), basified with aqueous NaOH to pH = 8 ~ 9, and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine and dried in Na ₂ SO _4, then concentrated to give the desired product (770 mg, 71.6%), as a white solid. MS: M/e 257 (M+1) ⁺ step K: (S)-2-((5-amino-4-carbamoyl-3-((R)-1,2,3,4-four) Hydronaphthalen-2-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Step J The product (100 mg, 0.39 mmol), BL-2 (166 mg, 0.47 mmol) and _{Cs 2 CO 3 (254 mg,} 0.78 mmol) mixture in DMF (5 mL) was stirred at 70 ℃ 24 hours . The resulting solution was poured into H ₂ O (20 mL) and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO _4, concentrated, and then purified by column chromatography (petroleum ether / EtOAc = 4: 1 ~ EtOAc ) to afford the title compound (45 mg, 26%), as a Yellow solid. MS: M/e 440 (M+1) ⁺ step L: 5-amino-1-((S)-pyrrolidin-2-ylmethyl)-3-((R)-1,2,3,4 -tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step K (45 mg, 0.102 mmol) was added TFA (1 mL) was stirred in CH ₂ Cl ₂ (5 mL) in the. After the addition, the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to give a crystal. MS: M/e 340 (M + 1) ⁺ Step M: 1-(((S)-1-propenylpyrrolidino-2-yl)methyl)-5-amino-3-((R)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

Add NaHCO ₃ (17.1 mg, 0.204 mmol), propylene oxime chloride (9.28 mg) to the product of step L (0.102 mmol) in CH ₃ CN/H ₂ O (3 mL / 3 mL). , 0.102 mmol) in CH ₃ CN (1 mL). The reaction mixture was extracted with EtOAc (5 mL EtOAc). The combined organic layers were washed with brine, dried over Na ₂ SO _4, concentrated and then purified by preparative HPLC, to give the desired product (12 mg, 29.7%), which is in the form of TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ + D ₂ O) δ 7.08 (s, 4H), 6.59 (dd, J = 16.8, 10.4 Hz, 1H), 6.26 - 6.12 (m, 1H), 5.79 - 5.40 (m, 1H), 4.43 - 4.14 (m, 1H), 4.08 - 3.86 (m, 2H), 3.49 - 3.31 (m, 3H), 3.05 - 2.73 (m, 4H), 2.10 (d, J = 11.6 Hz , 1H), 1.98 - 1.61 (m, 5H) ppm. MS: M/e 394 (M+1) ⁺ Compound 1.15: 1-((R)-1-propenylindazin-3-yl)-5-amino-3-(1,2,3,4- Tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (3R)-3-(5-Amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazol-1-yl)acridine Tert-butyl 1-carboxylic acid

The product of Step F in the synthesis of compound 1.14 (714 mg, 3 mmol), (S)-3-(toluenesulfonyloxy) acridine-1-carboxylic acid tert-butyl ester (BL-1, 1.6 g, 4.5 A mixture of mmol and Cs ₂ CO ₃ (1.95 g, 6 mmol) in DMF (6 mL) was stirred at 70 ° C for 24 hours. Then another portion of BL-1 (1.6 g, 4.5 mmol) was added and the mixture was heated at 70 °C for 24 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH solid. MS: M/e 422 (M+1) ⁺ step B: (3R)-3-(5-amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalene-2- -1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product of Step A (650 mg, crude) in a solution (5 mL) in EtOH was added sequentially DMSO (2 mL), aqueous 5N NaOH (2 mL) and _{H 2 O 2 (2 mL)} . The solution was stirred at 50 ° C for 2 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate sulfatessssssssssssssssssssssssssssssss It is a yellow solid. MS: M/e 440 (M + 1) ⁺ Step C: 5-amino-1-((R)- azeridin-3-yl)-3-(1,2,3,4-tetrahydronaphthalene-2 -yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step B (300 mg, EtOAc. The solution was stirred at room temperature for 2 hours. The resulting solution was treated with saturated aqueous Na ₂ CO ₃ to pH = 8, and extracted with DCM (30 mL x 2). The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 340 (M+1) ⁺ Step D: 1-((R)-1-propenylindazin-3-yl)-5-amino-3-(1,2,3,4- Tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step C (160 mg, 0.47 mmol) was added saturated aqueous NaHCO ₃ (1 mL) in a mixture (5 mL) in CH ₃ CN in. The resulting solution was cooled to 0 ℃, then added dropwise chloro-Bing Xixi (43 mg, 0.47 mmol) solution (1 mL) in the CH ₃ CN. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then EA (30 mL &lt The combined organic layers were washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.06 - 7.02 (m, 4H), 6.90 - 6.75 (m, 1H), 6.60 (s, 2H), 6.23 (s, 2H), 6.10 - 5.99 (m , 1H), 5.72 - 5.58 (m, 1H), 4.44 - 3.90 (m, 3H), 3.50 - 3.38 (m, 1H), 3.15 - 2.76 (m, 6H), 2.18 - 2.08 (m, 1H), 2.00 - 1.79 (m, 3H), 1.78 - 1.62 (m, 1H), 1.55 - 1.35 (m, 1H) ppm. MS: M/e 394 (M+1) ⁺ compound 1.15a or 1.15b: (R or S) 1-((R)-1-propenyloxaridin-3-yl)-5-amino-3- (1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (R or S) (3R)-3-(5-Amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-1 -yl) acridine-1-carboxylic acid tert-butyl ester

A mixture of the product of Step F (4.7 g, 20 mmol), BL-1 (8.52 g, 24 mmol) and Cs ₂ CO ₃ (13 g, 40 mmol) in DMF (50 mL) Stir at 70 ° C for 80 hours. Two additional portions of BL-1 (2 g, 5.6 mmol) were added during this time period. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHH solid. MS: M/e 422 (M+1) ⁺ Step B: (R or S) (3R)-3-(5-amino-4-carbamoyl-3-(1,2,3,4-tetra Hydronaphthalen-2-yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

The product of Step A (2.1 g, 5 mmol) in a solution (20 mL) in EtOH was added sequentially DMSO (5 mL), aqueous 5N NaOH (5 mL) and _{H 2 O 2 (5 mL)} . The solution was stirred at 50 ° C for 4 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc (40 mL The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH solid. MS: M/e 440 (M+1) ⁺ . The product was isolated by preparative HPLC on palms to give peak 1 and peak 2.

The conditions for palm separation are as follows: Step C: (R or S) 5-amino-1-((R)-acridin-3-yl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridin Oxazol-4-carboxamide

To a solution of the product from EtOAc (EtOAc (EtOAc). The solution was stirred at room temperature overnight. The resulting solution was concentrated to give a crude material which was used directly in the next step. MS: M/e 340 (M+1) ⁺ Step D: (R or S) 1-((R)-1-propenyl acridine-3-yl)-5-amino-3-(1,2 ,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step C and the mixture (3 mL) is added ₂ O H _{NaHCO 3 (1 g, 12 mmol} ) in CH ₃ CN (15 mL). The resulting solution was cooled to 0 ℃, Bing Xixi then added dropwise chloro (300 mg, 1.86 mmol) solution (2 mL) in the CH ₃ CN. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (30 <RTIgt; The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. Most of the CH ₃ CN in the resulting solution was removed by concentration. The resulting solution was treated to pH 8 with saturated NaHCO ₃ solution and extracted with DCM (50 mL x 3). The combined organic layers were washed with EtOAc EtOAc EtOAc.

Peak 1 (compound 1.15a, retention time: 5.85 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.12 - 7.04 (m, 4H), 6.90 - 6.71 (m, 1H), 6.59 (s, 2H ), 6.22 (s, 2H), 6.15 - 6.02 (m, 1H), 5.75 - 5.58 (m, 1H), 4.44 - 3.94 (m, 3H), 3.50 - 3.38 (m, 1H), 3.15 - 2.75 (m , 6H), 2.16 - 2.08 (m, 1H), 2.00 - 1.79 (m, 3H), 1.78 - 1.62 (m, 1H), 1.55 - 1.35 (m, 1H) ppm. MS: M/e 394 (M+1) ⁺

Peak 2 (compound 1.15b, retention time: 6.944 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.12 - 7.04 (m, 4H), 6.90 - 6.71 (m, 1H), 6.58 (s, 2H ), 6.21 (s, 2H), 6.15 - 6.02 (m, 1H), 5.75 - 5.58 (m, 1H), 4.45 - 3.94 (m, 3H), 3.50 - 3.36 (m, 1H), 3.15 - 2.75 (m , 6H), 2.18 - 2.06 (m, 1H), 2.00 - 1.80 (m, 3H), 1.76 - 1.62 (m, 1H), 1.55 - 1.35 (m, 1H) ppm. MS: M/e 394 (M+1) ⁺

The analysis conditions for palmity are as follows.

Compound 1.15a is prepared in accordance with the procedures described for the palm-forming synthetic compound 1.14a under suitable conditions known to those of ordinary skill in the art. Compound 1.15a: 1-((R)-1-Prodecylacridin-3-yl)-5-amino-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl )-1H-pyrazole-4-carbamide, in the form of CF ₃ COOH salt

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.93-6.70 (m, 1H), 6.59 (s, 2H), 6.38-5.97 (m, 2H), 5.66 (dd, J =28.8, 10.4 Hz, 1H), 4.48-3.91 (m, 3H), 3.60-3.48 (m, 1H), 3.15-2.75 (m, 6H), 2.22-2.06 (m, 1H), 2.05-1.79 (m , 3H), 1.68 (s, 1H), 1.45 (s, 1H) ppm. MS: M/e 394 (M+1) ⁺

Compounds 1.16 to 1.17 are prepared according to the procedures described for compound 1.15 under the appropriate conditions known to those of ordinary skill in the art. Compound 1.16: 1-((R)-1-propenylpyrrolidin-3-yl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridyl Oxazol-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.06 - 7.02 (m, 4H), 6.54 - 6.20 (m, 3H), 6.12 - 6.07 (m, 1H), 5.25 - 5.15 (m, 2H ), 5.62 (d, J = 9.6 Hz, 1H), 4.87 - 4.80 (m, 1H), 3.95 - 3.29 (m, 5H), 3.01 - 2.65 (m, 4H), 2.35 - 2.05 (m, 3H), 1.80 - 1.69 (m, 1H) ppm. MS: M/e 380 (M+1) ⁺ compound 1.17: 1-((S)-1-propenylindazin-3-yl)-5-amino-3-(1,2,3,4- Tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.06 - 7.02 (m, 4H), 6.80 - 6.65 (m, 1H), 6.34 (s, 2H), 6.10 - 5.97 (m, 1H), 5.68 - 5.57 (m, 1H), 4.30 - 3.90 (m, 3H), 3.38 - 3.28 (m, 1H), 3.06 - 2.75 (m, 6H), 2.18 - 2.06 (m, 1H), 2.00 - 1.65 (m , 4H), 1.56 - 1.40 (m, 1H) ppm. MS: M/e 394 (M+1) ⁺ compound 1.18: 1-(2-propenylaminobenzyl)-5-amino-3-(chroman-3-yl)-1H-pyrazole-4-methyl Guanamine Step A: 4-oxochroman-3-carboxylic acid ethyl ester and 4-hydroxy-2H-chromene-3-carboxylic acid ethyl ester

To a solution of chroman-4-one (8.8 g, 60 mmol) in dry THF (200 mL) EtOAc (EtOAc) After stirring for 40 min, ethyl cyanoformate (4.5 g, 90 mmol) was added, and then the mixture was stirred from -78 ° C to room temperature for 2 hr. Saturated NH ₄ Cl solution (200 mL), and extracted with EA (200 mL × 3), the organic layers were combined, dried over Na ₂ SO _4, the solvent was evaporated, and the residue was purified by column chromatography (PE / EA = 100: 5 Purification afforded 9.0 g of ethyl 4-oxochroman-3-carboxylate in a yield of 68% as a mixture of tautomers. Step B: Color full of 3-carboxylic acid

Solution of 4-oxo-chroman-3-carboxylate (7.7g, 35 mmol), and HClO ₄ (2 mL) was added Pd / C (770 mg) in AcOH (40 mL), and the resulting mixture was Stir at room temperature under H ₂ (0.4 MPa) for 6 hours. The Pd/C was removed by filtration, and the filtrate was evaporated, washed with water and brine (100 mL? It was then hydrolyzed with a solution of LiOH (1.5 g, 36 mmol) in THF / H2O / MeOH (30 mL / 30 mL / 30 mL), stirred at room temperature for 1 hour, then evaporated solvent and water was added to the residue. (20 mL), EtOAc (EtOAc) (EtOAc) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.00-7.06 (m, 2 H), 6.80 (t, J = 7.6 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 4.35 ( Dd, J = 10.8 Hz, 1.6 Hz, 1H), 4.08-4.13 (m, 1 H), 2.94-3.01 (m, 3 H). MS (ESI) m/e [M-1] + 177. Step C: 2-(chroman-3-yl(hydroxy)methylene)malononitrile

The full-color 3-carboxylic acid (1.5 g, 8.4 mmol) was added _{Et 3 N (1.02 g, 10.1} mmol), HOBt (1.37 g, 10.1 mmol), EDCI (1.935 g solution (75 mL) in AcOEt and 10.1 mmol), the mixture was stirred at rt for 0.5 h then EtOAc (EtOAc &lt Water (100 mL) was added, the organic layer was separated, then washed with brine and dried over Na ₂ SO ₄ . Removed by filtration Na ₂ SO _4, the solvent was evaporated, the residue was dissolved in AcOEt (100 mL) was added _{H 2 SO 4 (1 N,} 20 mL), and the mixture was stirred for 0.5 h, then the organic layer was separated, the solvent was evaporated, The crude product was obtained which was used in the next step without further purification. MS (ESI) m/e [M+1] + 227.0. Step D: 5-Amino-3-(chroman-3-yl)-1 H -pyrazole-4-carbonitrile

A solution of the crude 2-(chroman-3-yl(hydroxy)methylene)malononitrile (8.4 mmol) in trimethoxymethane (50 mL) was evaporated. The solvent was then evaporated, the residue was taken from EtOAc EtOAc EtOAc. The solvent was then evaporated and the residue was used in the next step without further purification. MS (ESI) m/e [M+1] + 241.0. Step E: 5-Amino-3-(chroman-3-yl)-1 H -pyrazole-4-carboxamide

The crude 5-amino-3- (chroman-3-yl) lH-pyrazole-4-carbonitrile (8.4 mmol) was heated at 130 ℃ in a solution of concentrated _{H 3 PO 4 (20 mL)} 20 minute. The mixture was then cooled to room temperature, with vigorous stirring dropwise to water (40 mL), followed by ₃ to 7-8 and extracted with EA (20 mL × 3) with NaHCO pH was adjusted, and the organic layers were combined, washed with brine ( 50 mL × 2) washed, dried over Na ₂ SO _4, filtered to remove Na ₂ SO _4, then the filtrate was evaporated to give 550 mg crude product, which was used without further purification in the next step. MS (ESI) m/e [M+1] + 259.0. Step F: 5-Amino-3-(chroman-3-yl)-1-(2-nitrobenzyl)-1 H -pyrazole-4-carboxamide

5-Amino-3-(chroman-3-yl)-1H-pyrazole-4-carboxamide (380 mg, 1.47 mmol) and 1-(bromomethyl)-2-nitrobenzene (382 mg) , 1.77 mmol) The mixture in DMF (10 mL) was stirred at room temperature for 1 hour. Water (50 mL) and NaCl (solid) were added to the mixture, and the brown precipitate was collected by filtration. The filter cake was washed with H ₂ O and then dried in vacuo. In the next step. MS (ESI) m / e [M+1] + 393.9 Step G: 5-amino-1-(2-aminobenzyl)-3-(chroman-3-yl)-1 H -pyrazole-4- Formamide

To a crude 5-amino-3-(chroman-3-yl)-1-(2-nitrobenzyl)-1 H -pyrazole-4-carboxamide (1.0 mmol) in MeOH at rt (50 mL) was added Pd / C (100 mg), then stirred under H ₂ balloon overnight. The Pd/C was removed by filtration and the solvent was evaporated. MS (ESI) m/e [M+1] ⁺ 364.0. Step H: 1-(2-Acrylaminobenzyl)-5-amino-3-(chroman-3-yl)-1 H -pyrazole-4-carboxamide

To 5-amino-1-(2-aminobenzyl)-3-(chroman-3-yl)-1 H -pyrazole-4-carboxamide (135 mg, 0.37 mmol) in CH ₃ at 0 ° NaHCO ₃ (62 mg, 0.74 mmol) and propylene sulfonium chloride (34 mg, 0.37 mmol) were successively added to a solution of CH (10 mL) and H ₂ O (2 mL), and the mixture was stirred for 15 minutes. Purification by preparative HPLC gave the product (29 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.01 (s, 1 H), 7.63 (d J = 7.6 Hz, 1H,), 7.29 (t, J = 7.6 Hz, 1H), 7.05-7.13 (m , 3 H), 6.94 (d, J = 7.2 Hz, 1H), 6.76-6.84 (m, 4 H). 6.49-6.56 (m, 1H), 6.29 (t, J = 8.0 Hz, 2 H), 5.79 (d, J = 10.8 Hz, 1H), 5.13 (s, 2 H), 4.41 (dd, J = 10.4, 2.4 Hz, 1H), 3.90 (t, J = 10.4 Hz, 1H), 3.68-3.76 (m , 1 H), 2.99 (d, J = 8.0 Hz, 2H). MS (ESI) m/e [M+1] ⁺ 417.9. Compound 1.19: 1-((R)-1-Prodecylacridin-3-yl)-5-amino-3-(chroman-3-yl)-1H-pyrazole-4-carboxamide Step A: (3 R )-3-(5-Amino-4-carbamoyl-3-(chroman-3-yl)-1 H -pyrazol-1-yl)acridine-1-carboxylic acid Butyl ester

(5-Amino-3-(chroman-3-yl)-1H-pyrazole-4-carboxamide (product of step E in the synthesis of compound 1.18, 0.50 g, 1.93 mmol), ( S )-3 a mixture of -(toluenesulfonyloxy) acridine-1-carboxylic acid tert-butyl ester (BL-1, 0.897 g, 2.52 mmol), cesium carbonate (0.943 g, 2.90 mmol), DMF (10 mL) at 70 After stirring for 16 hours at ° C, cooling. Add ( S )-3-(toluenesulfonyloxy) acridine-1-carboxylic acid tert-butyl ester (0.897 g, 2.52 mmol), cesium carbonate (0.943 g, 2.90 mmol), then Heat to 70 ° C and hold for 4 hours, cool. Add ethyl acetate (100 mL), another batch with the same procedure and similar procedures (5-amino-3-(chroman-3-yl)-1 H - pyrazole-4-acyl-amine (0.107 g, 0.416 mmol)) were combined and filtered. the filtrate was washed with water (10 mL), dried with brine (20 mL x2) to Na ₂ SO _4, then concentrated and purified by silica gel chromatography ( silica gel: 30 g, ethyl acetate: petroleum ether = 2: 3, then dichloromethane: methanol = 40: 1) to obtain (3 R) -3- (5- amino-4-carbamoyl acyl -3-(chroman-3-yl)-1 H -pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester (0.238 g, 28%) as a brown solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.05-7.12 (m, 2H), 6.73-6.85 (m, 4H), 6.20-6.21 (m, 2H), 4.39-4.42 (m, 1H), 3.62 -4.04 (m, 5H), 3.34-3.40 (m, 1H), 2.97-3.01 (m, 3H), 2.75-2.85 (m, 1H), 1.79-1.91 (m, 3H), 1.39 (s, 9H) . MS (ESI) m/e [M+1] ⁺ 442. Step B: 5-Amino-3-(chroman-3-yl)-1-(( R )-acridin-3-yl)-1 H -pyrazole-4-carboxamide

( 3R )-3-(5-Amino-4-carbamoyl-3-(chroman-3-yl)-1 H -pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester (0.238 g, 0.54 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI><RTIID=0.0> 3-yl)-1-(( R )-acridin-3-yl)-1 H -pyrazole-4-carboxamide, in the form of a trifluoroacetate salt, as a brown semi-solid (0.452 g, 417 %, crude product, 0.54 mmol). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.74-8.75 (m, 2H), 8.47-8.50 (m, 1H), 8.31-8.32 (m, 1H), 7.09-7.13 (m, 2H), 6.77 -6.84 (m, 4H), 4.36-4.39 (m, 2H), 4.04-4.06 (m, 1H), 3.69-3.73 (m, 1H), 3.32-3.37 (m, 2H), 2.89-3.10 (m, 4H), 1.65-1.91 (m, 4H). MS (ESI) m/e [M+1] ⁺ 342. Step C: 1-(( R )-1-Prodecyl acridine-3-yl)-5-amino-3-(chroman-3-yl)-1 H -pyrazole-4-carboxamide

5-Amino-3-(chroman-3-yl)-1-(( R )-acridin-3-yl)-1 H -pyrazole-4-carboxamide (0.452 g, crude product, 0.54 mmol), acetonitrile (3 mL), water (1.5 mL), NaHCO ₃ (solid, 0.36 g, 4.31 mmol) was cooled to 0 ℃, Bing Xixi chloride solution (73 mg, 0.81 mmol) was added. The reaction mixture was stirred at EtOAc (3 mL)EtOAc. The organic phase was separated, washed with brine (10 mL×2), dried over Na ₂ SO ₄ and then concentrated and passed to preparative HPLC ( instrument: gilson-281; column: 21.2×150×5uM, gemini-new; flow rate: 20ML/MIN; UV: 254 nm; Method: 0.1% FA/water and CH ₃ CN, CH ₃ CN from 35 to 45 in 11 minutes, then from 45 to 90 in 3 minutes, for 3 minutes at 90, then Equilibrate for 2 minutes. Total execution time is 20 minutes. Purify by single gradient method to give 1-(( R )-1-propenyl acridine-3-yl)-5-amino-3-(chroman-3 -yl)-1 H -pyrazole-4-carboxamide (61 mg, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.03-7.09 (m, 2H), 6.68-6.83 (m, 3H), 6.49 (s, 2H), 6.01-6.06 (m, 3H), 5.60-5.63 (m, 1H), 4.38-4.41 (m, 1H), 3.87-4.16 (m, 4H), 3.62-3.64 (m, 1H), 2.97-3.02 (m, 4H), 1.84-1.97 (m , 3H), 1.47-1.50 (m, 1H). MS (ESI) m/e [M+1] ⁺ 396. Compound 1.20: 1-(2-Acrylaminobenzyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: 5-Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

5-Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile (product of Step F in Compound 1.14, 1.5 g, 6.3 mmol) The mixture in methanesulfonic acid (5 mL) was stirred at 110 ° C for 1 h, then poured into ice-water and the mixture was neutralized to pH 7-8 with K ₂ CO ₃ . The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried Na ₂ SO _4, and concentrated in vacuo to give the desired product (1.2 g, 75%), as a yellow solid, which was used without further purification by In the next step. MS (ESI) m / e [M+1] ⁺ 257.0 Step B: 5-amino-1-(2-nitrobenzyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl )-1H-pyrazole-4-carboxamide

5-Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (1.2 g, 4.68 mmol), 1-(bromomethyl) The reaction mixture of -2-nitrobenzene (1.01 g, 4.68 mmol) and K ₂ CO ₃ (1.3 g, 9.36 mmol) in DMF (10 mL) was stirred at room temperature for 16 h then poured into water then Extract with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc MS (ESI) m / e [M+1] ⁺ 392 Step C: 5-amino-1-(2-aminobenzyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazole-4-carboxamide

5-Amino-1-(2-nitrobenzyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (1 g, The reaction mixture of 2.55 mmol), Fe powder (0.86 g, 15.3 mmol), MH ₄ Cl (95 mg, 1.785 mmol) in EtOH (45 mL) and H ₂ O (15 mL) was stirred at 80 ° C for 3 h then It was poured into water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS (ESI) m / e [M+1] ⁺ 362.0 Step D: 1-(2-propenylaminobenzyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalene-2- -1H-pyrazole-4-carboxamide

To 5-amino-1-(2-aminobenzyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (0.41 g, 1.13 _{mmol), NaHCO 3 (0.19 g} , 2.26 mmol) was added Bing Xixi chloride CH ₃ CN (18 mL) and a mixture of H ₂ O (4 mL) in the (0.113 g, 1.25 mmol) in CH ₃ CN (2 mL The solution was then stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between water and DCM. The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) ¹ H NMR (DMSO- d ₆ ) δ 10.20 (s, 1H), 7.70 (d, 1H, J = 8 Hz), 7.30 (t, 1H, J = 7.6 Hz), 7.13 (t, 1H, J = 7.6 Hz), 7.07 (s, 5H), 6.66 (s, 2H), 6.54-6.47 (dd, 1H, J = 10.4 Hz), 6.35 (s, 2H), 6.28-6.32 (dd, 1H, J =1.6 Hz ), 5.77-5.80 (dd, 1H, J = 1.6 Hz), 5.13 (s, 2H), 3.42 (m, 1H), 2.77-3.04 (m, 4H), 2.13-2.16 (m, 1H) and 1.69- 1.73 (m, 1H). MS (ESI) m/e [M+1] ⁺ 416. The separation conditions were as follows: Instrument: Gilson-281, column size: 21.2 x 150 5 μm Gemini-new, flow rate: 20 mL/min, UV: 214 nm. Method: 0.1% TFA/water, CH ₃ CN was from 42 to 50 in 11 minutes, then from 50 to 90 in 3 minutes, held at 90 for 3 minutes, and then equilibrated for 2 minutes. Total execution time: 20 minutes. Single gradient method.

Compound 1.20 was separated into two enantiomeric stereoisomers 1.20a (peak 1, R or S, prior peak, retention time in palmarity analysis was 6.59 minutes) by palm preparative HPLC. And compound 1.20b (peak 2, S or R, in the post-peak, retention time in the palmity analysis was 10.46 minutes).

The conditions for palm separation are as follows.

The analysis conditions for palmity are as follows. Compound 1.21:1-(3-Propylaminophenyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: 5-Amino-1-(3-nitrophenyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

To 2-(methoxy(1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile (product of step E in the synthesis of compound 1.14, 10 g, 42 mmol) in EtOH (50 ml) was added (3-nitrophenyl) hydrazine hydrochloride (9.6 g, 50.4 mmol) and _{Et 3 N (13 g, 126} mmol). The mixture was stirred at 90 ° C for 6 hours under N ₂ . After cooling to room temperature, the solvent was removed in vacuo. It was then dissolved in H ₂ O (50 ml) and extracted with EtOAc (50 ml × 3), dried over Na ₂ SO _4, filtered, and concentrated to give the crude product by using EtOAc: PE: Et ₃ N = The 1:4: 0.001 eluted silica gel column (200 g) was further purified to give the product (2.8 g, 19%) as a brown solid. MS (ESI) m/e [M+1] ⁺ 360. Step B: 5-Amino-1-(3-nitrophenyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

5-Amino-1-(3-nitrophenyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile (2.8 g, 7.8 mmol) 85 ℃ was stirred under N ₂ in solution in ₃ H (50 ml) MeSO 40 minutes. LC/MS showed the reaction was completed. The mixture was then poured into ice-water, basified with NaOH to pH = 10 then extracted with EtOAc (100 mL The organic layer was dried over Na ₂ SO _4, filtered, and concentrated to give the product (2 g, 69%), as a brown oil, which was used without further purification in the next step. MS (ESI) m/e [M+1] ⁺ 378. Step C: 5-Amino-1-(3-aminophenyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To 5-amino-1-(3-nitrophenyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (2 g, 5.3 mmol) Iron powder (1.5 g, 26.5 mmol) and NH ₄ Cl (843 mg, 15.9 mmol) were added to a solution of EtOH (50 ml) and H ₂ O (10 ml). The mixture was stirred at 90 ° C for 1 hour. The solid was filtered and the filtrate was concentrated to give a crude material. H ₂ O (50 ml) was added to EtOAc (EtOAc m. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated to give the crude product (1.5 g, 83%), as a brown solid, which was used without further purification in the next step. MS (ESI) m/e [M+1] ⁺ 348. Step D: 1-(3-Propylaminophenyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To 5-amino-1-(3-aminophenyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide at 0 ° C (1.5 g, 4.3 mmol) added NaHCO (5 ml) was ₂ O in CH ₃ CN (20 ml) and _{H 3 (1.1 g, 12.9 mmol} ) Bingxi Xi and chloride (391 mg, 4.3 mmol). The mixture was stirred at 0&lt;0&gt;C for 10 min then EtOAc (EtOAc) The organic layer was dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified further by preparative HPLC, to give the product (781.02 mg, 45%), as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 7.87-7.79 (m, 1H), 7.69-7.73 (m, 1H), 7.43-7.48 (m, 1H), 7.24- 7.28 (m, 1H), 7.06-7.12 (m, 3H), 6.79 (s, 2H), 6.26-6.49 (m, 4H), 5.77-5.81 (m, 1H), 3.43-3.49 (m, 1H), 2.81-3.08 (m, 4H), 2.20-2.24 (m, 1H) and 1.73-1.78 (m, 1H). MS (ESI) m/e [M+1] ⁺ 402. Compound 1.22: 1-(((R)-4-Prodecylmorpholin-2-yl)methyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazole-4-carboxamide Step A: 5-Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

A solution of the product from Step F (2.3 g, 8.8 mmol) in M.sub. The resulting solution was poured into water, neutralized with aq. 5N NaOH to pH = 8 and then extracted with EA (50 mL x 3). The combined organic layers were washed with EtOAc EtOAc m. The solid was recrystallized from EtOAc (EtOAc:EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.60 (br.s, 1H), 7.27 - 6.97 (m, 4H), 6.71 (br.s, 2H), 5.48 (br.s, 2H), 3.450 -3.40 (m, 1H), 3.13-2.70 (m, 4H), 2.15-2.00 (m, 1H), 1.90-1.70 (m, 1H) ppm. MS: M/e 257 (M+1) ⁺ Step B: (R)-2-((Toluenesulfonyloxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

(R)-2-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (2.0 g, 9.21 mmol), DMAP (114 mg, 0.92 mmol), toluenesulfonyl chloride (TsCl, 1.93 g, 10.13 mmol ) and _{Et 3 N (2.65 mL, 18.42} mmol) was stirred at room temperature in a mixture (20 mL) in DCM 2 hours. The resulting solution was washed with water and extracted with DCM (10 mL x 3). The combined organic layers were washed with EtOAc EtOAc EtOAc m. solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.10 - 3.94 (m, 2H), 3.94 - 3.72 (m, 3H), 3.65-3.55 (m, 1H), 3.53 - 3.38 (m, 1H), 3.01 - 2.80 (m, 1H), 2.69-2.61 (m , 1H), 2.45 (s, 3H), 1.45 (s, 9H) ppm. MS: M/e 372 (M+1) ⁺ step C: (2R)-2-((5-amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalene-2) -yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester

A mixture of the product of Step A (200 mg, 0.78 mmol), product from step B (348 mg, 0.94 mmol) and Cs ₂ CO ₃ (509 mg, 1.56 mmol) in DMF (10 mL) was stirred at 70 ° C 4 hour. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 456 (M+1) ⁺ Step D: 5-amino-1-((R)-morpholin-2-ylmethyl)-3-(1,2,3,4-tetrahydronaphthalene -2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from EtOAc (EtOAc, EtOAc. The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (yield: 171 mg, 100%) as a yellow oil. MS: M/e 356 (M + 1) ⁺ Step E: 1-(((())-propenyl phenyl morpholin-2-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step D (171 mg, 0.48 mmol) and _{NaHCO 3 (242 mg, 32.88 mmol} ) / H mixture (4 mL / 4 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (43 mg, 0.48 mmol) was added dropwise at 0 °C. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHH solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.10-7.00 (m, 4H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.37 (s, 2H), 6.07 (dd, J = 16.8, 2.0 Hz, 1H), 5.94 (br.s, 2H), 5.64 (dd, J = 10.6, 2.0 Hz, 1H), 4.20-3.85 (m, 5H), 3.75-3.65 (m, 1H) , 3.48 - 3.27 (m, 2H), 3.04 - 2.71 (m, 6H), 2.20-2.05 (m, 1H), 1.81-1.75 (m, 1H) ppm. MS: M/e 410 (M+1) ⁺

Compounds 1.23 to 1.31 are prepared according to the procedures described for compound 1.22 under the appropriate conditions known to those of ordinary skill in the art. Compound 1.23: 1-(((S)-4-Prodecylmorpholin-2-yl)methyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl) -1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.12 - 6.99 (m, 4H), 6.66 (dd, J = 16.8, 10.6 Hz, 1H), 6.37 (s, 2H), 6.07 (dd, J = 16.8, 2.2 Hz, 1H), 5.93 (s, 2H), 5.64 (dd, J = 10.6, 2.2 Hz, 1H), 4.22 - 3.80 (m, 5H), 3.77 - 3.64 (m, 1H), 3.47 - 3.29 (m, 2H), 3.01 - 2.70 (m, 6H), 2.20 - 2.07 (m, 1H), 1.85 - 1.68 (m, 1H) ppm. MS: M/e 410 (M+1) ⁺ compound 1.24: 1-(((S)-1-propenylazetidin-2-yl)methyl)-5-amino-3-(1, 2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.15 - 6.93 (m, 4H), 6.37 (s, 2H), 6.17 - 5.79 (m, 4H), 5.69 - 5.41 (m, 1H), 4.81 - 4.52 (m, 1H), 4.37 - 4.12 (m, 2H), 4.05 - 3.69 (m, 2H), 3.47 - 3.24 (m, 1H), 3.02 - 2.70 (m, 4H), 2.41 - 2.21 (m , 1H), 2.19 - 1.95 (m, 2H), 1.87 - 1.64 (m, 1H) ppm. MS: M/e 380 (M+1) ⁺ compound 1.25: 1-(((R)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.17 - 6.93 (m, 4H), 6.66 - 6.42 (m, 1H), 6.35 (s, 2H), 6.16 (d, J = 17.2 Hz, 1H), 5.99 (s, 2H), 5.78 - 5.35 (m, 1H), 4.48 - 4.14 (m, 1H), 4.14 - 3.97 (m, 1H), 3.99 - 3.78 (m, 1H), 3.64 - 3.24 ( m, 3H), 3.04 - 2.71 (m, 4H), 2.23 - 2.02 (m, 1H), 1.98 - 1.64 (m, 5H) ppm. MS: M/e 394 (M+1) ⁺ Compound 1.26: 1-(((S)-1-propenylpyrrolidin-3-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.18 - 6.93 (m, 4H), 6.60 - 6.40 (m, 1H), 6.34 (s, 2H), 6.08-6.03 (m, 3H), 5.62 (d, J = 10.0 Hz, 1H), 3.95 - 3.79 (m, 2H), 3.67 - 3.08 (m, 5H), 3.04 - 2.52 (m, 5H), 2.21 - 2.05 (m, 1H), 2.01 - 1.40 (m, 3H) ppm. MS: M/e 394 (M+1) ⁺ Compound 1.27: 1-(((R)-1-propenylpyrrolidin-3-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.18 - 6.93 (m, 4H), 6.60 - 6.40 (m, 1H), 6.34 (s, 2H), 6.10-6.03 (s, 2H), 5.60 (d, J = 10.0 Hz, 1H), 3.95 - 3.74 (m, 2H), 3.67 - 3.08 (m, 5H), 3.04 - 2.50 (m, 5H), 2.28 - 2.05 (m, 1H), 2.01 - 1.50 (m, 3H) ppm. MS: M/e 394 (M+1) ⁺ Compound 1.28: 1-((1-propenylhydrazinoazin-3-yl)methyl)-5-amino-3-(1,2,3, 4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.15 - 6.98 (m, 4H), 6.35 (s, 2H), 6.29 - 6.16 (m, 1H), 6.13 - 5.97 (m, 3H), 5.60 (d , J = 10.4 Hz, 1H), 4.31 - 3.63 (m, 6H), 3.42 - 3.27 (m, 1H), 3.05 - 2.68 (m, 5H), 2.17 - 2.03 (m, 1H), 1.86 - 1.67 (m , 1H) ppm. MS: M/e 380 (M+1) ⁺ compound 1.29: 1-(1-propenylfluorenylazetidin-3-yl)-5-amino-3-(1,2,3,4-tetrahydrol Naphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.20 - 6.99 (m, 4H), 6.72 (s, 2H), 6.47 - 6.31 (m, 1H), 6.26 (s, 2H), 6.13 (d, J = 16.8 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 5.25 - 5.06 (m, 1H), 4.59-4.55 (m, 1H), 4.50-4.40 (m, 1H), 4.37 - 4.12 ( m, 2H), 3.50 - 3.35 (m, 1H), 3.11 - 2.68 (m, 4H), 2.25 - 2.07 (m, 1H), 1.86 - 1.62 (m, 1H) ppm. MS: M/e 366 (M+1) ⁺ Compound 1.30: 1-(((R)-1-propenylindazin-3-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.85 - 6.51 (m, 3H), 6.20 (s, 2H), 6.10 - 5.98 (m, 1H), 5.60 (dd, J = 27.6, 10.0 Hz, 1H), 4.29 - 4.02 (m, 1H), 3.95 - 3.72 (m, 3H), 3.47 - 3.35 (m, 2H), 3.04 - 2.73 (m, 5H), 2.13 (d, J = 11.8 Hz, 1H), 2.00 - 1.59 (m, 4H), 1.40 - 1.08 (m, 2H) ppm. MS: M/e 408 (M+1) ⁺ compound 1.31:1-(((S)-1-propenyl acridine-3-yl)methyl)-5-amino-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.89 - 6.47 (m, 3H), 6.20 (s, 2H), 6.03 (d, J = 16.4 Hz, 1H), 5.60 ( Dd, J = 27.6, 10.8 Hz, 1H), 4.30 - 4.02 (m, 1H), 3.95 - 3.68 (m, 3H), 3.45 - 3.34 (m, 2H), 3.06 - 2.72 (m, 5 H), 2.17 -2.07 (m, 1H), 1.99 - 1.56 (m, 4H), 1.39 - 1.08 (m, 2H) ppm. MS: M/e 408 (M+1) ⁺ Compound 1.32: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3- -yl)-1H-pyrazole-4-carboxamide

Compound 1.32 was prepared according to the procedure described for compound 1.19 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.05-7.08 (m, 2H), 6.74-6.83 (m, 2H), 6.48-6.50 (m, 3H), 5.96-6.18 (m, 3H ), 5.48-5.68 (m, 1H), 4.37-4.41 (m, 1H), 3.90-4.21 (m, 4H), 3.47-3.66 (m, 3H), 2.98-3.02 (m, 2H), 1.81-1.82 (m, 4H). MS (ESI) m/e [M+1] ⁺ 396. Compound 1.33: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(8-chloro-1,2,3,4-tetrahydronaphthalene- 2-yl)-1H-pyrazole-4-carboxamide

Compound 1.33 was prepared according to the procedure described for compound 1.10 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.19-7.21 (dd, J = 2.0 Hz, 1H), 7.05-7.12 (m, 2H), 6.25-6.61 (m, 3H), 6.07- 6.14(m, 1H), 5.99 (s, 2H), 5.44-5.67 (m, 1H), 4.16-4.36 (m, 1H), 3.85-4.08 (m, 2H), 3.31-3.47 (m, 3H), 2.97-3.05 (m, 2H), 2.85-2.90 (m, 1H), 2.75-2.80 (m, 1H), 2.17-2.20 (m, 1H), 1.74-1.86 (m, 5H). MS (ESI) m/e [M+1] ⁺ 428.

Compound 1.33 was separated into two enantiomeric stereoisomers 1.33a (peak 1, R or S, prior peak, retention time in palmarity analysis 4.68 minutes) by palm preparative HPLC. Compound 1.33b (peak 2, S or R, in the post-peak, retention time in the palmity analysis was 5.30 minutes).

The separation conditions are as follows:

The analysis conditions for palmity are as follows.

Compounds 1.34 to 1.36 were prepared according to the procedures described for compound 1.7 under appropriate conditions known to those of ordinary skill in the art. Compound 1.34

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.90 (br.s, 2H), 6.83 - 6.76 (m, 1H), 6.64 - 6.48 (m, 4H), 6.30– 6.16 (m, 2H), 5.75 - 5.71 (m, 1H), 5.35 - 5.31 (m, 1H), 4.26 - 4.20 (m, 1H), 4.11 - 4.05 (m, 1H), 3.97 - 3.92 (m, 1H), 3.70 - 3.38 (m, 4H), 2.96 - 2.91 (m, 3H), 1.96 - 1.75 (m, 4H) ppm. MS: M/e 429 (M+1) ⁺ compound 1.35

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.90-6.56 (m, 7H), 6.31 - 6.16 (m, 2H), 5.75 - 5.71 (m, 1H), 5.20 - 5.16 (m, 1H), 4.28 - 4.18 (m, 1H), 4.12 - 3.90 (m, 2H), 3.65 - 3.28 (m, 4H), 2.91 (s, 3H), 2.01 - 1.75 (m, 4H)ppm. MS: M/e 429 (M+1) ⁺ compound 1.36

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 6.80 - 5.89 (m, 9H), 5.80 - 5.40 (s, 1H), 5.34 (dd, J = 8.0, 2.8 Hz, 1H), 4.50 - 3.80 (m, 3H), 3.65 - 3.30 (m, 4H), 2.87 (s, 3H), 1.95 - 1.75 (m, 4H), ppm. MS: M/e 429 (M+1) ⁺ .

Compounds 1.37 to 1.45 are prepared according to the procedures described for compound 1.10 under the appropriate conditions known to those of ordinary skill in the art. Compound 1.37

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.17 - 7.05 (m, 1H), 6.97 - 6.84 (m, 2H), 6.70 - 6.54 (m, 3H), 6.27 - 5.95 (m, 3H), 5.79 - 5.41 (m, 1H), 4.42 - 3.87 (m, 4H), 3.84 - 3.75-3.62 (m, 2H), 3.51 - 3.23 (m, 4H), 3.04 - 2.72 (m, 4H), 2.19 - 1.98 ( m, 2H), 1.96 - 1.62 (m, 2H). MS: M/e 442 (M+1) ⁺ compound 1.38

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.15 - 7.02 (m, , 4H), 6.71 - 6.53 (m, 2H), 6.28 - 5.98 (m, 3H), 5.79 - 5.42 (m, 1H), 4.44 - 3.87 (m, 4H), 3.81 - 3.65 (m, 2H), 3.48 - 3.40 - 3.35 (m, 1H), 3.30 - 3.25 (m, 3H), 3.05 - 2.73 (m, 4H), 2.20 - 1.97 (m, 2H), 1.96 - 1.62 (m, 2H). MS: M/e 424 (M+1) ⁺ compound 1.39

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.19 - 7.06 (m, 1H), 6.99 - 6.87 (m, 2H), 6.69 - 6.50 (m, 3H), 6.27 - 5.98 (m, 3H), 5.77 - 5.43 (m, 1H), 4.48 - 4.20 (m, 1H), 4.16 - 3.85 (m, 2H), 3.79 - 3.60 (m, 1H), 3.57 - 3.38 (m, 3H), 3.23 - 3.12 (m, 3H), 3.04 - 2.75 (m, 4H), 2.14 - 2.04 (m, 1H), 1.98 - 1.90 (m, 1H), 1.90 - 1.63 (m, 2H). MS: M/e 442 (M+1) ⁺ compound 1.40

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.74 - 6.45 (m, 3H), 6.25 - 5.98 (m, 3H), 5.78 - 5.41 (m, 1H), 4.52 - 4.22 (m, 1H), 4.15 - 3.85 (m, 2H), 3.79 - 3.60 (m, 1H), 3.58 - 3.36 (m, 3H), 3.22 - 3.14 (m, 3H), 3.06 - 2.74 (m, 4H) , 2.17 - 2.03 (m, 1H), 2.01 - 1.82 (m, 2H), 1.78 - 1.63 (m, 1H). MS: M/e 424 (M+1) ⁺ Compound 1.40a: 1-(((2S,4R)-1-propenyl-4-methoxypyrrolidin-2-yl)methyl)-5- Amino-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

Compound 1.40a was prepared according to the procedure described for the palm compound 1.14a under suitable conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.66 - 6.49 (m, 3H), 6.25 - 5.98 (m, 3H), 5.75 - 5.43 (m, 1H), 4.48 - 4.21 (m, 1H), 4.13 - 3.85 (m, 2H), 3.80 - 3.60 (m, 1H), 3.58 - 3.35 (m, 3H), 3.22 - 3.14 (m, 3H), 3.06 - 2.74 (m, 4H) , 2.16 - 2.04 (m, 1H), 2.02 - 1.83 (m, 2H), 1.78 - 1.66 (m, 1H). MS: M/e 424 (M+1) ⁺ compound 1.41

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.09 (d, J = 6.0 Hz, 1H), 6.95 - 6.75 (m, 2H), 6.60 - 6.25 (m, 3H), 6.25 - 6.04 (m, 1H) ), 5.90 (s, 2H), 5.79 - 5.43 (m, 1H), 4.76 - 4.40 (m, 1H), 4.23 - 3.95 (m, 3H), 3.78 (s, 1H), 3.46 - 3.23 (m, 1H) ), 3.02 - 2.54 (m, 5H), 2.47 - 2.29 (m, 1H), 2.18 - 1.99 (m, 1H), 1.86 - 1.65 (m, 1H) ppm. MS: M/e 448 (M + 1) ⁺ Compound 1.42: 1-(((S)-1-propenyl-4,4-difluoropyrrolidin-2-yl)methyl)-5-amino- 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: 5-Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

5-Amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile (2.1 g, 8.8 mmol) in methanesulfonic acid (10 mL) The solution was stirred at 70 ° C for 4 hours. The resulting solution was poured into water, neutralized with aq. 5N NaOH to pH = 8 and then extracted with EA (50 mL x 3). The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc EtOAc MS: M/e 257 (M+1) ⁺ Step A: (S)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

To (S)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5 g, 20.55 mmol) in anhydrous at -78 ° C over 30 min. Diethylaminosulfur trifluoride (DAST, 8.5 mL, 61.66 mol) was added dropwise to the stirred solution in DCM (100 mL). The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 16 hours. The reaction mixture was poured into a mixture of crushed ice and a saturated aqueous solution of NaHCO ₃ until pH = 8. The layers were separated and the aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, then concentrated to give the crude product (4.7 g, yellow oil), which was used directly in the next step. MS: M/e 210 (M-55) ⁺ . Step B: (S)-4,4-Difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step A (4.7 g, 17.72 mmol) in THF (20 mL) was successively added _{NaBH 4 (1.88 g, 44.30 mmol} ) and LiCl (1.48 g, 38.98 mmol) . The mixture solution was cooled to 0 ° C and EtOH (30 mL) was added dropwise. The final solution was stirred at room temperature for 15 hours. The solution was then cooled to 0 ° C, neutralized with 4N HCl to pH = 4 then concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO _4, then concentrated to give the crude product (3.7 g, 88%), as a yellow oil which was used directly in the next step. MS: M/e 182 (M-55) ⁺ . Step C: (S)-4,4-Difluoro-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step B (3.7 g, 15.6 mmol), TsCl (3.27 g, 17.2 mmol), DMAP (193 mg, 1.56 mmol) and Et in DCM (15 mL) in _{3 N (4.5 mL, 31.2 mmol} ) Stir at room temperature for 4 hours. The resulting solution was washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na ₂ SO _4, concentrated, and then by treatment with PE: EA = 5: 1 eluting purified by silica gel column chromatography, to give the desired product (5.2 g, 85%), as a yellow oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 4.33 - 3.92 (m, 3H), 3.89 - 3.67 (m, 1H), 3.64 - 3.41 (m, 1H), 2.58 - 2.24 (m, 5H), 1.47 (s, 9H) ppm. MS: M/e 292 (M-100+1) ⁺ Step D: (2S)-2-((5-amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalene) -2-yl)-1H-pyrazol-1-yl)methyl)-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step C (4.58 g, 11.7 mmol), 5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (2.0 g A mixture of 7.8 mmol) and Cs ₂ CO ₃ (5.08 g, 15.6 mmol) in DMF (20 mL) The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.17 - 6.98 (m, 4H), 6.61 (s, 2H), 6.10 (s, 2H), 4.41 - 4.18 (m, 1H), 4.13 - 3.95 (m , 2,,,,,,,,, - 1.59 (m, 1H), 1.40 (s, 9H) ppm. MS: M/e 476 (M+1) ⁺ Step E: 5-amino-1-(((S)-4,4-difluoropyrrolidin-2-yl)methyl)-3-(1,2 ,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step D (414 mg, EtOAc) The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material ( </RTI><RTIgt; MS: M/e 376 (M + 1) ⁺ Step F: 1-(((s)-1-propenyl-4,4-difluoropyrrolidin-2-yl)methyl)-5-amino- 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step E (326 mg, 0.86 mmol) and _{NaHCO 3 (289 mg, 3.44 mmol} ) / H mixture (8 mL / 8 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Solution (1 mL) is added dropwise in CH ₃ CN Bing Xixi chloride (78 mg, 0.86 mmol) at 0 ℃. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (20 mL The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.17 - 6.89 (m, 4H), 6.52 - 6.27 (m, 3H), 6.25 - 6.04 (m, 1H), 5.95 (s, 2H), 5.78 - 5.46 (m, 1H), 4.71 - 4.41 (m, 1H), 4.24 - 3.91 (m, 3H), 3.89 - 3.62 (m, 1H), 3.44 - 3.23 (m, 1H), 3.01 - 2.70 (m, 4H) , 2.70 - 2.52 (m, 1H), 2.44 - 2.28 (m, 1H), 2.21 - 2.01 (m, 1H), 1.87 - 1.65 (m, 1H) ppm. MS: M/e 430 (M+1) ⁺ compound 1.42a or 1.42b: ( R or S ) 1-(((S)-1-propenyl-4,4-difluoropyrrolidin-2-yl )methyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: ( R or S ) (2S)-2-((5-Amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridyl Zylidene-1-yl)methyl)-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

(S)-4,4-Difluoro-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.58 g, 11.7 mmol), 5-amino-3-( 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (2.0 g, 7.8 mmol) and Cs ₂ CO ₃ (5.08 g, 15.6 mmol) in DMF (20 The mixture in mL) was stirred at 70 ° C for 15 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Separation of palmate HPLC gave peak 1 (600 mg, prior peak) and peak 2 (600 mg, after peak).

The conditions for palm separation are as follows: Step B: ( R or S ) 5-Amino-1-((S)-4,4-difluoropyrrolidin-2-yl)methyl)-3-(1,2,3,4-tetrahydrogen Naphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from Step A (600 mg, 1.26 mmol The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (473 mg, 100%) MS: M/e 376 (M+1) ⁺ step C: ( R or S ) 1-(((S)-1-propenyl-4,4-difluoropyrrolidin-2-yl)methyl) -5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step B (473 mg, 1.26 mmol) and _{NaHCO 3 (423 mg, 5.04 mmol} ) / H mixture (12 mL / 12 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Solution (1 mL) is added dropwise in CH ₃ CN Bing Xixi chloride (113 mg, 1.26 mmol) at 0 ℃. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid. Peak 1 (compound 1.42a, retention time: 5.391 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.18 - 6.96 (m, 4H), 6.58 - 6.27 (m, 3H), 6.26 - 6.07 (m , 1H), 5.97 (s, 2H), 5.82 - 5.46 (m, 1H), 4.73 - 4.44 (m, 1H), 4.22 - 3.96 (m, 3H), 3.90 - 3.64 (m, 1H), 3.47 - 3.25 (m, 1H), 3.00 - 2.73 (m, 4H), 2.68 - 2.54 (m, 1H), 2.45 - 2.35 (m, 1H), 2.19 - 2.01 (m, 1H), 1.86 - 1.67 (m, 1H) Ppm. MS: M/e 430 (M+1) ⁺ . Ee: 100%. Peak 2 (compound 1.42b, retention time: 6.044 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.20 - 6.93 (m, 4H), 6.55 - 6.29 (m, 3H), 6.25 - 6.05 (m , 1H), 5.97 (s, 2H), 5.76 - 5.31 (m, 1H), 4.80 - 4.38 (m, 1H), 4.23 - 3.92 (m, 3H), 3.91 - 3.61 (m, 1H), 3.47 - 3.22 (m, 1H), 3.01 - 2.70 (m, 4H), 2.64 - 2.53 (m, 1H), 2.43 - 2.27 (m, 1H), 2.23 - 2.00 (m, 1H), 1.91 - 1.67 (m, 1H) Ppm. MS: M/e 430 (M+1) ⁺ . Ee: 100%.

The analysis conditions for palmity are as follows. Compound 1.42a: 1-(((S)-1-propenyl-4,4-difluoropyrrolidin-2-yl)methyl)-5-amino-3-((R)-1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (S)-2-((5-Amino-4-carbamoyl-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole -1-yl)methyl)-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

(S)-4,4-Difluoro-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (229 mg, 0.58 mmol), (R)-5-amino -3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (100 mg, 0.39 mmol) and Cs ₂ CO ₃ (254 mg, 0.78 mmol) The mixture in DMF (10 mL) was stirred at 70 ° C for 15 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 476 (M+1) ⁺ Step B: 5-amino-1-(((S)-4,4-difluoropyrrolidin-2-yl)methyl)-3-((R) -1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from Step A (100 mg, 0.21 mmol) The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (yield: MS: M/e 376 (M+1) ⁺ step C: 1-((())-1-propenyl-4,4-difluoropyrrolidin-2-yl)methyl)-5-amino- 3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step B (79 mg, 0.21 mmol) and _{NaHCO 3 (70 mg, 0.84 mmol} ) / H mixture (2 mL / 2 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (19 mg, 0.21 mmol) was added dropwise at 0 °C. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.18 - 6.96 (m, 4H), 6.58 - 6.27 (m, 3H), 6.26 - 6.07 (m, 1H), 5.97 (s, 2H), 5.82 - 5.46 (m, 1H), 4.73 - 4.44 (m, 1H), 4.22 - 3.96 (m, 3H), 3.90 - 3.64 (m, 1H), 3.47 - 3.25 (m, 1H), 3.00 - 2.73 (m, 4H) , 2.68 - 2.54 (m, 1H), 2.45 - 2.35 (m, 1H), 2.19 - 2.01 (m, 1H), 1.86 - 1.67 (m, 1H) ppm. MS: M/e 430 (M+1) ⁺ . Ee: 100%. Compound 1.43: 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)methyl)-5-amino-3-(1,2,3,4-tetrahydro) Naphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10 g, 40.77 mmol) in anhydrous DCM (100 mL) over 30 min. Diethylaminosulfur trifluoride (9.5 mL, 77.47 mol) was added dropwise to the stirred solution. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 16 hours. The reaction mixture was poured into a mixture of crushed ice and a saturated aqueous solution of NaHCO ₃ until pH = 8. The layers were separated and the aqueous layer was extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, then concentrated to give the crude product (10 g, yellow oil), which was used directly in the next step. MS: M/e 148 (M-100+1) ⁺ . Step B: (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step A (10 g, 40.44 mmol) in THF (100 mL) was successively added _{NaBH 4 (4.3 g, 101.10 mmol} ) and LiCl (3.3 g, 88.98 mmol) . The mixture solution was cooled to 0 ° C and EtOH (100 mL) was added dropwise. The final solution was stirred at room temperature for 15 hours. The solution was then cooled to 0 ° C, neutralized with 4N HCl to pH = 4 then concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were dried in Na ₂ SO _4, then concentrated to give the crude product (8.86 g, yellow oil), which was used directly in the next step. MS: M/e 164 (M-55) ⁺ . Step C: (2S,4R)-4-fluoro-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step B (8.86 g, 40.44 mmol), TsCl (8.48 g, 44.50 mmol), DMAP (496 mg, 4 mmol) and _{Et 3 N (8.7 mL, 60.67} mmol) mixture in DCM (40 mL) of Stir at room temperature for 4 hours. The resulting solution was washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na at ₂ SO _4, concentrated, and then by treatment with PE: EA = 5: 1 eluting purified by silica gel column chromatography, to give the desired product (6.0 g, 40% over 3 steps) as a yellow Oily. MS: M/e 274 (M-100+1) ⁺ Step D: (2S, 4R)-2-((5-Amino-4-carbamoyl-3-(1,2,3,4-tetra) Hydronaphthalen-2-yl)-1H-pyrazol-1-yl)methyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step C (3.26 g, 8.74 mmol), 5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (1.6 g The mixture of 6.24 mmol) and Cs ₂ CO ₃ (4.0 g, 12.48 mmol) in DMF (20 mL) was stirred at 70 ° C for 15 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc. MS: M/e 458 (M+1) ⁺ Step E: 5-amino-1-(((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)-3-(1,2, 3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step D (525 mg, 1.14 mmol) in DCM (3 mL) The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (410 mg, 100%) MS: M/e 358 (M+1) ⁺ Step F: 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)methyl)-5-amino-3 -(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step E (410 mg, 1.15 mmol) and _{NaHCO 3 (386 mg, 4.6 mmol} ) / H mixture (10 mL / 10 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (103 mg, 1.15 mmol) was added dropwise at 0 °C. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (20 mL The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.13 - 6.98 (m, 4H), 6.60 - 6.42 (m, 1H), 6.36 (s, 2H), 6.25 - 6.04 (m, 1H), 5.93 (s , 2H), 5.79 - 5.40 (m, 1H), 5.32 - 4.97 (m, 1H), 4.58 - 4.30 (m, 1H), 4.30 - 3.65 (m, 3H), 3.60 - 3.24 (m, 2H), 3.01 - 2.62 (m, 4H), 2.29 - 1.99 (m, 3H), 1.87 - 1.68 (m, 1H) ppm. MS: M/e 412 (M+1) ⁺ compound 1.43a or 1.43b: ( R or S ) 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl) Methyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: ( R or S ) (2S,4R)-2-((5-Amino-4-carbamoyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H -pyrazol-1-yl)methyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

tert-Butyl (2S,4R)-4-fluoro-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylate (3.26 g, 8.74 mmol), 5-amino-3-(1) , 2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (1.6 g, 6.24 mmol) and Cs ₂ CO ₃ (4.0 g, 12.48 mmol) in DMF (20 mL The mixture in the mixture was stirred at 70 ° C for 15 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc m. Separation by palm chromatography gave peak 1 (0.37 g, prior peak) and peak 2 (0.37 g, after peak).

The conditions for palm separation are as follows: Step B: ( R or S ) 5-Amino-1-((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)-3-((R)-1,2,3,4 -tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from step B (370 mg, 0.81 mmol) in DCM (5 mL) The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (yield: 291 mg, 100%). MS: M/e 358 (M+1) ⁺ Step C: ( R or S ) 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)methyl)- 5-amino-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step B (291 mg, 0.81 mmol) and _{NaHCO 3 (272 mg, 3.24 mmol} ) / H mixture (7 mL / 7 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (73 mg, 0.81 mmol) was added dropwise at 0 °C. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid. Peak 1 (compound 1.43a, retention time: 5.456 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.22 - 6.94 (m, 4H), 6.64 - 6.44 (m, 1H), 6.36 (s, 2H ), 6.22 - 6.06 (m, 1H), 5.91 (s, 2H), 5.79 - 5.44 (m, 1H), 5.35 - 4.90 (m, 1H), 4.64 - 4.31 (m, 1H), 4.20 - 3.71 (m , 3H), 3.54 - 3.26 (m, 2H), 3.02 - 2.67 (m, 4H), 2.34 - 1.97 (m, 3H), 1.89 - 1.69 (m, 1H) ppm. MS: M/e 412 (M+1) ⁺ . Ee: 100%. Peak 2 (compound 1.43b, retention time: 6.985 min): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.13 - 6.97 (m, 4H), 6.59 - 6.43 (m, 1H), 6.36 (s, 2H ), 6.23 - 6.05 (m, 1H), 5.93 (s, 2H), 5.77 - 5.46 (m, 1H), 5.32 - 4.99 (m, 1H), 4.63 - 4.31 (m, 1H), 4.28 - 3.66 (m , 3H), 3.58 - 3.22 (m, 2H), 3.00 - 2.69 (m, 4H), 2.26 - 1.96 (m, 3H), 1.89 - 1.69 (m, 1H) ppm. MS: M/e 412 (M+1) ⁺ . Ee: 100%.

The analysis conditions for palmity are as follows. Compound 1.43a: 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)methyl)-5-amino-3-((R)-1,2,3 ,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (2S,4R)-2-((5-Amino-4-carbamoyl-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H- Pyrazol-1-yl)methyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

(2S,4R)-4-fluoro-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (219 mg, 0.58 mmol), (R)-5-amino- 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide (100 mg, 0.39 mmol) and Cs ₂ CO ₃ (254 mg, 0.78 mmol) The mixture in DMF (10 mL) was stirred at 70 ° C for 15 hours. The resulting solution was concentrated. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 458 (M+1) ⁺ Step B: 5-amino-1-(((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)-3-((R)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of the product from Step B (90 mg, 0.20 mmol) The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated to give a crude material (yield: 70 mg, 100%). MS: M/e 358 (M+1) ⁺ Step C: 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)methyl)-5-amino-3 -((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step B (70 mg, 0.20 mmol) and _{NaHCO 3 (67 mg, 0.80 mmol} ) / H mixture (2 mL / 2 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (18 mg, 0.20 mmol) was added dropwise at 0 °C. The final solution was stirred at 0&lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAc EtOAc (EtOAc m. solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.13 - 6.95 (m, 4H), 6.62 - 6.43 (m, 1H), 6.35 (s, 2H), 6.22 - 6.06 (m, 1H), 5.92 (s, 2H), 5.78 - 5.39 (m, 1H), 5.32 - 4.94 (m, 1H), 4.61 - 4.32 (m, 1H), 4.26 - 3.70 (m, 3H), 3.57 - 3.22 (m, 2H ), 3.00 - 2.70 (m, 4H), 2.27 - 1.97 (m, 3H), 1.88 - 1.66 (m, 1H) ppm. MS: M/e 412 (M+1) ⁺ . Ee: 100%.

An alternative route to compound 1.43a: 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)methyl)-5-amino-3-((R)-1, 2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester)·2-methyl ester

Cool a solution of (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ester)·2-methyl ester (10 g, 40.77 mmol) in DCM (100 mL) - Stir at 78 ° C for 5 minutes. DAST (9.5 mL, 77.47 mmol) was then added dropwise over approximately 10 minutes. The final solution was stirred at -78 ° C to room temperature for 48 h. The resulting solution was poured into ice with 2 g NaHCO ₃ in - water and stirred for 15 minutes, then extracted with DCM (50 mL x 3). The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 248 (M+1) ⁺ step B: (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The crude product from Step A (10 g, 40 mmol) in THF (100 mL) was first added _{NaBH 4 (4.3 g, 100 mmol} ) and LiCl (3.3 g, 88 mmol) . The solution was cooled to 0 ° C and then EtOH (100 mL) was added dropwise. The final solution was stirred at 0 ° C to room temperature for 15 hours. The resulting solution was cooled to 0 ° C, 4N HCl was added until pH = 4 then concentrated. The residue was washed with water and extracted with DCM (50 mL The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 220 (M+1) ⁺ step C: (2S,4R)-4-fluoro-2-carbamimidyrrolidine-1-carboxylic acid tert-butyl ester

A solution of chloroform (4 mL, 47.43 mmol) in dry DCM (100 mL) was cooled to -78. To this solution was added dropwise a solution of DMSO (3.6 mL, 51.07 mmol) in DCM (10 mL) and a crude product from Step B (8 g, 36.48 mmol) in DCM (25 mL) at -78 °C. The solution was then added triethylamine (20 mL, 145.92 mmol). The final solution was stirred at -78 °C for 30 minutes and then at 0 °C for 1 h. The resulting solution was washed with water and extracted with DCM (50 mL The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 218 (M+1) ⁺ Step D: (2S,4R)-2-((2-(tert-butoxycarbonyl)indolyl)indolyl)-4-fluoropyrrolidine-1-carboxylic acid Tert-butyl ester

A mixture of the crude product from EtOAc (EtOAc,EtOAc. The solution was then cooled to 0 ℃, successively added HOAc (10 mL) and _{NaBH 3 CN (2.36 g, 36.82} mmol). The solution was stirred at 0 ° C for an additional 1 h. The resulting solution was concentrated. The residue was taken up in EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 334 (M+1) ⁺ step E: (2S, 4R)-4-fluoro-2-(indolyl)pyrrolidine

To a solution of the crude product from EtOAc (EtOAc,EtOAc. The solution was stirred at room temperature for 2 h. The resulting solution was concentrated. The residue was dissolved in a mixed solvent of MeOH / DCM = 1 / 20. To the solution was added K ₂ CO ₃ until pH = 8. The mixture solution was stirred for 30 minutes and filtered. The filtrate was concentrated to give a crude material (3. MS: M/e 134 (M+1) ⁺ Step F: 5-amino-1-(((2S,4R)-4-fluoropyrrolidin-2-yl)indolyl)-3-((R)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

The crude product of Step E (3.39 g, 25.45 mmol) and (R)-2-(methoxy(1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile (3) The mixture was stirred at rt for 4 h. The residue was washed with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc. MS: M/e 340 (M+1) ⁺ . Step G: 5-Amino-1-(((2S,4R)-4-fluoropyrrolidin-2-yl)indolyl)-3-((R)-1,2,3,4-tetrahydronaphthalene- 2-yl)-1H-pyrazole-4-carboxamide

A solution of the product from Step F (3.4 g, 10 mmol) in M. The resulting solution was cooled to room temperature, neutralized with aq. 5 N NaOH to pH = 8 and then extracted with DCM (20 mL x 3). The combined organic layers were washed with EtOAc EtOAc m. MS: M/e 358 (M+1) ⁺ step H: 1-(((2S,4R)-1-propenyl-4-fluoropyrrolidin-2-yl)indolyl)-5-amino-3 -((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The crude product of Step G (2.8 g, 7.83 mmol) and _{NaHCO 3 (1.3 g, 15.66 mmol} ) / H mixture (20 mL / 20 mL) is stirred ₂ O CH ₃ CN at 0 ℃ 5 minutes. Propylene hydrazine chloride (705 mg, 7.83 mmol) was added dropwise at 0 °C. The final solution was stirred at 0 &lt;0&gt;C for 5 min, quenched with water then extracted with EtOAc (EtOAc &lt The combined organic layers were washed with EtOAcq EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH White solid. ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.13 - 6.95 (m, 4H), 6.62 - 6.43 (m, 1H), 6.35 (s, 2H), 6.22 - 6.06 (m, 1H), 5.92 (s, 2H), 5.78 – 5.39 (m, 1H), 5.32 – 4.94 (m, 1H), 4.61 – 4.32 (m, 1H), 4.26 – 3.70 (m, 3H), 3.57 – 3.22 (m, 2H) ), 3.00 – 2.70 (m, 4H), 2.27 – 1.97 (m, 3H), 1.88 – 1.66 (m, 1H) ppm.MS: M/e 412 (M+1) ⁺ . Ee: 100%. Compound 1.44

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.17 - 7.02 (m, 1H), 6.95 - 6.77 (m, 2H), 6.67 - 6.23 (m, 3H), 6.21 - 5.80 (m, 3H ), 5.75 - 5.40 (m, 1H), 5.30 - 4.98 (m, 1H), 4.67 - 4.32 (m, 1H), 4.27 - 3.68 (m, 3H), 3.62 - 3.25 (m, 2H), 3.01 - 2.70 (m, 4H), 2.29 - 1.95 (m, 3H), 1.87 - 1.57 (m, 1H) ppm. MS: M/e 430 (M+1) ⁺ compound 1.45

¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.13 - 6.86 (m, 4H), 6.72 - 6.27 (m, 3H), 6.26 - 5.59 (m, 4H), 5.52 - 5.14 (m, 1H) ), 4.73 - 3.46 (m, 5H), 3.41 - 3.24 (m, 1H), 3.04 - 2.68 (m, 4H), 2.38 - 1.97 (m, 3H), 1.91 - 1.66 (m, 1H) ppm. MS: M/e 412 (M+1) ⁺

Compounds 1.46 to 1.49 were prepared according to the procedures described for compound 1.20 under the appropriate conditions known to those of ordinary skill in the art. Compound 1.46

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 7.70-7.73 (dd, J = 2.0, 11.2 Hz, 1H), 7.21-7.25 (dd, J = 7.2, 8.8 Hz, 1H ), 7.06-7.09 (m, 4H), 6.99-7.02 (m, 1H), 6.68 (s, 2H), 6.49-6.55 (m, 1H), 6.40 (s, 2H), 6.30-6.35 (m, 1H) ), 5.80-5.83 (m, 1H), 5.14 (s, 2H), 3.39-3.45 (m, 1H), 2.98-3.03 (m, 1H), 2.85-2.94 (m, 2H), 2.77-2.82 (m , 1H), 2.13-2.16 (m, 1H), 1.67-1.76 (m, 1H). MS (ESI) m/e [M+1] ⁺ 434. Compound 1.47

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 14.8, 8.2 Hz, 1H), 7.16-6.94 ( m, 5H), 6.69 (s, 2H), 6.51-6.45 (m, 1H), 6.39-6.17 (m, 3H), 5.81 (d, J = 11.4 Hz, 1H), 5.19 (t, J = 16.8 Hz , 2H), 3.42-3.40 (m, 1H), 2.99 (dd, J = 16.4, 4.0 Hz, 1H), 2.94-2.68 (m, 3H), 2.12 (d, J = 10.6 Hz, 1H), 1.70- 1.63 (m, 1H). (ESI) m/e [M+1] ⁺ 434. Compound 1.48

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.12 (s, 1H), 7.67 (dd, J = 8.8, 5.5 Hz, 1H), 7.15 (td, J = 8.6, 3.0 Hz, 1H), 7.07 ( s, 4H), 6.76 (dd, J = 9.6, 2.9 Hz, 1H), 6.69 (s, 2H), 6.49 (dd, J = 17.0, 10.2 Hz, 1H), 6.36 (s, 2H), 6.30 (dd , J = 17.0, 1.7 Hz, 1H), 5.80 (dd, J = 10.2, 1.6 Hz, 1H), 5.12 (s, 2H), 3.51-3.38 (m, 1H), 3.02 (dd, J = 16.5, 3.9 Hz, 1H), 2.97-2.84 (m, 2H), 2.81 (dd, J = 9.6, 6.8 Hz, 1H), 2.14 (d, J = 10.9 Hz, 1H), 1.71 - 1.66 (m, 1H). (ESI) m/e [M+1] ⁺ 434. Compound 1.49

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.96 (s, 1H), 7.32 - 7.15 (m, 2H), 7.07 (s, 4H), 6.65 (s, 2H), 6.58 (d, J = 7.6 Hz, 1H), 6.51 (dd, J = 17.0, 10.2 Hz, 1H), 6.31 (s, 1H), 6.26 (s, 2H), 5.81 (d, J = 11.1 Hz, 1H), 5.07 (s, 2H) ), 3.40 (d, J = 11.9 Hz, 1H), 3.01 (dd, J = 16.6, 4.3 Hz, 1H), 2.96 - 2.68 (m, 3H), 2.14 (d, J = 11.2 Hz, 1H), 1.72 - 1.66 (m, 1H). (ESI) m/e [M+1]+ 434. Compound 1.50

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.29 (s, 1H), 7.68-7.70 (d, J = 11.2 Hz, 1H), 7.24-7.26 (d, J = 7.6 Hz, 1H), 7.07 -7.19 (m, 3H), 6.96-7.01 (m, 1H), 6.68 (s, 2H), 6.49-6.56 (m, 1H), 6.40 (s, 2H), 6.30-6.35 (m, 1H), 5.82 -5.85 (m, 1H), 5.13 (s, 2H), 3.37-3.45 (m, 1H), 3.01-3.06 (m, 1H), 2.86-2.94 (m, 2H), 2.67-2.79 (m, 1H) , 2.20-2.23 (m, 1H), 1.70-1.75 (m, 1H). MS (ESI) m/e [M+1] ⁺ 468. Compound 1.51:1-(2-Acrylamino-4-fluorobenzyl)-5-amino-3-(8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridyl Oxazol-4-carboxamide Step A: N-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamide

A solution of 5,6,7,8-tetrahydronaphthalen-1-amine (12.7 g, 86.2 mmol) in EtOH (40 mL) was added dropwise to acetic anhydride (17.6 g, 172.4 mmol). ) in a solution of anhydrous EtOH (200 mL). The solvent was removed in vacuo <RTI ID=0.0>: </RTI></RTI></RTI></RTI></RTI> Purification can be used in the next step. MS (ESI) m/e [M+1] ⁺ 190 Step B: N-(8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide

The 15% MgSO ₄ (1.68 g in a solution of 10 mL H ₂ O in) is added to N- (5,6,7,8- tetrahydronaphthalen-1-yl) acetyl amine (1.9 g, 10 mmol) in In a suspension in acetone (30 mL), KMnO ₄ (4.74 g, 30 mmol) was then added in portions. The reaction mixture was stirred at rt for 2 h then filtered over EtOAc EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ CH ₄ The residue was purified by EtOAc (EtOAc EtOAc/EtOAc:EtOAc) Amine (1.2 g, 60%) as a yellow solid. MS (ESI) m/e [M+1] ⁺ 204 Step C: 8-chloro-3,4-dihydronaphthalene-1(2H)-one

Mixture of CuCl ₂ and tert-butyl nitrile (495 mg, 4.8 mmol) in CH ₃ CN (15 mL) at 65 ° C with N-(8-oxo-5,6,7,8 - tetrahydronaphthalen-1-yl) acetyl amine (484 mg, 3 mmol) solution in CH ₃ CN (5 mL) is treated. After 10 minutes, the mixture was cooled to room temperature and then the solvent was removed in vacuo. The residue was partitioned between aqueous and EtOAc, the organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It is a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.32-7.33 (m, 2H), 7.16 (t, J = 5.2 Hz, 1H), 2.97 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.07-2.13 (m, 1H). MS (ESI) m/e [M+1] ⁺ 181. Step D: Methyl 8-chloro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate

Add NaH (176 mg, 4.4 mmol) to methyl orthoformate (5 mL), then add 8-chloro-3,4-dihydronaphthalene-1(2H)-one (0.36 g, 2 mmol) A solution in methyl orthoformate (5 mL). The mixture was stirred at 100 &lt;0&gt;C for 1 h, cooled to rt. The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc/EtOAc:EtOAc) (0.28 g, 59%), yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.94 (s, 1H), 7.29-7.31 (dd, J = 1.2, 8 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.08- 7.10 (dd, J = 1.2, 7.2 Hz, 1H), 3.83 (s, 3H), 2.73-2.77 (m, 2H), 2.46-2.50 (m, 2H). MS (ESI) m/e [M+1] ⁺ 239. Step E: Methyl 8-chloro-1,2,3,4-tetrahydronaphthalene-2-carboxylate

Add triethyl decane (2 mL) to methyl 8-chloro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (0.28 g, 1.17 mmol) in trifluoroacetic acid (5) The solution in mL) was then stirred at room temperature for 16 hours. The solvent was removed in vacuo and aq. toluene was concentrated to give ethyl 8-chloro-1,2,3,4-tetrahydronaphthalene-2-carboxylate (0.31 g, >100%) as yellow oil Shape. The crude product was used in the next step without further purification. MS (ESI) m/e [M+1] ⁺ 225. Step F: 8-Chloro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

The NaOH (0.28 g, 6.9 mmol) solution in H ₂ O (5 mL) was added to 8-chloro-1,2,3,4-tetrahydronaphthalene-2-carboxylate (0.31 g, 1.38 mmol) The reaction mixture was stirred at room temperature for 1 hour in MeOH (10 mL). The organics were removed under vacuum and the remaining aqueous layer was acidified to pH 2-3 with aqueous HCI. The solid was collected via EtOAc (EtOAc) (EtOAc) This solid was used in the next step without further purification. MS (ESI) m/e [M-1] ⁺ 209. Step G: 2-((8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)(hydroxy)methylene)malononitrile

Add HOBT (154 mg, 1.14 mmol), EDCI (220) to a mixture of 8-chloro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (200 mg, 0.95 mmol) in DCM (10 mL) mg, 1.14 mmol) and _{Et 3 N (192 mg, 1.9} mmol), stirred at room temperature for 10 minutes, to which was added malononitrile (63 mg, 0.95 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed, the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ under vacuum. The organic layer was washed with aqueous ₄ Cl _{NH, 1.25 N H 2 SO 4} , washed with brine, dried Na ₂ SO _4, and concentrated in vacuo to give 2 - ((8-chloro-1,2,3,4-tetrahydro Naphthalen-2-yl)(hydroxy)methylene)malononitrile (200 mg, 81%) as a yellow solid. MS (ESI) m/e [M-1] ⁺ 257. Step H: 2-((8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)(methoxy)methylene)malononitrile

2-((8-Chloro-1,2,3,4-tetrahydronaphthalen-2-yl)(hydroxy)methylene)malononitrile (200 mg, 0.77 mmol) in trimethyl orthoformate (5 mL The reaction mixture in the mixture was stirred at 100 ° C for 1 hour, then cooled to room temperature and the solvent was removed in vacuo. The crude product was recrystallized from MeOH to give 2-((8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)(methoxy)methylene)malononitrile (120 mg, 57%), which is a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.22 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 4.43 (s, 3H), 3.24-3.29 (m, 1H), 3.05-3.11 (m, 1H), 2.90-2.93 (m, 2H), 2.73-2.80 (m, 1H), 2.01-2.04 (m, 1H) , 1.81-1.87 (m, 1H). Step I: 5-Amino-3-(8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

Add hydrazine hydrate (0.84 g, 16.8 mmol) to 2-((8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)(methoxy)methylene)malononitrile (2.3 g, 8.4 mmol) in EtOAc (20 mL). The solvent was removed in vacuo and the residue was crystallised from MeOH to afford 5-amino-3-(8-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4 - carbonitrile (2 g, 87%) as a white solid. MS (ESI) m/e [M+1] ⁺ 273.

Compound 1.51 is prepared using the product of Step I according to the procedure described for compound 1.20, under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.27 (s, 1H), 7.67-7.71 (dd, J = 2.4, 11.6 Hz, 1H), 7.19-7.25 (m, 2H), 7.09-7.16 (m , 2H), 6.97-7.02 (m, 1H), 6.72 (s, 2H), 6.46-6.53 (m, 1H), 6.33 (s, 2H), 6.28-6.33 (m, 1H), 5.75-5.78 (m , 1H), 5.15 (s, 2H), 3.44-3.50 (m, 1H), 3.14-3.19 (m, 1H), 2.80-2.95 (m, 2H), 2.67-2.74 (m, 1H), 2.08-2.12 (m, 1H), 1.65-1.72 (m, 1H). MS (ESI) m/e [M+1] ⁺ 468.

Compound 1.52 is prepared according to the procedure described for compound 1.10 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (d, J = 7.6 Hz, 1H), 7.08-7.15 (m, 2H), 6.52-6.64 (m, 3H), 6.00-6.23 (m , 3,,,,, -2.94 (m, 3H), 2.07 (m, 1H), 1.66-1.94 (m, 5H). MS (ESI) m/e [M+1] ⁺ 428.

Compound 1.53 was prepared according to the procedure described for compound 1.11 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.22-7.25 (m, 1H), 7.11-7.15 (m, 2H), 6.73-6.88 (m, 1H), 6.60 (s, 2H), 6.24 (s , 2H), 6.04-6.14 (m, 1H), 5.61-5.71 (m, 1H), 4.24-4.42 (m, 1H), 3.96-4.05 (m, 2H), 2.71-3.11 (m, 5H), 2.19 -2.22 (m, 1H), 1.69-1.92 (m, 5H), 1.42-1.47 (m, 1H), 1.23-1.25 (m, 1H). MS (ESI) m/e [M+1] ⁺ 428.

Compound 1.53 was separated into two enantiomeric stereoisomers, compound 1.53a (peak 1, R or S, prior peak) and compound 1.53b (peak 2, S or R, by preparative HPLC). After the peak).

Compound 1.53a: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (dd, J = 2.8, 6.4 Hz, 1H), 7.10-7.15 (m, 2H), 6.73-6.88 (m, 1H) , 6.60 (s, 2H), 6.24 (s, 2H), 6.04-6.14 (m, 1H), 5.61-5.71 (m, 1H), 4.16-4.42 (m, 1H), 3.96-4.05 (m, 2H) , 3.37-3.44 (m, 1H), 2.71-3.07 (m, 6H), 2.20 (m, 1H), 1.42-1.92 (m, 5H). MS (ESI) m/e [M+1] ⁺ 428.

Compound 1.53b: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (dd, J = 2.0, 7.6 Hz, 1H), 7.10-7.15 (m, 2H), 6.73-6.88 (m, 1H) , 6.60 (s, 2H), 6.24 (s, 2H), 6.04-6.10 (m, 1H), 5.62-5.71 (m, 1H), 4.16-4.42 (m, 1H), 3.96-4.05 (m, 2H) , 3.37-3.44 (m, 1H), 2.71-3.07 (m, 6H), 2.20 (m, 1H), 1.42-1.92 (m, 5H). MS (ESI) m/e [M+1] ⁺ 428.

The separation conditions are as follows.

Compounds 1.54 to 1.60 are prepared according to the procedures described for compound 1.14 under the appropriate conditions known to those of ordinary skill in the art. Compound 1.54

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (d, J = 7.2 Hz, 1H), 7.08-7.15 (m, 2H), 6.51-6.63 (m, 2H), 6.01-6.20 (m , 3H), 5.47-5.72 (m, 1H), 4.23-4.43 (m, 1H), 3.88-4.14 (m, 2H), 3.38-3.78 (m, 4H), 3.16-3.19 (m, 3H), 2.67 -3.05 (m, 4H), 1.75-2.23 (m, 4H). MS (ESI) m/e [M+1] ⁺ 458. Compound 1.55

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (d, J = 6.4 Hz, 1H), 7.08-7.15 (m, 2H), 6.51-6.62 (m, 2H), 6.03-6.21 (m , 3H), 5.49-5.74 (m, 1H), 5.08-5.33 (m, 1H), 4.34-4.59 (m, 1H), 3.82-4.21 (m, 3H), 3.35-3.47 (m, 3H), 2.67 -3.04 (m, 4H), 1.71-2.20 (m, 4H). MS (ESI) m/e [M+1] ⁺ 446. Compound 1.56

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (d, J = 6.8 Hz, 1H), 7.08-7.15 (m, 2H), 6.43-6.63 (m, 2H), 6.21-6.25 (m , 1H), 6.12 (s, 1H), 6.03-6.08 (s, 1H), 5.47-5.79 (m, 1H), 4.49-4.67 (m, 1H), 3.73-4.17 (m, 4H), 3.35-3.42 (m, 1H), 2.66-3.05 (m, 5H), 2.32-2.49 (m, 1H), 2.17-2.29 (m, 1H), 1.68-1.77 (m, 1H). MS (ESI) m/e [M+1] ⁺ 464. Compound 1.57

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.20 - 7.07 (m, 3H), 6.81 (m, 1H), 6.59 (s, 2H), 6.21 (s, 2H), 6.18 - 5.97 (m, 1H ), 5.77 - 5.54 (m, 1H), 4.50 - 3.90 (m, 3H), 3.43 (s, 1H), 3.15 - 2.71 (m, 6H), 2.17 - 2.01 (m, 1H), 1.99 - 1.77 (m , 3H), 1.77 - 1.59 (m, 1H), 1.44 (s, 1H). MS (ESI) m/e [M+1] ⁺ 428. Compound 1.58

^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.21 - 7.05 (m, 3H), 6.82 (m, 1H), 6.59 (s, 2H), 6.21 (s, 2H), 6.17 - 5.98 (m, 1H ), 5.74 - 5.53 (m, 1H), 4.46 - 3.89 (m, 3H), 3.48 - 3.33 (m, 1H), 3.14 - 2.73 (m, 6H), 2.19 - 2.03 (m, 1H), 2.01 - 1.79 (m, 3H), 1.79 - 1.62 (m, 1H), 1.44 (s, 1H). MS (ESI) m/e [M+1] ⁺ 428. Compound 1.59

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.38 (s, 1H), 7.18 - 6.92 (m, 4H), 6.57 (s, 2H), 6.23 - 5.93 (m, 3H), 5.57 (dd, J = 8.8, 3.6 Hz, 1H), 4.22 - 4.02 (m, 2H), 3.34 - 3.26 (m, 1H), 3.06 - 2.68 (m, 4H), 2.12 (d, J = 13.2 Hz, 1H), 1.69 ( m, 1H), 0.74 (m, 2H), 0.65 - 0.55 (m, 2H). MS (ESI) m/e [M+1] ⁺ 380. Compound 1.60

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.23 (s, 1H), 7.07 (s, 4H), 6.58 (s, 2H), 6.24-6.05 (m, 2H), 5.91 (s, 2H), 5.57 (dd, J = 10.0, 2.3 Hz, 1H), 4.21 (s, 2H), 3.38-3.36 (m, 1H), 3.02-2.77 (m, 4H), 2.28-2.26 (m, 2H), 2.19 - 1.99 (m, 3H), 1.91 - 1.52 (m, 3H). MS (ESI) m/e [M+1] ⁺ 394. Compound 1.61:1-((1-(Acrylaminomethyl)cyclopropyl)methyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H- Pyrazole-4-carboxamide Step 1: (1-(Hydroxymethyl)cyclopropyl)methylcarbamic acid tert-butyl ester

To a solution of ethyl 1-cyanocyclopropanecarboxylate (200 mg, 1.4 mmol) in THF (10 mL). The reaction mixture was heated to 65 °C for 4 hours and then cooled to 0 °C. Water was added (10 ml), filtered and washed with THF, was added (Boc) ₂ O (1.1 eq.), Stirred at room temperature for 2 hours. This was purified by preparative TLC (P/EtOAc = 2:1) to afford white solid (50 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.11 (s, 1H), 3.50 (s, 1H), 3.38 (s, 2H), 3.11 (d, J = 6.4 Hz, 2H), 1.44 (d, J = 8.7 Hz, 9H), 0.44 (d, J = 6.0 Hz, 4H). Step 2: ((1-((5-Amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazol-1-yl)methyl) Cyclopropyl)methyl)carbamic acid tert-butyl ester

To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)methylcarbamate (200 mg, 1.01 mmol) in DCM (10 mL) , 2.0 mmol) and MsCl (126 mg, 1.1 mmol). Add 10 ml NaHCO _3, then (10 ml) and extracted with EA, dried over Na ₂ SO _4, and concentrated in vacuo to give a colorless oil which was used directly in the next step. The crude product was dissolved in DMF (5 ml) at 60 ° C and 5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile ( 190 mg, 0.8 mmol), and the mixture was stirred at 60 ° C for 1 hour. TLC showed complete consumption of starting material (SM). Was added 25 ml of water, and then extracted with EA (20 ml), The combined organic layer was washed with brine (20 ml) was washed, dried over Na ₂ SO _4, evaporated in vacuo to give a colorless oil (400 mg), the It was purified by preparative TLC (P/E = 1:1) to afford white solid (290 mg). MS (ESI) m/e [M+1] + 422. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.11 (m, 4H), 6.80 (s, 1H), 6.56 (s, 1H), 3.87 (s, 2H), 3.05-2.90 (m, 5H), 2.84 (dd, J = 9.1, 5.4 Hz, 2H), 2.10 (d, J = 13.9 Hz, 1H), 1.84 (dd, J = 12.9, 8.6 Hz, 1H), 1.37 (m, 9H), 1.31 (s , 2H), 0.43 (dd, J = 23.2, 3.6 Hz, 4H). Step 3: 5-Amino-1-((1-(aminomethyl)cyclopropyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole -4-carboxamide

((1-((5-Amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane yl) methyl) carbamate (290 mg) was dissolved in _{CH 3 SO 3 H (6 ml} ) in. The reaction mixture was heated to 110 ° C for 40 minutes. LC-MS showed complete consumption of SM. The mixture was cooled to 5 ℃, NaHCO ₃ was added was adjusted to pH 7 ~ 8, and extracted with EA (10 ml), the organic layers were dried over Na ₂ SO _4, evaporated in vacuo to give a yellow solid (280 mg). MS (ESI) m/e [M+1] ⁺ 340. Step 4: 1-((1-(Acrylaminomethyl)cyclopropyl)methyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H- Pyrazole-4-carboxamide

To 5-amino-1-((1-(aminomethyl)cyclopropyl)methyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrene at 0 °C acyl-4-amine (280 mg, 0.83 mmol) was added _{NaHCO 3 (208 mg, 2.48 mmol} ) and Bing Xixi chloride (89 mg in CH (10 ml) and water (10 ml) was ₃ CN in 0.99 mmol). The reaction mixture was stirred at 0 °C for 20 min. Add 10 ml of water, extract with EA (10 ml), dry over Na ₂ SO ₄ and then The residue was purified by preparative EtOAc (EtOAc:EtOAc) MS (ESI) m/e [M+1] ⁺ 394. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (d, J = 5.1 Hz, 1H), 7.07 (s, 2H), 6.61 (s, 2H), 6.27 (dd, J = 17.0, 10.0 Hz, 1H), 6.09 (d, J = 17.0 Hz, 1H), 5.61 (d, J = 10.2 Hz, 1H), 3.89 (s, 2H), 3.38 (s, 1H), 3.17 (d, J = 4.6 Hz, 2H), 3.04 - 2.72 (m, 4H), 2.12 (d, J = 13.7 Hz, 1H), 1.81 - 1.66 (m, 1H), 0.53 (s, 2H), 0.40 (s, 2H). Compound 1.62: 1-((R)-2-Acrylamino-3-cyclopropylpropyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H -pyrazole-4-carboxamide Step 1: (R)-2-(tert-Butoxycarbonylamino)-3-cyclopropylpropionic acid

(R)-2-Amino-3-cyclopropylpropionic acid (0.5 g, 3.9 mmol) was suspended in ethanol (8 ml) and water (4 ml), then 1N NaOH (5 ml). The reaction mixture was cooled to 10 ℃, was added (Boc) solution _{2 O (950 mg, 4.3 mmol} ) (4 ml) in the THF, then stirred at room temperature overnight. After adding 15 ml of water, it was washed with EtOAc (EtOAc) (EtOAc). The combined organic layers were dried Na ₂ SO _4, evaporated in vacuo to give a colorless oil (640 mg). Step 2: (R)-1-Cyclopropyl-3-hydroxypropan-2-ylcarbamic acid tert-butyl ester

To a solution of (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (780 mg, 3.4 mmol) in THF (15 ml) Methyl) and isopropyl chloroformate (513 mg). The reaction mixture was stirred at room temperature for 0.5 h, filtered and washed with of THF, then cooled to 0 deg.] C, was added _{NaBH 4 (260 mg, 6.8 mmol} ) in water (1.5 ml) in. The reaction mixture was stirred at room temperature for 2 hours. 20 ml of water was added, and then (20 ml) and extracted with EA, the combined organic layers were washed with brine (20 ml) was washed, dried over Na ₂ SO _4, evaporated in vacuo to give a white solid (809 mg). Step 3: (R)-1-(5-Amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazol-1-yl)-3 - tert-butyl propionate of cyclopropylpropan-2-ylcarbamate

To a solution of tert-butyl (R)-1-cyclopropyl-3-hydroxypropan-2-ylcarbamate (809 mg, 3.8 mmol) in DCM (20 mL) 7.5 mmol) and MsCl (0.32 ml, 4.1 mmol). The reaction mixture was stirred at 0 ° C for 1 hour. Was added NaHCO ₃ (20 ml), then (20 ml) and extracted with DCM, and dried over Na ₂ SO _4, which was used directly in the next step. The crude product was dissolved in DMF (6 mL) then Cs ₂ CO ₃ (1. <RTI ID=0.0></RTI></RTI></RTI> 7.5 mmol) and 5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)- 1H-pyrazole-4-carbonitrile (716 mg, 3.0 mmol). The reaction mixture was heated to 60 ° C for 2 hours. The residue was purified by preparative EtOAc (EtOAc/EtOAc) MS (ESI) m/e [M+1] + 436. Step 4: 5-Amino-1-((R)-2-amino-3-cyclopropylpropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridyl Oxazole-4-carbonitrile hydrochloride

(R)-1-(5-Amino-4-cyano-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazol-1-yl)-3-cyclo tert-Butyl propylpropan-2-ylcarbamate (500 mg) was dissolved in HCl / dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The TLC shows that the SM is completely consumed. The solvent was removed in vacuo to give a white solid (460 mg). MS (ESI) m/e [M+1]+ 336. Step 5: 5-Amino-1-((R)-2-amino-3-cyclopropylpropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyridyl Oxazol-4-carboxamide

To 5-amino-1-((R)-2-amino-3-cyclopropylpropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole- To a solution of 4-carbonitrile hydrochloride (460 mg) in methanol (15 ml) was added 5M EtOAc (5 mL). The reaction mixture was cooled to 10 ° C then DMSO (1 mL) and 30% H ₂ O ₂ (2 mL). The mixture was heated to 50 ° C for 2 hours. The TLC shows that the SM is completely consumed. The solvent was removed under EtOAc (EtOAc)EtOAc. MS (ESI) m/e [M+1] + 354. Step 6: 1-((R)-2-Propylamino-3-cyclopropylpropyl)-5-amino-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H -pyrazole-4-carboxamide

To 5-amino-1-((R)-2-amino-3-cyclopropylpropyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H- at 0 °C pyrazole-4-acyl-amine (170 mg, 0.48 mmol) was added _{NaHCO 3 (81 mg, 0.96 mmol} ) and Bing Xixi chloride (48 mg in CH ₃ CN (10 ml) and a solution (8 ml) in water , 0.53 mmol). The reaction mixture was stirred at 0 ° C for 15 minutes. Addition of 10 ml of water, EtOAc, EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.21 - 8.09 (m, 1H), 7.16 (d, J = 2.8 Hz, 4H), 6.65 (s, 2H), 6.37 - 6.10 (m, 4H), 5.67 (dd, J = 10.1, 2.2 Hz, 1H), 4.25 (dd, J = 8.5, 4.7 Hz, 1H), 4.00 - 3.91 (m, 2H), 3.49 - 3.42 (m, 1H), 3.10 - 2.80 ( m, 4H), 2.19 (d, J = 10.4 Hz, 1H), 1.89 - 1.70 (m, 1H), 1.54 - 1.30 (m, 2H), 0.78 (d, J = 6.5 Hz, 1H), 0.51 - 0.37 (m, 2H), 0.21 - 0.13 (m, 1H), 0.01 (dt, J = 8.7, 4.8 Hz, 1H). MS (ESI) m/e [M+1] + 408.

Compound 1.63 is prepared according to the procedure described for the synthesis of compound 1.62 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (dd, J = 8.3, 4.3 Hz, 1H), 7.16 (d, J = 2.9 Hz, 4H), 6.65 (s, 2H), 6.34 - 6.11 ( m, 4H), 5.67 (dd, J = 10.1, 2.2 Hz, 1H), 4.30 - 4.20 (m, 1H), 3.96 (d, J = 6.1 Hz, 2H), 3.50 - 3.43 (m, 1H), 3.10 - 2.81 (m, 4H), 2.19 (d, J = 13.1 Hz, 1H), 1.88 - 1.71 (m, 1H), 1.54 - 1.30 (m, 2H), 0.79 (s, 1H), 0.51 - 0.38 (m , 2H), 0.22-0.12 (m, 1H), 0.05-0.04 (m, 1H). MS (ESI) m/e [M+1] + 408.

Compound 1.64 is prepared according to the procedure described for the synthesis of compound 1.11 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23-7.25 (d, J = 7.2 Hz, 1H), 7.08-7.15 (m, 2H), 6.59-6.68 (m, 4H), 6.23 (s, 2H ), 3.94-4.39 (m, 3H), 3.32-3.51 (m, 2H), 2.71-3.19 (m, 8H), 2.21 (s, 6H), 1.45-1.91 (m, 5H). MS (ESI) m/e [M+1] ⁺ 485. Compound 1.65: 1-(((2S,4S)-1-propenyl-4-(dimethylamino)pyrrolidin-2-yl)methyl)-5-amino-3-(1,2,3 ,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: (2S,4S)-4-(Dimethylamino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Stirred solution of (2S,4S)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.9 g, 18 mmol) in THF at 0 °C NaBH ₄ (1.7 g, 45 mmol) and LiCl (1.67 g, 40 mmol) were added, followed by dropwise addition of EtOH. After the addition, the mixture was stirred at room temperature for 16 hours. The mixture was concentrated, followed by addition of 50 mL NaHCO ₃ solution and extracted with _{CH 2 Cl 2 (50 mL x} 3). The combined extracts were washed with brine (50 mL x 2) washed, dried over Na ₂ SO _4, and concentrated to give 2.9 g of crude product. The 1.6 g crude product with CH ₂ Cl ₂ / MeOH elution was purified (100: 1: 1 to 40) column chromatography to give the title product (810 mg, yield: 32%) as a pale yellow solid. MS: M/e 245 (M+1) ⁺ . Step B: (2S,4S)-4-(Dimethylamino)-2-carboxanylpyrrolidine-1-carboxylic acid tert-butyl ester

At -78 ℃, under N _2, the DMSO (400 mg, 5.1 mmol) was added dropwise to oxalyl acyl chloride in ₂ mL CH 2 Cl 2 solution (510 mg, 4 mmol) in ₂ mL CH 2 Cl 2 in In the solution. After stirring for 10 minutes, slowly added below -60 ℃ product of Step A (250 mg, 1 mmol) solution in ₂ mL CH 2 Cl 2 in. The mixture was stirred for 4 hours. Injection _{Et 3 N (800 mg, 8} mmol) in CH ₂ Cl ₂ was 2 mL, and then the mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with 20 mL _{CH 2 Cl 2, (20 mL} x 3) and washed with brine, dried, and concentrated to dryness to give the crude product (280 mg), as a pale yellow oil which was used directly in the next step . MS: M/e 243 (M+1) ⁺ . Step C: (2S,4S)-2-((E)-(2-(tert-Butoxycarbonyl)phosphonium)methyl)-4-(dimethylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of the product from step B (280 mg, EtOAc) The mixture was concentrated to dryness to give crystals crystals crystals crystals crystals MS: M/e 357 (M+1) ⁺ . Step D: (2S,4S)-2-((2-(tert-Butoxycarbonyl)indolyl)methyl)-4-(dimethylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

Was added _{NaBH 3 CN (160 mg, 2.6} mmol) was stirred in a solution of: (1, 5 mL 1) was then ₂ O in a mixed solvent of AcOH / H in the product solution of Step C (380 mg, crude) The mixture was stirred for 5 hours. The mixture was concentrated, followed by addition of 10 mL NaOH aq (2M), and extracted with _{CH 2 Cl 2 (10 mL x} 5). The combined extracts were washed with brine (10 mL x 3), dried in Na ₂ SO _4, then concentrated to dryness by using _{CH 2 Cl 2 / MeOH (50} : 1 ~ 30: 1, 0.3% NH 3 / MeOH Purification by column chromatography eluting to give the title product (105 mg, yield: MS: M/e 359 (M+1) ⁺ . Step E: (3S,5S)-5-(cyanomethyl)-N,N-dimethylpyrrolidin-3-amine

HCl/EA (5 mL, 5 M) was added to a stirred solution of &lt;RTI ID=0.0&gt;&gt; The mixture was concentrated to dryness. EtOAc (EtOAc) MS: M/e 159 (M+1) ⁺ . Step F: 5-Amino-1-((2S,4S)-4-(dimethylamino)pyrrolidin-2-yl)methyl)-3-(1,2,3,4-tetrahydronaphthalene -2-yl)-1H-pyrazole-4-carbonitrile

The product of Step E (86 mg, 0.28 mmol) and 2-(methoxy(1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile (68 mg, 0.29 mmol) in a mixture of EtOH (2 mL) was added _{Et 3 N (200 mg, 2} mmol), and then the mixture was stirred for 3 hours. The mixture was concentrated to dryness to give title crystals (jjjjjjj MS: M/e 365 (M+1) ⁺ . Step G: 5-Amino-1-((2S,4S)-4-(dimethylamino)pyrrolidin-2-yl)methyl)-3-(1,2,3,4-tetrahydronaphthalene -2-yl)-1H-pyrazole-4-carboxamide

The product of Step F (158 mg, crude) was heated for 3 hours at 70 deg.] C in a solution of ₃ H (5 mL) MeSO. The mixture was cooled to room temperature, and then aqueous NaOH was added dropwise to pH~9. The mixture was extracted with CH ₂ Cl ₂ (20 mL×5). The combined extracts were washed with EtOAc EtOAc EtOAc m. MS: M/e 383 (M+1) ⁺ . Step H: 1-(((2S,4S)-1-propenyl-4-(dimethylamino)pyrrolidin-2-yl)methyl)-5-amino-3-(1,2,3 ,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

And _{NaHCO 3 (100 mg, 1.2 mmol} ) ₂ O in a mixed solvent of MeCN / H at room temperature, the product from Step G (145 mg, crude): Bing Xixi chloride was added dropwise a mixture of (1 1, 4 mL) in the (25 mg, 0.28 mmol) in MeCN (1 mL). The mixture was stirred for 2 hours. EA (10 mL) was added, the mixture was washed with brine (5 mL×3), dried and concentrated to dryness and then the residue was passed to the preparative TLC (CH ₂ Cl ₂ /MeOH = 12:1, 0.5% NH) Purification by ₃ /MeOH) EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.10 - 6.98 (m, 4H), 6.65-6.25 (m, 3H), 6.20 - 6.02 (m, 1H), 5.92 (s, 2H), 5.65 (s, 1H), 4.34 - 3.69 (m, 4H), 3.41 - 3.25 (m, 1H), 3.01 - 2.72 (m, 5H), 2.65 - 2.52 (m, 1H), 2.15 (s, 6H), 2.13 - 1.90 (m, 2H), 1.83 - 1.71 (m, 2H). MS: M/e 437 (M+1) ⁺ . Compound 1.65a: 1-(((2S,4S)-1-propenyl-4-(dimethylamino)pyrrolidin-2-yl)methyl)-5-amino-3-((R)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: 5-Amino-1-((2S,4S)-4-(dimethylamino)pyrrolidin-2-yl)methyl)-3-((R)-1,2,3,4 -tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

To (3S,5S)-5-(cyanomethyl)-N,N-dimethylpyrrolidin-3-amine (190 mg, 0.63 mmol) and (R)-2-(methoxy) at room temperature (1,2,3,4-tetrahydronaphthalen-2-yl) methylene) malononitrile (165 mg, 0.69 mmol) in a mixture of EtOH (5 mL) was added _{Et 3 N (600 mg, 2} mmol Then, the mixture was stirred for 3 hours. The mixture was concentrated. The residue was treated with 10 mL diluted with CH ₂ Cl _2, washed with brine (50 mL x 3) were washed, dried over Na ₂ SO _4, then concentrated to give the title product (280 mg, crude) as a dark brown solid, direct Used in the next step. MS: M/e 365 (M+1) ⁺ . Step B: 5-Amino-1-((2S,4S)-4-(dimethylamino)pyrrolidin-2-yl)methyl)-3-((R)-1,2,3,4 -tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product of Step A (280 mg, crude) was heated for 3 hours at 70 deg.] C in a solution of ₃ H (5 mL) MeSO. The mixture was cooled to room temperature, and then aqueous NaOH was added dropwise to pH~9. The mixture was extracted with CH ₂ Cl ₂ (20 mL×5). The combined extracts were washed with brine (20 mL EtOAc)EtOAc. MS: M/e 383 (M+1) ⁺ . Step C: 1-(((2S,4S)-1-propenyl-4-(dimethylamino)pyrrolidin-2-yl)methyl)-5-amino-3-((R)-1 ,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

And _{NaHCO 3 (180 mg, 1.2 mmol} ) ₂ O in a mixed solvent of MeCN / H in the product solution of Step B (170 mg, crude): Bing Xixi chloride was added dropwise a mixture of (1 1, 5 mL) in the (40 mg, 0.45 mmol) in MeCN (1 mL). The mixture was stirred for 2 hours. EA (20 mL) was added and the mixture was washed with brine (10 mL EtOAc) The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ , 80 ° C) δ 7.05 (s, 4H), 6.75-6.25 (m, 3H), 6.20 - 6.02 (m, 1H), 5.92 (s, 2H), 5.75 - 5.45 (m, 1H), 4.45 - 3.69 (m, 4H), 3.45 - 3.25 (m, 1H), 3.01 - 2.72 (m, 5H), 2.66 - 2.50 (m, 1H), 2.15 (s, 6H), 2.13 - 1.90 (m, 2H), 1.83 - 1.71 (m, 2H). MS: M/e 437 (M+1) ⁺ . Ee: 100%, retention time: 9.662 minutes.

The analysis conditions for palmity are as follows.

Compound 1.66a was prepared according to the procedure described for the synthesis of compound 1.65a under the appropriate conditions known to those of ordinary skill in the art.

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.70 - 6.50 (m, 3H), 6.27 - 5.98 (m, 3H), 5.81 - 5.40 (m, 1H), 4.47 - 4.20 (m, 1H), 4.06 - 3.84 (m, 2H), 3.80 - 3.49 (m, 1H), 3.31 - 3.15 (m, 2H), 3.08 - 2.72 (m, 4H), 2.61 - 2.52 (m, 1H ), 2.19 - 2.06 (m, 7H), 2.04 - 1.93 (m, 1H), 1.84 - 1.63 (m, 2H)ppm. MS: M/e 437 (M+1) ⁺ . Compound 1.67a: 1-(((2S,4R)-1-propenyl-4-(2-(dimethylamino)ethoxy)pyrrolidin-2-yl)methyl)-5-amino- 3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide Step A: 2-Chloro-N,N-dimethylethylamine hydrochloride

To a solution of 2-(dimethylamino)ethanol (2.0 g, 22.5 mmol) in DCM (20 mL), EtOAc (EtOAc) The reaction mixture was then stirred at room temperature overnight. The solvent was removed and the residue was suspended in EtOAc:EtOAc (EtOAc) The mixture was filtered, then the solid was collected and dried to give product (3.2 g, yield: 100%) Step B: (2S,4R)-4-(2-(dimethylamino)ethoxy)pyrrolidine-1, 2-tert-butyl 2-dicarboxylate 2-methyl ester

Add NaH to a solution of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.3 g, 17.5 mmol) in DMF (50 mL). (1.75 g, 43.8 mmol). The reaction mixture was stirred at 0 ° C for 15 minutes. The product of Step A (3.0 g, 21 mmol) was then added at 0 °C. Warm to room temperature and stir the mixture at room temperature overnight. The reaction mixture was at 0 ℃ with H ₂ O (20 mL) and quenched. The mixture was diluted with H ₂ O (50 mL), then extracted with DCM (50 mL x 3). The combined extracts were washed with brine (50 mL x 2) washed, dried over Na ₂ SO _4, and concentrated to give the product, which was by treatment with CH ₂ Cl ₂ / MeOH: elution was purified (101) by column chromatography, The title product was obtained (650 mg, yield: 12%) as pale yellow solid. MS: M/e 317 (M+1) ⁺ . Step C: (2S,4R)-4-(2-(Dimethylamino)ethoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Add NaBH ₄ (190 g, 5.0 mmol) and LiCl (187 g, 4.4 mmol) to a stirred solution of the product from step B (650 mg, 2.0 mmol) in THF (6 mL). EtOH (4 mL). After the addition, the mixture was stirred at room temperature for 2 days. The mixture was concentrated and the mixture was suspended in DCM (50 mL). The mixture was filtered and the filtrate was concentrated to give the crude product, which was by treatment with CH ₂ Cl ₂ / MeOH: purification eluting (20 1) column chromatography to give the title product (300 mg, yield: 50%), which It is a yellow oil. MS: M/e 289 (M+1) ⁺ . Step D: (2S,4R)-4-(2-(Dimethylamino)ethoxy)-2-carboxyryrrolidine-1-carboxylic acid tert-butyl ester

At -78 ℃, under N _2, to the acyl chloride oxalyl (635 mg, 5 mmol) in ₂ mL CH 2 Cl 2 was added dropwise DMSO (468 mg, 6 mmol) 2 mL CH 2 Cl 2 at The solution. After stirring for 10 minutes, a solution of the product of Step C (300 mg, 1 mmol) in 2 mL CH ₂ Cl ₂ was slowly added at -60 °C. The mixture was stirred for 2 hours. Injection _{Et 3 N (800 mg, 8} mmol) in CH ₂ Cl ₂ was 2 mL, the mixture was warmed to room temperature and then stirred for 1 hour. The mixture was diluted with H ₂ O 10 mL, and extracted with DCM (15 mL x 5), dried and concentrated to dryness to give the crude product (410 mg), as a yellow oil which was used directly in the next step. MS: M/e 287 (M+1) ⁺ . Step E: (2S,4R)-2-((E)-(2-(tert-Butoxycarbonyl)phosphonium)methyl)-4-(2-(dimethylamino)ethoxy)pyrrole Alkyl-1-carboxylic acid tert-butyl ester

A mixture of the product from step D (410 mg, EtOAc) elute The mixture was concentrated to dryness to give crystals crystals crystals crystals MS: M/e 401 (M+1) ⁺ . Step F: (2S,4R)-2-((2-(tert-Butoxycarbonyl)indolyl)methyl)-4-(2-(dimethylamino)ethoxy)pyrrolidine-1-carboxylic acid Tert-butyl ester

At room temperature in Step E product (500 mg, crude) ₂ O in a mixed solvent of AcOH / H: was added _{NaBH 3 CN (95 mg, 1.5} mmol) was stirred in a (1 1, 4 mL) the solution was then The mixture was stirred for 3 hours. The mixture was concentrated and the residue was taken to aq. The mixture was then extracted with _{CH 2 Cl 2 (10 mL x} 5). The combined organic extracts were washed with brine (10 mL) was washed, dried Na ₂ SO _4, concentrated to dryness, then with CH ₂ Cl ₂ / MeOH: elution (251, 0.3% NH ₃ / MeOH) to Purification by column chromatography gave the title product (260 mg, EtOAc, MS: M/e 403 (M+1) ⁺ . Step G: 2-(((3R,5S)-5-(Cyanomethyl)pyrrolidin-3-yl)oxy)-N,N-dimethylethylamine hydrochloride

HCl/EA (5 mL, 5 M) was added to a stirred solution of EtOAc (EtOAc, EtOAc. The mixture was concentrated to dryness to give the title product (360 mg, yield: 100%) as white solid. MS: M / e 203 (M + 1) +. Step H: 5-Amino-1-((2S,4R)-4-(2-(dimethylamino)ethoxy)pyrrolidin-2-yl)methyl)-3-((R)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carbonitrile

The product of Step E (360 mg, 0.65 mmol) and (R)-2-(methoxy(1,2,3,4-tetrahydronaphthalen-2-yl)methylene)malononitrile at room temperature (155 mg, 0.65 mmol) was added in EtOH (5 mL) of the Et ₃ N (0.5), and then the mixture was stirred for 1 hour. The mixture was concentrated to dryness, then with CH ₂ Cl ₂ / MeOH: elution was purified (101, 0.3% NH ₃ / MeOH) column chromatography to give the title product (150 mg, crude) as a yellow solid. MS: M/e 409 (M+1) ⁺ . Step I: 5-Amino-1-((2S,4R)-4-(2-(dimethylamino)ethoxy)pyrrolidin-2-yl)methyl)-3-((R)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

The product from Step H (150 mg, crude) was heated for 3 hours at 70 deg.] C in a solution of ₃ H (5 mL) MeSO. The mixture was cooled to room temperature and then adjusted to pH ~ 8 by dropwise addition of aqueous NaOH (2N) at 0 °C. The mixture was extracted with CH ₂ Cl ₂ (15 mL×5). The combined extracts were washed with EtOAc EtOAc m. MS: M/e 427 (M+1) ⁺ . Step J: 1-(((2S,4R)-1-propenyl-4-(2-(dimethylamino)ethoxy)pyrrolidin-2-yl)methyl)-5-amino-3 -((R)-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazole-4-carboxamide

And _{NaHCO 3 (87 mg, 1.0 mmol} ) ₂ O in a mixed solvent of MeCN / H in the product of step I 0 ℃ (110 mg, crude): Bing Xixi chloride was added dropwise a mixture of (1 1, 4 mL) in the (24 mg, 0.26 mmol) in MeCN (1 mL). The mixture was stirred for 10 minutes. Add EA (50 mL), EtOAc (EtOAc (EtOAc)EtOAc. ), which is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.07 (s, 4H), 6.71 - 6.50 (m, 2H), 6.26 - 5.99 (m, 3H), 5.76 - 5.42 (m, 1H), 4.51 - 4.22 (m, 1H), 4.13 - 4.02 (m, 1H), 3.98 - 3.82 (m, 1H), 3.64 - 3.49 (m, 1H), 3.46 - 3.37 (m, 3H), 3.04 - 2.76 (m, 4H) , 2.39 - 2.28 (m, 2H), 2.15 - 1.65 (m, 12H). MS: M/e 481 (M+1) ⁺ . Example 2 : Synthesis of Compound 2.1 to 2.11 Compound 2.1: 1-(2-Acrylaminobenzyl)-5-amino-3-(6,7,8,9-tetrahydro-5H-benzo[7] Cycloalkenyl-6-yl)-1H-pyrazole-4-carboxamide

Compound 2.1 was prepared according to the procedure described for compound 1.20 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.41 (br.s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.19 - 7.02 (m, 6H), 6.78 - 6.50 (m, 3H), 6.29 (d, J = 18.4 Hz, 1H), 5.79 (d, J = 10.4 Hz, 1H), 4.31 (s, 2H), 3.18 (d, J = 9.2 Hz, 2H), 2.88 - 2.71 (m, 3H), 2.17 - 1.78 (m, 3H), 1.40 (d, J = 14.0 Hz, 1H) ppm. MS: M/e 430 (M+1) ⁺ compound 2.2: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(6,7, 8,9-tetrahydro-5H-benzo[7]cycloalkenene-6-yl)-1H-pyrazole-4-carboxamide

Compound 2.2 is prepared according to the procedure described for compound 1.14 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.16 - 7.00 (m, 4H), 6.56 (br.s, 1H), 6.43 - 5.95 (m, 3H), 5.80 - 5.38 (m, 2H), 4.45 - 4.18 (m, 1H), 4.12 - 3.85 (m, 2H), 3.49 (br.s, 2H), 3.16 - 2.68 (m, 5H), 2.13 - 2.01 (m, 2H), 1.84 (s, 5H) , 1.53 - 1.33 (m, 1H) ppm. MS: M/e 408 (M+1) ⁺ compound 2.3: 1-((R)-1-propenylindazin-3-yl)-5-amino-3-(6,7,8,9- Tetrahydro-5H-benzo[7]cyclopentene-6-yl)-1H-pyrazole-4-carboxamide

Compound 2.3 is prepared according to the procedure described for compound 1.15 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23 - 7.00 (m, 4H), 6.95 - 6.72 (m, 1H), 6.48 (br.s, 2H), 6.21 - 6.01 (m, 1H), 5.77 - 5.60 (m, 1H), 4.41 - 3.97 (m, 3H), 3.44 - 2.67 (m, 7H), 2.16 (d, J = 12.4 Hz, 1H), 2.06 - 1.72 (m, 5H), 1.45 - 1.36 (m, 2H) ppm. MS: M / e 408 (M + 1) + Compound 2.4: 1 - ((R) -1- Bing Xixi piperidin-3-yl) -5-amino-3- (2,3,4,5- Tetrahydrobenzo[b]oxacyclohepten-4-yl)-1H-pyrazole-4-carboxamide Step A: ethyl 4-(2-methylnonylphenoxy)butanoate

To a solution of 2-hydroxybenzaldehyde (122 g, 1.0 mol) and ethyl 4-bromobutyrate (195 g, 1.0 mol) in DMF (500 mL) was added Cs ₂ CO ₃ (325 g, 1.0 mol), the reaction mixture was stirred at room temperature for 3 hours. The mixture (1500 mL) and quenched with H ₂ O, was added EA (1500 mL), the organic layer was washed with brine (500 mL) washed, dried Na ₂ SO _4, then concentrated to give a yellow oil (W = 224 g, Y = 95%) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 7.62-7.70 (m, 2H), 7.22 (d, 1H, J = 8.4 Hz), 7.07 (t, 1H, J = 7.2 Hz), 4.16 (t, 2H, J = 6.0 Hz), 4.05 (q, 2H, J = 7.2 Hz), 2.50-2.51 (m, 2H), 1.99-2.08 (m, 2H) and 1.15.19.19 (q , 3H, J = 7.2 Hz). MS (ESI) m / e [M+1] ⁺ 237 Step B: 2,3,4,5-tetrahydrobenzo[b]oxepane-4-carboxylic acid methyl ester

Add CH ₃ ONa (5.4 M in MeOH) to a solution of ethyl 4-(2-carbamidophenoxy)butanoate (32 g, 135 mmol) in dimethyl carbonate (600 mL) at 50 °C Solution (30 mL, 162 mmol), which was stirred at 50 ° C for an additional 2 hours. The mixture was quenched with H ₂ O (600 mL), was added EA (600 mL; The organic layer was washed with brine (200 mL), dried Na ₂ SO _4, then concentrated and the residue was dissolved in EA / MeOH (100. In mL/100 mL), 10% palladium on carbon (50% aqueous, 5.0 g) was then added, and the reaction mixture was subjected to hydrogenation reaction with H ₂ at a pressure of 1.5 MPa and allowed to react overnight. The catalyst was removed by filtration, and the filtrate was concentrated. the residue was purified by using PE / EA for (1: 10: 5-1) as the eluent to silica gel chromatography to afford 19.0 g (Y = 68%) product as a yellow oil ¹ H NMR (400. MHz, DMSO- d ₆ ) δ 7.13-7.22 (m, 2H), 6.92-7.01 (m, 2H), 4.18-4.23 (m, 1H), 3.74-3.79 (m, 2H), 3.61 (s, 3H) , 2.96-2.97 (m, 2H), and 1.99-2.13 (m, 2H) .MS ( ESI) m / e [m + 1] + 207 step C: 2,3,4,5- tetrahydrobenzo [b Oxepane-4-carboxylic acid

To 2,3,4,5-tetrahydrobenzo[b]oxepane-4-carboxylic acid methyl ester (19.0 g, 92.2 mmol) in MeOH/H ₂ O (150 mL/) at 5 °C - 10 °C. Lithium hydroxide (13.8 g, 276.6 mmol) was added to the solution in 50 mL), and the mixture was stirred at room temperature for 5 hr. The solvent was then removed under reduced pressure. The residue was acidified to pH = 3-4 with 1N EtOAc and filtered to give a white solid, which was dried in an infrared oven (W = 17.0 g, Y = 96%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.36 (s, 1H), 7.12-7.22 (m, 2H), 6.92-7.00 (m, 2H), 4.14-4.24 (m, 1H), 3.73-3.78 (m, 2H), 2.90-2.99 (m, 2H) and 1.99-2.13 (m, 2H). MS (ESI) m / e [M+1] ⁺ 193 Step D: 2-(hydroxy(2,3,4,5-tetrahydrobenzo[b]oxacyclohept-4-yl)methylene Malononitrile

2,3,4,5-Tetrahydrobenzo[b]oxaepene-4-carboxylic acid (24.6 g, 128 mmol) was suspended in EA (200 mL) then HOBt (19.0 g, 141 mmol) ), and the mixture was stirred at room temperature for 0.5 h, then _{Et 3 N (38.8 g, 384} mmol was added), the reaction mixture was stirred for 0.5 hours and then was added EDCI (27.09 g, 141 mmol) , the mixture was stirred for 0.5 hours, Then malononitrile (9.3 g, 141 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H ₂ O quenched by adding EA (200 mL), washed with aqueous NaHCO ₃ (500 mL), then the organic layer with H ₂ SO ₄ aqueous solution _{(25g / 200 mL H 2 O} ) was stirred for 3 hours. It was then concentrated directly to give a yellow oil which was crude (w = 27.0 g, Y = 88%). MS (ESI) m/e [M+1] ⁺ 241. Step E: 5-Amino-3-(2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carbonitrile

Dissolving 2-(hydroxy(2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)methylene)malononitrile (27.0 g, 112.5 mmol) in trimethoxy In methane (600 mL), the reaction mixture was heated to 100 ° C for 5 h. The solvent was removed under reduced pressure to give a crude material, which was dissolved in EtOH (100 mL), and then hydrated hydrazine (6.12 g, 123.75 mmol) was added at 5 ° C to 10 ° C for 0.1 hour. The reaction mixture was stirred at room temperature overnight then the solvent was evaporated. The residue was purified by EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.66 (s, 1H), 7.14-7.20 (m, 2H), 6.94-7.01 (m, 2H), 6.30 (s, 2H), 4.37-4.40 (m , 1H), 3.66-3.71 (m, 1H), 3.35 (m, 1H), 2.85-2.89 (m, 2H) and 2.06-2.23 (m, 2H). Step F: 5-Amino-3-(2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide

5-Amino-3-(2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carbonitrile (4.7 g, 18.5 mmol) The solution in H ₃ PO ₄ (60 mL) was stirred at 130 ° C for 1 hour. LC/MS showed the reaction was complete. The mixture was poured into ice water and then adjusted to pH > 8 with aqueous NaOH. The mixture (100 mL × 3) extracted with EtOAc, dried over Na ₂ SO _4, filtered, and concentrated to give a crude product, which was purified by with EtOAc (3 L) eluting silica gel (150 g) column chromatography, to give Product (2 g, 40%) as a brown solid. MS (ESI) m/e [M+1] ⁺ 273. Step G: (3R)-3-(5-Amino-4-carbamoyl-3-(2,3,4,5-tetrahydrobenzo[b]oxeph-4-yl)- 1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester

To 5-Amino-3-(2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide (600 mg, 2.21 mmol ( S )-3-(Toluenesulfonyloxy)acridine-1-carboxylic acid tert-butyl ester (BL-1, 1.6 g, 4.42 mmol) and Cs ₂ CO were added to a solution in DMF (30 mL) ₃ (1.44 g, 4.42 mmol). The mixture was stirred at 70 ° C overnight. After cooling to room temperature, the solvent was removed in vacuo. H ₂ O (50 mL) was added toEtOAc. The organic layer was purified by EtOAc EtOAc (EtOAc) MS (ESI) m/e [M+1] ⁺ 456. Step H: 5-Amino-1-((R)-acridin-3-yl)-3-(2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl) -1H-pyrazole-4-carboxamide

To (3R)-3-(5-amino-4-carbamyl-3-(2,3,4,5-tetrahydrobenzo[b]-oxepan-4-yl)-1H - pyrazol-1-yl) piperidine-1-carboxylate (200 mg, 0.44 mmol) was added _{CF 3 CO 2 H (2 mL} (20 mL) solution in DCM), then stirred for 30 minutes. TLC showed the reaction was complete. ₃ the mixture is adjusted pH> 8 with saturated NaHCO. The aqueous layer was extracted with DCM (20 mL), dried over Na ₂ SO _4, filtered, and concentrated to give the product (390 mg, 250%), as a brown oil, which was used without further purification for the next In one step. Step I: 1-((R)-1-Prodecylacridin-3-yl)-5-amino-3-(2,3,4,5-tetrahydrobenzo[b]oxeene -4-yl)-1H-pyrazole-4-carboxamide

To 5-amino-1-((R)-acridin-3-yl)-3-(2,3,4,5-tetrahydrobenzo[b]oxacyclohept-4-yl at 0 °C ) acyl lH-pyrazole-4-amine (390 mg, 1.1 mmol) and Et ₃ N (2ml) was slowly added dropwise Bing Xixi chloride solution in DCM (99 mg, 1.1 mmol). The mixture was stirred at 0 ℃ 2 minutes, treated with H ₂ O (30 ml) was quenched and extracted with DCM (30 ml × 2), dried over Na ₂ SO _4, filtered, and concentrated, to give a crude product which was purified by preparative Purification by HPLC gave the product (46.32 mg, 10%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.11-7.18 (m, 2H), 6.92-6.99 (m, 2H), 6.73-6.89 (m,1H), 6.56 (s, 2H), 6.20 (s , 2H), 6.04-6.15 (m, 1H), 5.61-5.71 (m, 1H), 4.35-4.40 (m, 1H), 3.94-4.27 (m, 2H), 3.69-3.74 (m, 1H), 3.27 -3.45 (m, 2H), 2.80-3.12 (m, 4H), 1.83-2.12 (m, 5H), 1.34-1.47 (m, 1H). MS (ESI) m/e [M+1] ⁺ 410.

Compound 2.4 was separated into two stereoisomers (pre-peak compound 2.4a and post-peak compound 2.4b) by palm-prepared HPLC. The conditions for palm separation are as follows: Compound 2.5: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(2,3,4,5-tetrahydrobenzo[b]oxy Heterocyclic heptene-4-yl)-1H-pyrazole-4-carboxamide

Compound 2.5 was prepared according to the procedure described for compound 2.4 under appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.11-7.16 (m, 2H), 6.92-6.99 (m, 2H), 6.55-6.93 (m, 1H), 6.36 (s, 2H), 6.17-6.19 (m,1H), 6.96 (s, 2H), 5.64-5.69 (m, 1H), 4.36-4.41 (m, 1H), 4.21-4.23 (m, 1H), 4.04-4.07 (m, 1H), 3.89 -3.94 (m, 1H), 3.72-3.79 (m, 1H), 3.45-3.47 (m, 2H), 3.24-3.29 (m, 1H), 2.87-2.93 (m, 1H), 2.12-2.15 (m, 1H) and 1.76-1.83 (m, 4H). MS (ESI) m/e [M+1] ⁺ 410. Compound 2.6: 1-(2-Acrylaminobenzyl)-5-amino-3-(2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H- Pyrazole-4-carboxamide

Compound 2.6 is prepared according to the procedure described for compound 1.20 under the appropriate conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.11-7.17 (m, 3H), 6.93-7.00 (m, 3H), 6.49-6.64 (m, 3H), 6.29-6.34 (m, 3H), 5.81 (d, J = 10.0 Hz, 1H), 5.13 (s, 2H), 4.36 -4.40 (m, 1H), 3.69-3.75 (m, 1H), 3.29-3.32 (m, 1H), 2.89-3.07 (m, 2H), 2.06-2.15 (m, 2H). MS (ESI) m/e [M+1] ⁺ 432. Compound 2.7: 1-((R)-1-propenyloxaridin-3-yl)-5-amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxy Heterocyclic heptene-4-yl)-1H-pyrazole-4-carboxamide Step A: 4-fluoro-2-hydroxybenzaldehyde

Add 3-ethylamine (34 mL, 190 mmol) and paraformaldehyde (11 g, 372) to a mixture of 3-fluorophenol (5 mL, 51 mmol), anhydrous magnesium chloride (14.1 g, 372 mmol) in 250 mL EtOAc. Mm). The mixture was then heated to reflux and held for 5 hours. After cooling to room temperature, 250 mL of 5% aqueous HCl solution was added and extracted with EA (100 mL×2). The combined organic layers were washed with 5% aqueous HCl (100 mL × 2), washed with brine, dried over Na ₂ SO _4, concentrated and purified by column chromatography to give the desired product (2.7 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.36 (s, 1H), 9.84 (s, 1H), 7.54-7.58 (m, 1H), 6.65-6.75 (m, 2H) Step B: 4-(5- Ethyl fluoro-2-formylphenoxy)butyrate

4-Fluoro-2-hydroxybenzaldehyde (2.7 g, 19.3 mmol), ethyl 4-bromobutyrate (4.0 g, 20.5 mmol) and K ₂ CO ₃ (3.5 g, 25.4 mmol) in DMF (30 mL) The mixture was heated to 80 ° C for 2 hours. After cooling to room temperature, the mixture was poured into water (200 mL), extracted with EA (100 mL×2), and the combined organic layers were washed with brine to Na ₂ sulfate SO _4, concentrated and then purified by column chromatography to give the product (4.8 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 7.76 (dd, J = 8.8, 7.2 Hz, 1H), 7.15 (dd, J = 11.6, 2.4 Hz, 1H), 6.91 ( Dd, J = 8.4, 2.0 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 2.49-2.51 (m, 2H), 2.04-2.06 (m , 2H), 1.17 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M+1] ⁺ 255. Step C: (E)-8-Fluoro-2,3-dihydrobenzo[b]oxepane-4-carboxylic acid methyl ester

Add CH ₃ ONa (5.4 M) to a solution of ethyl 4-(5-fluoro-2-carboxyphenoxy)butanoate (3.81 g, 15 mmol) in dimethyl carbonate (30 mL) at 50 °C Solution in MeOH) (3.0 mL, 15 mmol). The reaction mixture was stirred at 50 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with EA (100 mL) and H ₂ O (100 mL) quenched, the organic layer was washed with brine (100 mL) washed, dried Na ₂ SO _4, then concentrated to give a yellow oil The material was crude (w = 3.0 g, Y = 90%). MS (ESI) m/e [M+1] ⁺ 223. Step D: Methyl 8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxeph-4-carboxylate

Methyl (E)-8-fluoro-2,3-dihydrobenzo[b]oxepane-4-carboxylate (3.0 g, 13.5 mmol) was dissolved in MeOH (30 mL) then 10 % palladium on carbon (50% aqueous, 5.0 g), the reaction mixture was hydrogenated with hydrogen at a pressure of 1.5 Mpa overnight. The catalyst was removed and the filtrate was evaporated to give a crystallite. MS (ESI) m / e [ M + 1] + 225. Step E: 8-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxepene-4-carboxylic acid

To a solution of methyl 8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxacycloheptene-4-carboxylate (2.8 g, 12.5 mmol) in MeOH/H ₂ O at 5 ° C - 10 ° C Lithium hydroxide (1.76 g, 62.5 mmol) was added to a solution (20 mL / 20 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was then removed under reduced pressure. The residue was acidified to pH = 2-4 with 1N EtOAc (EtOAc)EtOAc. MS (ESI) m / e [M+1] ⁺ 211. Step F: 2-((8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl) (hydroxy)methylene)malononitrile

8-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxacycloheptene-4-carboxylic acid (1.8 g, 8.6 mmol) was suspended in EA (50 mL) then HOBt (1.16) g, 8.6 mmol), and the mixture was stirred at room temperature for 0.5 hours, then _{Et 3 N (1.74g, 17.2 mmol} ), the reaction mixture was stirred for 0.5 hours and then was added EDCI (1.65 g, 8.6 mmol) . After the mixture was stirred for additional 0.5 hours, malononitrile (577 mg, 8.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with EA (150 mL), (100 mL) and extracted with H ₂ O, then the organic layer with H ₂ SO ₄ aqueous solution _{(10g / 100 mL H 2 O} ) was stirred for 3 hours and then directly concentrated to give Yellow oil, which was crude (w = 2.7 g, Y = 100%). MS (ESI) m/e [M+1] ⁺ 259. Step G: 2-((8-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)(methoxy)methylene)malononitrile

2-((8-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)(hydroxy)methylene)malononitrile (2.70 g, 10.5 mmol) Dissolved in trimethoxymethane (30 mL) and the reaction mixture was heated to 100 ° C under N ₂ for 3 h. The solvent was removed under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS (ESI) m/e [M+1] ⁺ 273. Step H: 5-Amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl)-1H-pyrazole-4-carboxamide

2-((8-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)(methoxy)methylene)malononitrile (1.5 g, 5.5 mmol) was dissolved in EtOH (10 mL), then hydrazine hydrate (1.38 g, 27.5 mmol) was added at 5 ° C - 10 ° C over 0.1 hr. The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give a crude material which was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj and adjusted to pH = 7-9, and extracted with EA (50 mL × 2), then washed, dried Na ₂ SO ₄ with brine (100 mL), then concentrated to give the product as a white solid (800 mg, Y=50%). MS (ESI) m/e [M+1] ⁺ 291. Step I: (3R)-3-(5-Amino-4-carbamoyl-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepanene-4 -yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester:

5-Amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)-1H-pyrazole-4-carboxamide (290 Mg, 1 mmol), tert-butyl (S)-3-(toluenesulfonyloxy)acridine-1-carboxylate (710 mg. 2 mmol) and Cs ₂ CO ₃ (650 mg, 2 mmol) In DMF (10 mL), the reaction mixture was then heated to 70 ° C and kept overnight. After cooling to room temperature, the reaction mixture was diluted with _{EA (100 mL) / H 2} O (50 mL) quenched, and the organic layer was washed with brine (50 mL), dried Na ₂ SO _4, then concentrated. The residue was purified by EtOAc EtOAc (EtOAc) MS (ESI) m/e [M+1] ⁺ 474. Step J: 1-((R)-1-propenylfluoren-3-yl)-5-amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxy Heterocyclic heptene-4-yl)-1H-pyrazole-4-carboxamide

(3R)-3-(5-Amino-4-carbamimido-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl) -1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester (200 mg, 0.42 mmol) was suspended in DCM/TFA (3 mL / 1 mL). Then the solvent was removed under reduced pressure. The residue was dissolved in CH ₃ CN / H ₂ O in, NaHCO then added ₃ (84 mg, 1.26 mmol) and Bing Xixi chloride (38 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 3 hours and then with _{EA (50 mL) / H 2} O (50 mL) quenched, the organic layer was washed with brine, dried Na ₂ SO _4, then concentrated. The residue was purified by preparative HPLC to afford white solid (w=30, ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.16-7.20 (m, 1H), 6.78-6.83 (m, 3H), 6.60 (s, 2H), 6.05-6.10 (m, 3H), 5.63-5.71 (m,1H), 4.38-4.41 (m, 1H), 3.74-4.06 (m, 3H), 3.27-3.29 (m, 1H), 2.67-2.83 (m, 4H), 1.83-2.11 (m, 5H) And 1.23 (m, 1H). MS (ESI) m/e [M+1] ⁺ 428. Compound 2.8: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo [b]oxephen-4-yl)-1H-pyrazole-4-carboxamide Step A: (2S)-2-((5-Amino-4-carbamoyl-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepanene- 4-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

5-Amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide (compound) 2.7 Product of Step H in Synthesis, 500 mg, 1.72 mmol), tert-butyl (S)-2-(toluenesulfonyloxymethyl)pyrrolidine-1-carboxylate (BL-2, 1.22 g. 3.44 mmol And Cs ₂ CO ₃ (1.22 g, 2 mmol) was suspended in DMF (10 mL) then the mixture was warmed to 70 ° C and kept overnight. After cooling to room temperature, the reaction mixture was diluted with _{EA (100 mL) / H 2} O (50 mL) quenched, and the organic layer was washed with brine (50 mL), dried Na ₂ SO _4, then concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.16-7.20 (br.s, 1H), 6.78-6.83 (m, 2H), 6.56 (s, 2H), 6.04 (s, 2H), 4.3-4.42 (m, 1H), 3.74-3.95 (m, 3H), 3.27-3.29 (m, 2H), 2.94-3.18 (m, 4H), 2.10 (m, 2H), 1.72 (m, 3H) and 1.23 (m) , 9H). MS (ESI) m/e [M+1] ⁺ 474. Step B: 1-((()-1-propenylpyridrol-2-yl)methyl)-5-amino-3-(8-fluoro-2,3,4,5-tetrahydrobenzo [b]oxephen-4-yl)-1H-pyrazole-4-carboxamide

(2S)-2-((5-Amino-4-carbamoyl-3-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepane-4- tert-butyl-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylate (250 mg, 0.53 mmol) was suspended in DCM/TFA (3 mL / 1 mL). for 2 hours. the solvent was removed under reduced pressure. the residue was dissolved in CH ₃ CN / H ₂ O was added _{NaHCO 3 (89 mg, 1.06 mmol} ) and Bing Xixi chloride (48 mg, 0.53 mmol). the reaction mixture chamber temperature for 2 hours, then H ₂ O (50 mL) and extracted with EA (50 mL) /,, dried organic layer was washed with brine (50 mL) with at Na ₂ SO _4, and concentrated. the residue was purified by preparative HPLC Purification afforded the product (w = 80 mg, Y = 35%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.15-7.18 (m, 1H), 6.70-6.83 (m, 2H), 6.51-6.62 (m, 3H), 6.05-6.22 (m, 3H), 5.48-5.74 (m, 1H), 4.38-4.41 (m, 1H), 3.77-4.17 (m, 4H), 3.31- 3.49 (m, 3H), 2.95-3.01 (m, 2H), 2.08-2.11 (m, 2H) and 1.78-1.79 (m, 4H) MS (ESI) m/e [M+1] ⁺ 428. 2.9: 1-((R)-1-Prodecylacridin-3-yl)-5-amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxa Cycloheptene-4- -1H-pyrazole-4-carboxamide Step A: Methyl 4-(4-fluoro-2-methylnonylphenoxy)butanoate

To a solution of 5-fluoro-2-hydroxybenzaldehyde (42 g, 0.3 mol) and ethyl 4-bromobutyrate (58.5 g, 0.3 mol) in DMF (500 mL) at room temperature over 1 h Cs ₂ CO ₃ (117 g, 0.36 mol). The reaction mixture was diluted with EA (600 mL) and H ₂ O (1500 mL) was quenched, and the organic layer was washed with brine (500 mL × 2), dried over Na ₂ SO _4, then concentrated to give the product as a yellow oil (W = 75 g, Y = 98%) was used in the next step without further purification. MS (ESI) m/e [M+1] ⁺ 241. Step B: Methyl 7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxeph-4-carboxylate

To a solution of methyl 4-(4-fluoro-2-carboxyphenoxy)butanoate (75 g, 135 mmol) in dimethyl carbonate (1000 mL) at 50 ° C was added CH ₃ ONa (5.4 A solution of M in MeOH (60 mL, 325 mmol). The reaction mixture was stirred at 50 ° C for 2 hours. Mixture and H ₂ O (500 mL) quenched with EA (500 mL), the organic layer was washed with brine (500 mL), dried and concentrated. The residue was taken up in MeOH (500 mL) and 10% palladium / carbon (50% aqueous, 6.5 g). The reaction mixture was hydrogenated with hydrogen at a pressure of 1.5 Mpa overnight. The catalyst was removed and the filtrate was evaporated to give crystalljjjjjjjjjjjjjj MS (ESI) m/e [M+1] ⁺ 225. Step C: 7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxepene-4-carboxylic acid

To a solution of 7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepane-4-carboxylic acid methyl ester (50 g, 223 mmol) at MeOH/H ₂ O (500) Lithium hydroxide (17.86 g, 446 mmol) was added to the solution in mL / 100 mL) and the mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure. The residue was acidified with 6N HCl adjusted to pH = 3-4, and extracted with EA (500 mL × 2), and the organic layer was washed with brine (500 mL), dried over Na ₂ SO _4, then concentrated to give the crude product ( W = 31 g, Y = 67%), which was a white solid. MS (ESI) m/e [M+1] ⁺ 211. Step D: 2-((7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)(hydroxy)methylene)malononitrile

7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxepene-4-carboxylic acid (31 g, 147.6 mmol) was suspended in EA (200 mL) then HOBt (19.9) g, 147.6 mmol). The mixture was stirred at room temperature for 0.5 h, then _{Et 3 N (44.7 g, 443} mmol) was added. The reaction mixture was stirred for 0.5 h then EDCI (28.3 g, 147.6 mmol). After the mixture was stirred for additional 0.5 hours, malononitrile (9.74 g, 147.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with EA (200 mL), washed the organic layer with H ₂ SO ₄ aqueous solution _{(40g / 400 mL H 2 O} ) was stirred for 3 hours with H ₂ O (100 mL), and then directly concentrated to give a crude Product (w = 21 g, Y = 55%) as a yellow oil. MS (ESI) m/e [M+1] ⁺ 259. Step E: 5-Amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide

2-((7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)(hydroxy)methylene)malononitrile (21 g, 81.4 mmol) Dissolved in trimethoxymethane (150 mL) and the reaction mixture was heated to 100 ° C under N ₂ for 4 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) The mixture was then dissolved in EtOH (100 mL) over a period of 0.1 hr, and hydrazine hydrate (8.14 g, 162.8 <RTIgt; The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give crystals (16 g, m. MS (ESI) m/e [M+1] ⁺ 273. Step F: 5-Amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl)-1H-pyrazole-4-carboxamide

5-Amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide (16 g, 59 mmol) was suspended in methanesulfonic acid (60 mL) and the mixture was warmed to <RTI ID=0.0> After cooling to room temperature, the reaction mixture was quenched with ice/water (500 mL) then EtOAc (EtOAc) Washed, dried over Na ₂ SO ₄ and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.59 (br.s, 1H), 6.91-7.04 (m, 3H), 6.60 (s, 2H), 5.49 (br.s, 2H), 4.36-4.39 (m, 1H), 3.60-3.65 (m, 1H), 3.04-3.10 (m, 1H), 2.80-2.91 (m, 1H), 2.06-2.16 (m, 2H) and 0.82-0.85 (m, 1H) . MS (ESI) m/e [M+1] ⁺ 291. Step G: (3R)-3-(5-Amino-4-carbamoyl-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepanene-4 -yl)-1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester:

5-Amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide (1.5 g, 5.17 mmol), (s)-3-(toluenesulfonyloxy)acridine-1-carboxylic acid tert-butyl ester (BL-1, 3.67 g. 10.34 mmol) and Cs ₂ CO ₃ (3.38 g, 10.34 Methyl) was suspended in DMF (20 mL). The reaction mixture was heated to 80 ° C under N ₂ and kept overnight. After cooling to room temperature, the mixture was diluted with _{EA (100 mL) / H 2} O (100 mL) quenched, the organic layer was washed with brine (100 mL) washed, dried Na ₂ SO _4, then concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.94-7.00 (m, 3H), 6.58 (s, 2H), 6.21 (s, 2H), 4.32-4.35 (m, 1H), 4.04-4.08 (m , 1H), 3.70-3.89 (m, 3H), 3.30-3.34 (m, 1H), 2.67-3.03 (m, 3H), 1.83-2.11 (m, 5H) and 1.36-1.39 (m, 11H). MS (ESI) m/e [M+1] ⁺ 474. Step H: 1-((R)-1-propenyloxaridin-3-yl)-5-amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxy Heterocyclic heptene-4-yl)-1H-pyrazole-4-carboxamide

(3R)-3-(5-Amino-4-carbamimido-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl -1H-pyrazol-1-yl)acridine-1-carboxylic acid tert-butyl ester (800 mg, 1.69 mmol) was suspended in DCM/TFA (3 mL / 1 mL). . The solvent was removed under reduced pressure. The residue was dissolved in _{CH 3 CN / H 2 O (} 12 mL / 12 mL) , followed by addition of _{NaHCO 3 (286 mg, 3.4 mmol} ) and Bing Xixi chloride (183 mg, 2.02 mmol). The reaction mixture was stirred at room temperature for 3 hours and then with _{EA (50 mL) / H 2} O (50 mL) quenched, the organic layer was washed with brine, dried Na ₂ SO _4, then concentrated. The residue was purified by preparative EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.73-7.03 (m, 4H), 6.59 (s, 2H), 6.05-6.21 (m, 3H), 5.61-5.71 (m,1H), 3.95-4.36 (m, 3H), 3.68-3.70 (m, 1H), 3.27-3.42 (m, 2H), 2.82-3.11 (m, 4H), 1.83-2.09 (m, 5H) and 1.23 (m, 1H). MS (ESI) m / e [M+1] ⁺ 428 Compound 2.10: 1-(((S)-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(7- Fluorin-2,3,4,5-tetrahydrobenzo[b]oxacyclohepten-4-yl)-1H-pyrazole-4-carboxamide Step A: (2S)-2-((5-Amino-4-carbamoyl-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepanene- 4-yl)-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

5-Amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxaepene-4-yl)-1H-pyrazole-4-carboxamide (compound) 2.9 Product of Step F in the synthesis, 1.5 g, 5.17 mmol), (s)-2-(toluenesulfonyloxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.67 g, 10.34 mmol) and Cs ₂ CO ₃ (3.36 g, 10.34 mmol) was suspended in DMF (20 mL) and the mixture was warmed to 70 &lt;0&gt;C overnight. The reaction mixture was _{EA (100 mL) / H 2} O (50 mL) quenched the organic layer was washed with brine (50 mL) washed, dried Na ₂ SO _4, then concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.93-6.95 (m, 3H), 6.58 (s, 2H), 6.03 (s, 2H), 4.34-4.46 (m, 2H), 3.71-3.86 (m , 3H), 2.89-3.07 (m, 5H), 1.71-1.93 (m, 6H) and 1.23 (m, 9H). MS (ESI) m/e [M+1] ⁺ 474. Step B: 1-((())-1-propenylpyrrolidin-2-yl)methyl)-5-amino-3-(7-fluoro-2,3,4,5-tetrahydrobenzo [b]oxephen-4-yl)-1H-pyrazole-4-carboxamide

(2S)-2-((5-Amino-4-carbamoyl-3-(7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepane-4- tert-butyl-1H-pyrazol-1-ylmethyl)pyrrolidine-1-carboxylate (900 mg, 1.9 mmol) was suspended in DCM/TFA (5 mL / 2 mL). stirred for 2 hours. the solvent was removed under reduced pressure. the residue was dissolved in _{CH 3 CN / H 2 O (} 12 mL / 12 mL), then _{NaHCO 3 (319 mg, 3.8 mmol} ) was added and Bing Xixi chloride (206 mg, 2.28 mmol). the reaction mixture was stirred at room temperature for 2 hours, followed by _{EA (50 mL) / H 2} O (50 mL) quenched, and the organic layer was washed with brine (50 mL), dried over Na ₂ SO _4, and then and concentrated. the residue was purified by preparative HPLC to give the product (w = 300 mg, Y = 37%), as a white ^{solid. 1 H NMR (400 MHz,} DMSO- d 6) δ 6.91-7.01 (m, 3H), 6.50-6.70 (m, 3H), 6.02-6.23 (m, 3H), 5.49-5.74 (m, 1H), 4.33-4.39 (m, 2H), 3.27-3.91 (m, 6H), 2.87- 3.04 (m, 2H), 2.08-2.11 (m, 2H) and 1.78-1.79 (m, 4H). MS (ESI) m/e [M+1] ⁺ 428. Compound 2.11:1-(((()) 1-propenylpyridylpyrrolidin-2-yl)methyl)-5-amino-3-(2,3,4,5-tetrahydrobenzo[b]oxepan-4-yl)- 1H-pyrazole- 4-carboxamide

Compound 2.11 was prepared according to the procedure described for compound 2.5 under suitable conditions known to those of ordinary skill in the art.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.11-7.16 (m, 2H), 6.92-6.99 (m, 2H), 6.57-6.60 (m, 3H), 6.14-6.23 (m, 3H), 5.65 -5.74 (m, 1H), 4.37-4.41 (m, 1H), 4.17-4.18 (m, 1H), 3.89-4.03 (m, 2H), 3.71-3.74 (m, 1H), 3.26-3.43 (m, 3H), 2.89-3.02 (m, 2H), 2.10-2.13 (m, 2H) and 1.79-1.83 (m, 4H). MS (ESI) m/e [M+1] ⁺ 410 EGFR assay

Targeting the WT EGFR kinase domain (669-1210 amino acids, Carna Biosciences, 08-115), EGFR T790M/ in a time-resolved fluorescence-resonance energy transfer methodology assay The L858R kinase domain (amino acids 669-1210, Carna Biosciences, 08-510) and the EGFR L858R kinase domain (amino acids 669-1210, Carna Biosciences, 08-502) were tested for compounds of the invention. The assay is in a reaction mixture in 384-well low-volume black plates (containing EGFR kinase, 20 μM ATP (for EGFR WT and T790M/L858R), 125 μM (for EGFR L858R), biotin-TK substrate, and 0-0.5 μM Compound) was carried out in a solution of buffer (50 mM HEPES pH 7.5, 10 mM MgCl ₂ , 1 mM EGTA, 0.01% Brij-35, 2.5 mM DTT, 0.1% BSA). The kinase was incubated with the compounds of the invention for 120 minutes at room temperature and then initiated by the addition of ATP and biotin-TK substrate. After reacting for 40 minutes at room temperature, an equal volume of termination/detection solution was added according to the manufacturer's instructions (CisBio Bioassays). The termination/test solution contains TK-antibody-cryptate and streptavidin-XL665 in a buffer containing 25 mM Tris pH 7.4, 400 mM KF, 50 mM EDTA, 0.01% BSA, 0.01% Triton X-100. Solution in. The assay plates were sealed and incubated for 1 hour at room temperature before reading the TR-FRET signal on a BMG PHERAstar FS instrument. By the Graphpad Prism software% inhibition of each compound at a concentration of data and fitting a four parameter logistic equation to yield IC ₅₀ inhibitor.

1.1 to 1.67 and 2.1-2.11 compound EGFR kinase inhibition IC ₅₀ values ranging from 0.01 nM to 1 μM.

Table 1: IC ₅₀ (nM)

The above invention has been described in detail by way of examples and examples for clarity and understanding. It will be apparent to those skilled in the art that modifications and variations are possible within the scope of the appended claims. Therefore, the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined by reference to the appended claims

The entire disclosures of all patents and patent applications cited in the present application are hereby incorporated by reference.

no

no

no

Claims (31)

a compound selected from the group consisting of a compound of formula (I), a stereoisomer of a compound of formula (I), and a pharmaceutically acceptable salt of a compound of formula (I), ( I ) wherein: R ₁ , R ₂ and R _{3 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; L is a linking group selected from the group consisting of a bond, -(CR ₅ R ₆ )n-, S, -O- and -NR ₈ -, wherein n is an integer 1, 2 or 3; From an aryl or heteroaryl group, the aryl or heteroaryl group is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R'',NR'COR'',NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl; or W and R ₄ together with the nitrogen to which they are attached form optionally another hetero atom selected from NR ₈ , O and S a 4- or 5- or 6-membered heterocyclic ring optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R'',NR'COR'',NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl; R _7, at each occurrence, is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy; and wherein p is an integer 2, 3 or 4; Y is selected from -CR ₅ R ₆ - and -O-; Z are selected from -(CR ₅ R ₆ ) _m -, -CR ₅ R ₆ -O-, -O- and -NR'-, wherein m is an integer of 1 or 2; ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R _{8 is} selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; R' and R '', at each occurrence, is independently selected from the group consisting of hydrogen, C _1-6 alkyl, and C _1-6 haloalkyl; and * is the palm center. The compound of claim 1, wherein R ₁ , R ₂ and R ₃ are hydrogen. The compound of claim 1, wherein R ₄ is hydrogen. The compound of claim 1, wherein L is a bond, and W is an aryl or heteroaryl group. The compound of claim 4, wherein L is a bond and W is a phenyl or pyridyl group. As a compound according to the request, wherein L is _{- (CR 5 R 6) n} -, and W is aryl or heteroaryl, wherein n is an integer of 1, 2 or 3, and R ₅ and R ₆ independently It is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl. The compound of claim 6, wherein L is -(CR ₅ R ₆ ) _n -, and W is phenyl or pyridyl, wherein n is an integer 1, 2 or 3, and R ₅ and R _{6 are} independently selected From hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl. The compound of claim 7, wherein L is -CH ₂ - and W is phenyl or pyridyl. The compound of claim 1, wherein L is a bond or -(CR ₅ R ₆ ) _n -, and W and R ₄ together with the nitrogen to which they are attached form another impurity selected from the group consisting of NR ₈ , O and S a 4- or 5- or 6-membered heterocyclic ring of an atom, which heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CN, NO ₂ , OR ₈ , NR'R '', NR'COR'', NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne a group, a C _3-8 cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein R ₅ , R ₆ , R ₈ , R′, R′′ and n are as defined above. The compound of claim 9, wherein L is a bond or -(CR ₅ R ₆ ) _n -, and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heteroatom selected from the group consisting of a ring: azetidinyl, pyrrolidinyl, acridinyl and morpholinyl, and wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl; n is an integer of 1, 2 or 3. The compound of claim 9, wherein L is a bond, and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of: azetidinyl, pyrrolidine Base, acridinyl and morpholinyl. The compound of claim 9, wherein L is -CH ₂ -, and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of: azacyclobutyl , pyrrolidinyl, acridinyl and morpholinyl. The compound of claim 1, wherein Y is -O- and Z is -O-. The compound of claim 1, wherein Y is -O-, and Z is -NR'-, wherein R' is independently selected from the group consisting of hydrogen, _C1-6 alkyl, and _C1-6 haloalkyl. The compound of claim 1, wherein Y is -CR ₅ R ₆ -, and Z is -NR'-, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _{1 -6} haloalkyl; and R' is independently selected from the group consisting of hydrogen, _C1-6 alkyl and _C1-6 haloalkyl. The compound of claim 1, wherein Y is -CR ₅ R ₆ -, and Z is -CR ₅ R ₆ -, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _1-6 haloalkyl. The compound of claim 1, wherein Y is -CR ₅ R ₆ -, and Z is -O-, wherein R ₅ and R _{6 are} independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _{1- 6} haloalkyl. The compound according to claim 1, wherein Y is -CR ₅ R ₆ -, and Z is -(CR ₅ R ₆ ) ₂ -, wherein R ₅ and R _{6 are} independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 haloalkyl. The compound of claim 1, wherein Y is -CR ₅ R ₆ -, and Z is -CR ₅ R ₆ O-, wherein R ₅ and R _{6 are} independently selected from hydrogen, halogen, C _1-6 alkyl And C _1-6 haloalkyl. The compound according to the request 1, wherein the compound of a pharmaceutical compound (I-1) or Formula (I-1) or stereoisomers of the compounds of formula (I-1) The compound is a salt, ( I-1 ), wherein: R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; L is a linking group selected from a bond or —CH ₂ —; W is selected from phenyl or Pyridyl; or R ₇ , at each occurrence, independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy And wherein p is an integer of 0, 1, 2, 3 or 4; Y is selected from -CH ₂ - and -O-; Z is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, - O- and -NMe-; and * is the center of the palm. The compound according to a request, wherein the pharmaceutical compound (I-2) or the compound of formula of formula (I-2) or a stereoisomer of the compound of formula (I-2) of a salt compound, ( I-2 ), wherein: L is a bond or -CH ₂ -; and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of azacyclobutyl, Pyrrolidinyl, acridinyl and morpholinyl, optionally substituted by 1, 2 or 3 substituents selected from halogen, CN, NO ₂ , OR ₈ , NR'R'',NR'COR'',NR'SO ₂ R'', CONR'R'', COOR', SO ₂ R', C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-8 cycloalkyl, heterocyclyl, aryl and heteroaryl; R ₇ , at each occurrence, independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy and C _1-6 haloalkoxy; and wherein p is an integer of 0, 1, 2, 3 or 4; R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkane R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; R' and R'', at each occurrence, are independently selected from hydrogen, C _1-6 alkyl and C _{1 -6} haloalkyl; Y is selected from -CH ₂ - and -O-; Z is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -O- and -NMe-; and * is a pair Palm center. The compound according to claim 21, wherein: L is a bond or -CH ₂ -, and W and R ₄ together with the nitrogen to which they are attached form a 4- or 5- or 6-membered heterocyclic ring selected from the group consisting of: with Azacyclobutyl; selected from with Pyrrolidinyl group; , with Acridine group, and selected from with Morpholinyl, and wherein the wavy line indicates the point of attachment to the linking group L, and the acryloyl group on the nitrogen atom has been omitted; R ₇ , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, C _{1 a -6} alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, and a C _1-6 haloalkoxy group; and wherein p is an integer of 0, 1, 2, 3 or 4; Y is selected from -CH ₂ - And -O-; Z are selected from the group consisting of -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -O-, and -NMe-; and * is the palm center. The compound according to claim 21, wherein the carbon atom to which the linking group L is bonded to the 4- or 5- or 6-membered heterocyclic ring formed by the combination of W and R ₄ with the nitrogen atom is (R) or (S) structure. The compound according to a request, wherein the pharmaceutical compound (I-3) or formula (I-3) is a compound of the formula or a stereoisomer of the compound of formula (I-3) a compound of a salt, ( I-3 ), wherein: R ₇ , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _{1- 6} haloalkoxy; and wherein p is an integer of 0, 1, 2, 3 or 4; Y is selected from -CH ₂ - and -O-; Z is selected from -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ O-, -O-, and -NMe-; and * is the center of the palm, R _{9 is} selected from the group consisting of F, Cl, Br, OR ₈ , NR'R'', O-(CH ₂ )n-NR'R''; n = 1, 2, 3; R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; R' and R'', at each occurrence, are independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl. The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds, stereoisomers of the following compounds, and pharmaceutically acceptable salts of the following: . The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds, stereoisomers of the following compounds, and pharmaceutically acceptable salts of the following: . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound according to any one of claims 1-26, a stereoisomer of the compound or a pharmaceutically acceptable salt of the compound. A use of at least one compound according to any one of claims 1 to 26, a stereoisomer of the compound or a pharmaceutically acceptable salt of the compound for the preparation of a medicament for inhibiting EGFR-T790M kinase. A use of at least one compound according to any one of claims 1 to 26, a stereoisomer of the compound or a pharmaceutically acceptable salt of the compound for the preparation of a medicament for treating cancer, the cancer being selected from the group consisting of an ovary Cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, including non-small cells Lung cancer, liver cell carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple Myeloma, melanoma and mesothelioma. A method of treating a cancer responsive to inhibition of T790M-EGFR kinase, comprising administering to a subject in need of treatment an effective amount of at least one compound of any one of claims 1-26, the compound Stereoisomer or a pharmaceutically acceptable salt of the compound. A method of treating a cancer responsive to inhibition of T790M-EGFR kinase, comprising administering to a subject in need of treatment an effective amount of at least one compound of any one of claims 1-26, the compound A stereoisomer or a pharmaceutically acceptable salt of the compound selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, Lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer including non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, Anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, and mesothelioma.