ENL / AF9 YEATS inhibitors

Abstract

The present application discloses a method and composition for treating leukemia. Acylated 6-aminoindole, acylated 6-aminopyrrolopyridine and acylated 3-aminopyrrolo[3,2-c]pyridazine as shown in the following formula can inhibit ENL / AF9YEATS and thus can be used to treat leukemia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 949,160, filed on December 17, 2019, the entire contents of which are incorporated herein by reference in their entirety.

[0003] Government Rights Statement

[0004] This application was made with government support under Grant No. K99CA226399-01 from the National Institutes of Health. The government has certain rights in this application. Technical Field

[0005] The present application is generally directed to compounds that inhibit ENL / AF9YEATS and are therefore useful in treating leukemia. These compounds are acylated 6-aminoindoles and acylated 6-aminopyrrolopyridines. Background Art

[0006] Cancer cells are characterized by abnormal epigenetic landscapes and often use chromatin machinery to activate oncogene expression programs. The recognition of modified histones by "reader" proteins constitutes a key mechanism for these processes. Therefore, targeting these pathways has clinical prospects, such as the development of BET (bromodomain and terminal extradomain) bromodomain inhibitors. The YEATS domain is an acetyl-lysine binding module. Recent studies have shown [Wan et al.Nature 543, 265-269 (2017)] that the protein ENL containing the YEATS domain is essential for acute myeloid leukemia (AML) disease maintenance. The consumption of ENL leads to anti-leukemic effects, including increased terminal bone marrow differentiation and inhibition of leukemia growth. ENL binds to acetylated histone H3 and co-localizes with H3K27ac and H3K9ac on the promoters of active transcriptional genes essential for leukemia. The interaction between the YEATS domain and histone acetylation is destroyed by structure-based mutations, which reduces the recruitment of RNA polymerase II to ENL target genes, thereby inhibiting oncogene expression programs. Importantly, disruption of ENL function further sensitized leukemic cells to BET inhibitors. Therefore, ENL inhibitors—either alone or in combination with BET inhibitors—are promising therapeutic approaches for curing AML.

[0007] Many BET inhibitors are currently or recently in clinical trials. For example, the oral BET inhibitor Birabresib (OTX015) (CAS No.: 202590-98-5) is currently in clinical trials in patients with acute leukemia and selected patients with advanced solid tumors. BET-d246 (CAS No.: 2140289-17-2) has been reported to show strong antitumor activity in preclinical studies in mice. Mivebresib (ABBV-075) (CAS No. 1445993-26-9) was well tolerated in a 2-part Phase 1 study in patients with solid tumors (Part 1) and acute myeloid leukemia (AML; Part 2) and showed anti-leukemic effects in patients with relapsed and refractory AML. I-BET 151 (CAS No.: 1300031-49-5) reduced myeloma in mice; in vivo treatment with I-BET151 impaired leukemic engraftment in patient-derived primary samples and reduced disease burden in mice. RO6870810 / TEN-010 (CAS No. 1349719-98-7) is in clinical trials for patients with AML and myelodysplastic syndrome. CPI-0610 (CAS No. 1380087-89-7) is in clinical trials for patients with progressive lymphoma and multiple myeloma. Molibresib (I-BET-762) (CAS No. 1260907-17-2) is in clinical trials for NUT cancer. CPI203 (CAS No. 1446144-04-2) is in Phase 2 clinical trials for patients with myelofibrosis. PFI-1 (CAS No. 1403764-72-6) is in Phase 1 clinical trials for solid tumors. JQ1 (CAS No. 1268524-70-4) is a potent inhibitor of the BET family of bromodomain proteins. Although widely used in laboratory applications, JQ1 has a short half-life and cannot be used as a human therapeutic. Summary of the invention

[0008] The present application relates to a compound, pharmaceutical composition and method for inhibiting YEATS / ENL and thereby treating various cancers, particularly blood cancers (eg, leukemia).

[0009] In one aspect, the present application relates to a compound shown in the following formula Ia:

[0010]

[0011] in:

[0012] X 1 , X 2 and X 3 Independently selected from N and CR 4 , the condition is:

[0013] (1)X 1 , X 2 , X 3 No more than two of them are N; and

[0014] (2) When X 1 and / or X 2 CR 4 When X 3 Not for N;

[0015] R 1 Selected from: H, (C 1-6 ) alkyl, aryl (C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkyl, heterocyclic group, heterocyclic group (C 1-6 ) alkyl, (C 1-6 ) alkylamino (C 1-6 ) alkyl, heterocyclic amino (C 1-6 ) alkyl, heterocyclic group (C 1-6 ) alkylamino (C 1-6 ) alkyl, (C 3-12 )cycloalkylamino(C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkylamino (C 1-6 ) alkyl, arylamino (C 1-6 ) alkyl and aryl (C 1-6 ) alkylamino (C 1-6 )alkyl;

[0016] R 4 is selected from H, CH3 and Cl;

[0017] R 5 is selected from a 5-membered or 6-membered carbocyclic or heterocyclic ring; a bicyclic 5:6 carbocyclic or heterocyclic ring and a bicyclic 6:6 carbocyclic or heterocyclic ring, and is not attached to the nitrogen of the heterocyclic ring, wherein the carbocyclic or heterocyclic ring may be optionally replaced by (C 1-8 ) alkyl, (C 1-10 ) oxaalkyl, halogen, (C 1-6 ) haloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 0-3 H 1-7 )、-CONH(C 0-3 H 1-7 )、-SO2NH(C 1-6 )Oxyalkyl, -CN, CH2CN, CH2NH2, -NH2, NR 14 One or more groups are substituted, where R 14are independently selected from hydrogen, (C 1-6 ) fluoroalkyl and (C 1-3 ) oxaalkyl, -CH2OH, benzyloxy, -C(=NH)-NH2, -A-Het; In addition, when R 5 is a 5-membered or 6-membered heterocycle, a bicyclic 5:6 heterocycle, quinoline, isoquinoline, quinazoline or benzo[b][1,4]oxazine, =O, wherein A is selected from a direct bond, -(C 1-6 )alkyl-, -(C 1-10 )Oxaalkyl-, -CO(C 1-6 )alkyl-, SO2(C 1-6 )alkyl-, SO2NH(C 1-6 )alkyl- and -CONH(C 1-6 )alkyl-; and Het is optionally substituted by (C 1-6 ) alkyl, (C 1-10 ) oxaalkyl, (C 1-10 ) oxaalkyl (C=O)-, hydroxy, =O or halogen-substituted heterocyclic group; and

[0018] The conditions are:

[0019] (1) When X 1 , X 2 and X 3 All are carbon and R 5 When it is an optionally substituted phenyl group, R 5 for and

[0020] (2)R 5 Not a 1,3-disubstituted pyrazole or 5-oxaalkylindazole;

[0021] R 6 Selected from: H, Me, F and Cl;

[0022] R 7 is hydrogen or a halogen; and

[0023] R 8 Selected from (C 1-10 ) oxaalkyl, heterocyclic and heterocyclic groups (C 1-10 ) oxaalkyl;

[0024] R 11 , R 12 and R 13 Choose from the following three groups:

[0025] (a)R 11 is H or CH3;

[0026] R 12is selected from H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl and 5-membered- or 6-membered-monocyclic heterocyclyl, wherein the heterocyclyl may be optionally substituted by (C1-C6)alkyl, hydroxy or hydroxy(C1-C6)alkyl; and R 13 is hydrogen or methyl; or

[0027] (b)R 11 and R 12 together to form an optionally substituted nitrogen-containing heterocycle linked through nitrogen, the nitrogen-containing heterocycle selected from (a) a monocyclic aliphatic nitrogen-containing heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogen-containing heterocycle, (c) a spiro bicyclic aliphatic nitrogen-containing heterocycle, and (d) 8-azabicyclo[3.2.1]octane; wherein the optional substituents are independently selected from (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) alkoxy, -(C 1-10 )Oxyalkyl, COOH, -SO2(C 1-6 )alkyl, =O, =S, =NH; and R 13 Selected from H, (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) alkoxy, -(C 1-10 )Oxyalkyl, -SO2(C 1-6 )alkyl, =O, =S, and =NH; or

[0028] (c)R 11 is H; and R 12 and R 13 Together they form a 3- to 7-membered aliphatic carbocyclic ring, wherein the carbocyclic ring may be optionally substituted by (C1-C6)alkyl, hydroxy or hydroxy(C1-C6)alkyl.

[0029] On the other hand, the present application relates to a compound shown in the following formula Ib:

[0030]

[0031] Where R 11 and R 12 Together, they form an optionally substituted nitrogen-containing heterocycle Q selected from (a) a monocyclic aliphatic nitrogen-containing heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogen-containing heterocycle, (c) a spirobicyclic aliphatic nitrogen-containing heterocycle, and (d) 8-azabicyclo[3.2.1]octane; wherein the optional substituents are independently selected from (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) alkoxy, -(C 1-10)Oxyalkyl, COOH, -SO2(C 1-6 )alkyl, =O, =S, =NH;

[0032] R 1 Selected from: H, (C 1-6 ) alkyl, aryl (C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkyl, heterocyclic group, heterocyclic group (C 1-6 ) alkyl, (C 1-6 ) alkylamino (C 1-6 ) alkyl, heterocyclic amino (C 1-6 ) alkyl, heterocyclic group (C 1-6 ) alkylamino (C 1-6 ) alkyl, (C 3-12 )cycloalkylamino(C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkylamino (C 1-6 ) alkyl, arylamino (C 1-6 ) alkyl and aryl (C 1-6 ) alkylamino (C 1-6 )alkyl.

[0033] On the other hand, the present application relates to a compound shown in the following formula I:

[0034]

[0035] in:

[0036] X 1 , X 2 and X 3 Independently selected from N and CR 4 , the condition is X 1 , X 2 and X 3 No more than two of them are N;

[0037] n is 1, 2 or 3;

[0038] R 1 Selected from: H, (C 1-6 ) alkyl, aryl (C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkyl, heterocyclic group, heterocyclic group (C 1-6 ) alkyl, (C 1-6 ) alkylamino (C 1-6 ) alkyl, heterocyclic amino (C 1-6 ) alkyl, heterocyclic group (C 1-6 ) alkylamino (C1-6 ) alkyl, (C 3-12 )cycloalkylamino(C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkylamino (C 1-6 ) alkyl, arylamino (C 1-6 ) alkyl and aryl (C 1-6 ) alkylamino (C 1-6 )alkyl;

[0039] R 2a and R 2b are independently selected from H and (C 1-6 ) alkyl, or R 2a and R 2b Together they form a spiro 4-, 5- or 6-membered carbocyclic or heterocyclic ring;

[0040] R 3 is independently selected at each occurrence from CHCOOH, NR 10 , O and CR 10a R 10b ;

[0041] R 10 , R 10a and R 10b are independently selected from H and (C 1-6 ) alkyl, or R 10a and R 10b together form a spiro 4-, 5- or 6-membered carbocyclic or heterocyclic ring; or

[0042] R 2a and R 10a together to form a fused 4-, 5- or 6-membered carbocyclic or heterocyclic ring;

[0043] R 4 is selected from H, CH3, F and Cl;

[0044] R 5 selected from 5-membered or 6-membered carbocyclic or heterocyclic rings; bicyclic 5-6 carbocyclic or heterocyclic rings and bicyclic 6-6 carbocyclic or heterocyclic rings, wherein the carbocyclic or heterocyclic rings may be optionally selected from (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halogen, (C 1-6 ) haloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 0-3 H 1-7 )、-CONH(C 0-3 H 1-7 ), -CN, -NH2, -CH2OH, benzyloxy, and optionally (C 1-6 ) alkyl, (C1-6 ) is substituted by one or more of alkoxy, hydroxy, =O or halogen-substituted heterocyclic groups;

[0045] The condition is that when X 1 , X 2 and X 3 All are carbon and R 5 When it is an optionally substituted phenyl group, R 5 for

[0046] R 6 Selected from: H, Me, F and Cl;

[0047] R 7 is hydrogen or a halogen; and

[0048] R 8 It is a heterocyclic group.

[0049] In another aspect, the present application relates to a method of inhibiting oncogene expression in a cell, comprising exposing the cell to a compound as described herein.

[0050] In another aspect, the present application relates to a method for treating a leukemia patient, comprising administering an effective dose of a compound as described herein.

[0051] In another aspect, the present application relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as described herein. DETAILED DESCRIPTION

[0052] The cyclic compound provided in the present application has the following structure:

[0053]

[0054] or

[0055]

[0056] or

[0057]

[0058] As mentioned above, compounds of formula I, Ia and Ib are useful for treating leukemia. Based on the central ring system, the genus Ia can be divided into five subgenera.

[0059] In the first subgenus, X 2 is nitrogen, and the compound is a pyrrolo[3,2-c]pyridine as shown in the following formula II:

[0060]

[0061] In the second subgenus, X 1is nitrogen, and the compound is a pyrrolo[3,2b]pyridine as shown in the following formula III:

[0062]

[0063] In the third subgenus, X 3 is nitrogen, and the compound is a pyrrolo[2,3-b]pyridine as shown in the following formula IV:

[0064]

[0065] In the fourth subgenus, X 1 , X 2 and X 3 All of them are carbon, and the compound is an indole as shown in the following formula V:

[0066]

[0067] In the fifth subgenus, X 1 and X 2 is nitrogen and X 3 is carbon, and the compound is a pyrrolo[3,2-c]pyridazine as shown in Formula VI below:

[0068]

[0069] Based on Q, the genus Ib can be divided into four subgenera. In the embodiment of Formula Ib, Q can be (a) a monocyclic aliphatic nitrogen-containing heterocycle, (b) a 5:5 or 5:6 bicyclic aliphatic nitrogen-containing heterocycle, (c) a spiro bicyclic aliphatic nitrogen-containing heterocycle, and (d) 8-azabicyclo[3.2.1]octane, which can be optionally replaced by (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) alkoxy, -(C 1-10 )Oxyalkyl, COOH, -SO2(C 1-6 )alkyl, =O, =S and =NH.

[0070] In some embodiments of Formula Ib, Q is a monocyclic aliphatic nitrogen-containing heterocycle, optionally substituted with one or more selected from (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) Hydrocarbon, halogenated (C 1-10 ) alkoxy, -(C 1-10 )Oxyalkyl, COOH, -SO2(C 1-6 )alkyl, =O, =S and =NH.

[0071] In some embodiments of Formula Ib, Q is a 5:5 or 5:6 bicyclic aliphatic nitrogen-containing heterocycle, optionally substituted with one or more selected from (C 1-10 ) Hydrocarbon, halogenated (C1-10 ) Hydrocarbon, halogen (C 1-10 ) alkoxy, -(C 1-10 )Oxyalkyl, COOH, -SO2(C 1-6 )alkyl, =O, =S and =NH.

[0072] In some embodiments of Formula Ib, Q is a spiro bicyclic aliphatic nitrogen-containing heterocycle.

[0073] In the embodiments of Formulas I-VI, R 5 It may be a carbocyclic or heterocyclic ring selected from phenyl, indazole, pyridine, imidazopyridine, pyrazolopyrimidine, imidazopyrazine, triazolopyridine and benzoxazine or reduced forms thereof. 5 may be optionally substituted, although as described above, when X 1 , X 2 and X 3 are carbon (i.e., Formula V) and R 5 When it is phenyl, the phenyl must be substituted by a heterocycle. In a specific embodiment, R 5 It is an indazole substituted with a methyl group.

[0074] In X 1 , X 2 and X 3 In the embodiment where all are carbon, the indole may have the following formula Vb:

[0075]

[0076] in:

[0077] R 5a is selected from 5-membered or 6-membered heterocyclic or aliphatic carbocyclic rings; bicyclic 5:6 carbocyclic or heterocyclic rings and bicyclic 6:6 carbocyclic or heterocyclic rings. The carbocyclic, heterocyclic or aliphatic carbocyclic ring may be optionally selected from (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halogen and (C 1-6 ) is substituted with a haloalkyl group.

[0078] When R 5 When is phenyl, the compound may be an indole of the following formula Vc:

[0079]

[0080] in:

[0081] R 5b yes

[0082] R 7 is hydrogen or a halogen; and

[0083] R8 It is a heterocyclic group.

[0084] In some embodiments of Formula Vc, R 8 It may be selected from pyrazine, pyrimidine, pyridazine and pyridine.

[0085] In the compounds of formula IV, in some embodiments, R 11 is hydrogen. In some embodiments, R 12 and R 13 Together they form a 3- to 7-membered aliphatic carbocyclic ring, wherein the carbocyclic ring may be optionally substituted by (C1-C6)alkyl, hydroxy or hydroxy(C1-C6)alkyl.

[0086] In the compounds of formula IV, in some embodiments, R 11 and R 13 is hydrogen, methyl, or a combination thereof. 12 is hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl and 5-membered or 6-membered monocyclic heterocyclic group, wherein the heterocyclic group may be optionally substituted by (C1-C6)alkyl, hydroxyl or hydroxy(C1-C6)alkyl.

[0087] In some embodiments of Formula I, R 1 can be hydrogen. In some embodiments, n can be 2. In some embodiments, R 2a , R 2b , R 10a and R 10b One of them can be methyl or carboxyl, and the remaining example is hydrogen. In some embodiments, R 3 It can be CHCOOH and R 2a , R 2b , R 10a and R 10b The remaining example is hydrogen. 2a is methyl, R 3 Yes CR 10a R 10b , and R 2b , R 10a and R 10b When it is hydrogen, R 2a and R 2b The attached carbon may be in the (S) absolute configuration. 4 is hydrogen. In some embodiments, R 6 is hydrogen or methyl; in other embodiments, R 6 is chlorine. In some embodiments, R 5 is pyridine substituted by optionally substituted heterocycle, -CN or -SO2NHCH3.

[0088] In the compounds of Formula I-IV, in some embodiments, R 5 is selected from one or more of (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halogen, (C 1-6 ) haloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 0-3 H 1-7 ), CN, NH2, CH2OH, benzyloxy substituted phenyl, and optionally substituted heterocyclic radicals by methyl, hydroxyl, =O or halogen. In particular, phenyl may be substituted by fluorine and / or optionally substituted heterocyclic.

[0089] In terms of methods, the present application relates to treating leukemia patients with the above-mentioned compounds. In addition, the method also includes administering a BET inhibitor. BET inhibitors are a class of well-known compounds, examples of which include OTX015, BET-d246, ABBV-075, I-BET151, RO6870810, TEN-010, CPI-0610, I-BET-762, CPI203, PFI-1 and JQ1. Administration can be concomitant, as used herein, referring to the administration of two separate drugs within a time period that is insufficient to partially or completely eliminate at least one drug. In some embodiments, concomitant administration includes administering the drug at the time of the first administration of the drug. As used herein, the term "combination therapy" includes administering two or more agents to a subject such that both agents and / or their active metabolites are present in the subject at the same time. Combination therapy can include simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition containing both agents.

[0090] It should be understood that in each embodiment, the pharmaceutical composition of the present application contains one or more pharmaceutically acceptable excipients, including but not limited to one or more adhesives, fillers, buffers, stabilizers, surfactants, wetting agents, lubricants, diluents, disintegrants, viscosity increasers or viscosity reducers, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, masking agents, fragrances, flavorings, diluents, polishing agents, polymer matrix systems, plasticizers and other known additives to obtain a good drug appearance or help prepare drugs or medicines including the composition of the present application. Examples of carriers and excipients well known to those skilled in the art are described in detail in the following articles: Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery System (Philadelphia: Lippincott, Williams & Wilkins, 2004); Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy (Philadelphia: Lippincott, Williams & Wilkins, 2000); and Rowe, Raymond C., Handbook of Pharmaceutical Excipients (Chicago, Pharmaceutical Press, 2005).

[0091] In various embodiments, non-limiting examples of excipients include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth gum, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (e.g., Nos. 2208, 2906, 2910), hydroxypropyl cellulose, titanium dioxide, talc, calcium carbonate (e.g., granular or powdered), microcrystalline cellulose, powdered cellulose, dextran, kaolin, silicic acid, sorbitol, starch, pregelatinized starch, agar lipids, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato starch or tapioca starch, other starch, pregelatinized starch, other starch, clay, other algin, other cellulose, gums, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut, cottonseed, sunflower, sesame, olive, corn, and soybean), zinc stearate, ethyl oleate, ethyl laurate, agar, Syloid silica (AEROSIL 200, W.R. Grace, Baltimore, MD Co. of Plano, Texas), condensation aerosols of synthetic silica (sold by Degussa Co. of Plano, Texas), CAB-O-SIL (a fumed silica product sold by Cabot Co. of Boston, Massachusetts), colorants, and mixtures thereof.

[0092] The terms "subject" or "subject in need thereof" are used interchangeably herein. These terms refer to a patient who has been diagnosed with the underlying disease to be treated. The subject may currently be experiencing symptoms associated with the condition or may have experienced these symptoms in the past. In addition, a "subject in need thereof" may be a patient at risk for developing a particular disease, or a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of such a disease may not have been made.

[0093] As used herein, the terms "treat" or "treatment" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to a therapeutic benefit. A therapeutic benefit includes eradication or amelioration of the underlying disease being treated; it also includes eradication or amelioration of one or more symptoms associated with the underlying disease, such that an improvement is observed in the patient, although the patient may still be suffering from the underlying disease.

[0094] As used herein, the term "optionally substituted" can be used interchangeably with "unsubstituted or substituted". The term "substituted" means that one or more hydrogen atoms in a specific group are replaced by a specific group. For example, substituted aryl, heterocyclic group, etc. refer to aryl or heterocyclic group, in which one or more H atoms in each residue are replaced by the following groups: halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, lower alkoxy, haloalkoxy, oxaalkyl, carboxyl, alkoxycarbonyl [-C (= O) O-alkyl], carboxamido [-C (= O) NH2], alkylaminocarbonyl [-C (= O) NH-alkyl], cyano, acetoxy, nitro alkylamino, alkylthio, alkylsulfinyl, benzyl, heterocyclyl, phenoxy, benzyloxy, heteroaryloxy, aminosulfonyl, amidino, guanidino and ureido; (C 1-6 )alkyl, -SO2alkyl, -SO2NH2 or -SO2NHalkyl.

[0095] Unless otherwise specified, alkyl is intended to include straight or branched hydrocarbon structures. Lower alkyl refers to an alkyl group of 1 to 6 carbon atoms. Examples of lower alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, etc. Preferably, the alkyl group is C 20 or less alkyl groups.

[0096] C1 to C 20 Hydrocarbon or hydrocarbon group (as substituent) comprises alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl, and their combination.Examples include cyclopropylmethyl, benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.Hydrocarbon refers to any substituent consisting of hydrogen and carbon as the only element components.Cycloalkyl is a subset of hydrocarbon group and includes cyclic hydrocarbon groups with 3 to 8 carbon atoms.Examples of cycloalkyl include c-propyl, c-butyl, c-pentyl, norbornyl etc.

[0097] Unless otherwise indicated, the term "carbocycle" is intended to include ring systems in which the ring atoms are all carbon but do not contain any oxidation states. Thus, (C3-C8)carbocycle refers to both non-aromatic and aromatic systems, including systems such as cyclopropane, benzene, and cyclohexene; (C8-C 12 )Carbocyclic refers to systems such as norbornane, decalin, indane and naphthalene. If there are no other restrictions, carbocyclic refers to monocyclic, bicyclic and polycyclic.

[0098] Alkoxy or alkoxy refers to a group and combination thereof having a straight chain, branched or cyclic configuration of 1 to 8 carbon atoms, which is connected to the parent structure by oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, etc. Lower alkoxy refers to a group containing one to four carbons. In order to achieve the purpose of the present application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.

[0099] Oxaalkyl refers to an alkyl residue in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-triacontacyl, and the like. Alkoxy (see previous paragraph) is a subset of oxaalkyl in which the carbon at the point of attachment is replaced by oxygen. The term oxaalkyl has the same meaning as understood in the art [see Chemical Abstracts, Nomenclature and Indexing of Chemical Substances, 196, but not limited to 127(a)], i.e., it refers to compounds in which oxygen is bonded to its adjacent atom by a single bond (forming an ether bond); it does not refer to the double-bonded oxygen found in a carbonyl group. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0100] Unless otherwise indicated, acyl refers to formyl and straight chain, branched, cyclic configuration, saturated, unsaturated and aromatic with 1,2,3,4,5,6,7 and 8 carbon atoms, and their combined groups, connected to the parent structure by the carbonyl functional group. As long as the point of attachment to the parent remains on the carbonyl, one or more carbons in the acyl residue can be replaced by nitrogen, oxygen or sulfur. Examples include acetyl, benzoyl, propionyl, isobutyryl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Low acyl refers to a group containing one to four carbons. When being referred to as a substituent, the double bond oxygen itself is called "oxo (oxo)".

[0101] Aryl and heteroaryl refer to (i) phenyl (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N or S; (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N or S. Aromatic 6- to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin and fluorene and 5- to 10-membered aromatic heterocyclic rings include, for example, imidazole, pyridine, indole, thiophene, benzopyrone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. As used herein, aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all rings are necessarily so.

[0102] Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure via an alkyl group. Examples are benzyl, phenethyl, etc. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure via an alkyl group. In one embodiment, the alkyl group of the arylalkyl or heteroarylalkyl group is an alkyl group of 1 to 6 carbons. Examples include, for example, pyridylmethyl, pyrimidylethyl, etc.

[0103] Heterocycle refers to a cycloalkyl or aryl carbocyclic residue in which 1 to 4 carbons are substituted with heteroatoms selected from a group consisting of N, O and S. Nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Unless otherwise indicated, heterocycles may be non-aromatic or aromatic. Examples of heterocycles falling within the scope of the present application include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxolane (commonly referred to as methylenedioxyphenyl when appearing as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, etc. It should be noted that heteroaryl is a subset of heterocycles in which heterocycles are aromatic. Examples of heteroaromatic rings include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, triazole, tetrazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, cinnamylene, phthalazine, and triazine. In addition, examples of heterocyclyl residues include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxacridinyl, acridinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidine, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.

[0104] An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygen, as well as other heteroatoms. A sulfur heterocycle is a heterocycle containing at least one sulfur in the ring; it may contain additional sulfur, as well as other heteroatoms. Oxyheteroaryls are a subset of oxygen heterocycles; examples include furan and oxazole. Sulfur heteroaryls are a subset of sulfur heterocycles; examples include thiophene and thiazine. Azoheterocycles are heterocycles containing at least one nitrogen in the ring; it may contain additional nitrogen, as well as other heteroatoms. Examples include piperidine, piperazine, morpholine, pyrrolidine, and thiomorpholine. Azoheteroaryls are a subset of nitrogen heterocycles; examples include pyridine, pyrrole, and thiazole.

[0105] Bicyclic nitrogen-containing heterocycles include (1) fused bicyclic rings, such as octahydrocyclopenta[c]pyrrole; (2) azaspirocyclohexanes, heptanes, and octanes, such as 6-oxa-2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, and 7-oxa-2-azaspiro[3.5]nonane; and (3) azabicycloalkanes: 8-azabicyclo[3.2.1]octane. In the compounds described herein, these bicyclic nitrogen-containing heterocycles may be attached to the carbon-bearing R in Formula I via nitrogen. 1 superior.

[0106] As used herein and as will be understood by those skilled in the art, unless expressly further limited, the recitation of a "compound" is intended to include salts of the compound. Thus, for example, the recitation of "a compound of Formula I" described above includes salts:

[0107]

[0108] Wherein X is any counterion. In a specific embodiment, the term "compound of formula I" refers to the compound or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or non-toxic base, including inorganic acids and inorganic bases and organic acids and organic bases. When the compound of the present application is alkaline (usually alkaline), the salt can be prepared from a pharmaceutically acceptable non-toxic acid, including an inorganic acid and an organic acid. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonic acid (benzenesulfonate), benzoate, borate, butyrate, camphorate, camphorsulfonate, carbonate, citrate, edisylate, ethanesulfonate, edetate, formate, fumarate, gluconate, gluconate, glutamate, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurylsulfonate, maleate, malate, mandelate, methanesulfonate, mucate, naphthenate, nitrate, oleate, pamoate, pantothenate, phosphate, pivalate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, tracheate, p-toluenesulfonate, and the like. When the compound contains an acidic side chain, for example when R 3When CHCOOH, suitable pharmaceutically acceptable base addition salts for the compounds of the present application include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Where appropriate, further, pharmaceutically acceptable salts include non-toxic ammonium cations and carboxylates, sulfonates and phosphonates attached to alkyl groups having 1 to 20 carbon atoms.

[0109] It should be understood that in various embodiments, the pharmaceutical composition of the present application contains one or more pharmaceutically acceptable excipients, including but not limited to one or more adhesives, fillers, buffers, stabilizers, surfactants, wetting agents, lubricants, diluents, disintegrants, viscosity increasers or viscosity reducers, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, masking agents, fragrances, flavorings, diluents, polishing agents, polymer matrix systems, plasticizers and other known additives to obtain a good drug appearance or help prepare drugs or medicines including the composition of the present application. Examples of carriers and excipients well known to those skilled in the art are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery System (Philadelphia: Lippincott, Williams & Wilkins, 2004); Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy (Philadelphia: Lippincott, Williams & Wilkins, 2000); and Rowe, Raymond C., Handbook of Pharmaceutical Excipients (Chicago, Pharmaceutical Press, 2005).

[0110] Unless otherwise indicated or described, structures described herein are also intended to include all stereoisomeric (e.g., enantiomers, diastereomers, and cis-trans isomers) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present application as well as mixtures of enantiomers, diastereomers, and cis-trans isomers (or conformations) are within the scope of the present application. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application. In addition, unless otherwise indicated, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing hydrogen with an enriched 13 C or 14 Compounds having the structures of the present application are within the scope of the present application except that the carbon of C is substituted with the carbon of C. For example, such compounds can be used as analytical tools or probes in biological assays.

[0111] The term "solvate" refers to a compound of formula I in the solid state, wherein molecules of a suitable solvent are incorporated into the crystal lattice together with the compound of formula I. Suitable solvents for therapeutic administration are physiologically tolerable doses. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is called a hydrate. Typically, a solvate is formed by dissolving the compound in an appropriate solvent and separating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotroped at ambient conditions.

[0112] In the process of chemical synthesis, various protecting groups can be used and then removed to produce the compounds of the present application. Exemplary protecting groups and their removal conditions are described in Protecting Groups in Organic Synthesis by Greene (PGM Wuts, TW Greene, 4th edition, Wiley, New York, 2006).

[0113] Examples

[0114] The following compounds were prepared, isolated and characterized using the methods of this application. They show part of the scope of this application and are not meant to limit the scope of this application.

[0115] General synthetic scheme

[0116] The compounds of the present application are prepared by methods well known in the field of synthetic organic chemistry. During a synthetic sequence, it is sometimes necessary or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional methods of protecting groups, such as those described by TW Greene and PGM Wuts in Protective Groups in Organic Synthesis(4th edition, John Wiley and Sons, 2006). The protecting groups are removed at some convenient subsequent stage using methods known in the art.

[0117] Generally, the compounds of the present application can be prepared by the methods described in the following general reaction schemes, or by methods modified thereon, using readily available starting materials, reagents and conventional synthetic procedures. However, those skilled in the art will recognize that other methods may also be suitable. In addition, in these reactions, variants known per se but not mentioned herein may be used.

[0118]

[0119] Aldehyde A.1 can be converted to amine A.2 using reductive amination conditions (e.g., Na(AcO)3BH or NaCNBH4 with an appropriate amine). Amine A.2 can be protected with an appropriate functional group such as BOC or SEM to produce protected intermediate A.3. Nitro intermediate A.3 can be reduced to amine A.4 (NH4Cl / Fe). Amine A.4 can be reacted by typical amide coupling conditions (e.g., HATU / base / R 5 CO2H) to produce intermediate A.5. The protecting group in A.5 can be removed using acidic conditions (such as HCl or TFA) to produce representative examples described in the specification.

[0120]

[0121] The methyl ester B.1 can be reduced to the alcohol B.2 using standard conditions known to those skilled in the art (e.g., LiAlH4). The alcohol B.2 can be oxidized to the aldehyde B.3 using a reagent such as Dess-Martin periodinane. The aldehyde B.3 can be converted to the amine B.4 using reductive amination conditions (e.g., Na(AcO)3BH or NaCNBH4 containing an appropriate amine). The NH in B.4 can be protected with an appropriate group (e.g., Boc or SEM) to obtain the protected intermediate B.5. The chlorine in B.5 can be converted to the BOC-protected intermediate B.6 by appropriate Pd(0) catalytic conditions (e.g., Pd(0) / ligand / NH2BOC). The protecting group in B.6 can be removed under acidic conditions (e.g., HCl or TFA) to give the amine B.7. The amine B.7 can be converted to the BOC-protected intermediate B.6 by standard amide coupling conditions (e.g., HATU / base / R 5 CO2H) conversion into a representative example.

[0122]

[0123] The ester C.1 can be converted to the alcohol C.2 using an appropriate reducing agent (e.g., LiAlH4). The alcohol C.2 can be converted to the aldehyde C.3 using appropriate oxidation conditions (e.g., Dess-Martin periodinane). The aldehyde C.3 can be converted to the amine C.4 using reductive amination conditions (e.g., Na(AcO)3BH or NaCNBH4 containing an appropriate amine). The amine C.4 can be protected with an appropriate protecting group to obtain C.5 (e.g., SEM). The chloro intermediate C.5 can be converted to the imine intermediate C.6 using a Pd(0) catalyst with benzophenone imine and an appropriate ligand. The imine in C.6 can be hydrolyzed to the amine C.7 (e.g., aqueous HCl). Standard amide coupling conditions (e.g., HATU / base / R 5 CO2H), the amine C.7 can be converted to SEM-protected C.8. The SEM group in C.8 can be removed using acidic conditions (such as TFA) to obtain a representative example.

[0124] The following abbreviations are used in the synthetic schemes: DCE (1,2-dichloroethane), THF (tetrahydrofuran), MeOH (methanol), DCM (dichloromethane), HBTU ((2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), Dess-Martin periodinane (3-oxo-1,3-dihydro-1λ 5 ,2-benzoiodooxolane-1,1,1-triacetic acid triester), DMF (N,N-dimethylformamide), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), ACN (acetonitrile), TEA (triethylamine), AcOH (acetic acid), EtOH (ethanol), EtOAc (ethyl acetate), DMAP (N,N-dimethylpyridin-4-amine), XPhos (2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl), TFA (trifluoroacetic acid), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinol 3-oxide hexafluorophosphate), SEMCl ((2-trimethylsilyl)ethoxymethyl chloride), dibenzylideneacetone ((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one) and PPh3 (triphenylphosphine).

[0125] Preparative high performance liquid chromatography (HPLC) purification refers to the use of a water / acetonitrile gradient, with or without additives (such as HCl, formic acid, TFA or NH4HCO3), using a moderately hydrophobic stationary phase.

[0126] Table A describes the acids used below. For known acids, the CAS number is shown in the reference column. Synthetic schemes for all other acids are described in the specification.

[0127] Table A

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139] Preparation of acid B

[0140]

[0141] Methyl 4-hydroxy-3-[(1E)-1-(hydroxyimino)ethyl]benzoate (B-2)

[0142] In a 250-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, methyl 3-acetyl-4-hydroxybenzoate (B-1, 4.80 g, 24.7 mmol, 1.0 equiv), EtOH (50.4 mL), H2O (21.6 mL), hydroxylamine hydrochloride (3.4 g, 49.504 mmol, 2.00 equiv), sodium acetate (5.1 g, 61.804 mmol, 2.50 equiv) were added. The resulting solution was stirred at 80 ° C for 2 hours. The reaction mixture was cooled and the resulting solution was diluted with 100 mL H2O, and the solid was collected by filtration. LCMS: [M+H] + =210.

[0143] 3-Methylbenzo[d]isoxazole-5-carboxylic acid methyl ester as a white solid (B-3)

[0144] In a 100 mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, (E)-methyl 4-hydroxy-3-(1-(hydroxyimino)ethyl)benzoate (B-2, 3.5 g, 16.8 mmol, 1.00 equiv), dioxane (19.3 mL), DMF-DMA (9.2 mL) were added. The resulting solution was stirred at 85 ° C for 2 hours, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column and eluted with ethyl acetate / petroleum ether (1:3). LCMS: [M+H] + =192.

[0145] 3-Methyl-1,2-benzoxazole-5-carboxylic acid as a white solid (acid B)

[0146] In a 50 mL round bottom flask, methyl 3-methyl-1,2-benzoxazole-5-carboxylate (1-3, 1.0 g, 5.23 mmol, 1.0 equiv), MeOH (10.0 mL), H2O (3.0 mL), sodium hydroxide (1.05 g, 26.3 mmol, 5.02 equiv) were added. The resulting solution was stirred at room temperature for 10 hours and the resulting mixture was concentrated. The resulting solution was diluted with 20 mL H2O and extracted with 2×20 mL ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to pH 3 and the resulting solid was collected by filtration. 1 H-NMR: (300MHz, DMSO-d6, ppm) δ13.17 (s, 1H), 8.47 (dd, J=1.8, 0.7Hz, 1H), 8.21 (dd, J=8.8, 1.7Hz, 1H), 7.79 (dd, J=8.7, 0.7Hz, 1H), 2.61 (s, 3H).

[0147] Preparation of acid E

[0148]

[0149] 6-Bromo-1,3-dimethylindazole (E-2)

[0150] In a 100-mL 3-neck round-bottom flask, 6-bromo-3-methyl-1H-indazole (E-1, 2.90 g, 13.74 mmol, 1.00 equiv) and DMF (60 mL), Cs2CO3 (8.95 g, 27.48 mmol, 2.0 equiv) were added at room temperature. MeI (2.34 g, 16.49 mmol, 1.2 equiv) was added dropwise to the above mixture at room temperature, and the resulting mixture was stirred at room temperature for another 2 hours. The resulting mixture was diluted with EtOAc (200 mL) and washed with 3×100 mL brine, and the resulting mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give white solid 6-bromo-1,3-dimethylindazole (E-2, 2.25 g, 72.75%) and white solid 6-bromo-2,3-dimethylindazole (0.8 g, 25.9%). 1 H-NMR: (300 MHz, methanol-d4, ppm) δ7.72 (m, 1H), 7.60 (dd, J = 8.7, 1.7 Hz, 1H), 7.23 (dd, J = 8.6, 1.7 Hz, 1H), 3.95 (d, J = 1.1 Hz, 3H), 2.52 (s, 3H).

[0151] 1,3-Dimethylindazole-6-carboxylic acid (acid E)

[0152] At -78 ° C, 6-bromo-1,3-dimethylindazole (E-2) was added to a 250-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, and n-butyl lithium (5.86 mL, 2M soln, 1.5 equivalents) was added dropwise. The resulting solution was stirred at -78 ° C for 30 minutes, followed by the slow addition of dry ice (20.0 g). The resulting solution was stirred at -78 ° C for 30 minutes, and the resulting solution was allowed to react for another 2 hours at -78 ° C with stirring. The reaction was then quenched by adding 100 mL of water / ice. The resulting solution was extracted with 2×30 mL of ethyl acetate, and the aqueous layers were combined. The pH value was adjusted to 3 using HCl (3 mol / L). The resulting solution was extracted with 3×30 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.4 g (75.31%) of white solid 1,3-dimethylindazole-6-carboxylic acid (E acid).

[0153] Preparation of Acid F

[0154] In an argon atmosphere at -78°C, 5-bromo-1,3-dimethylindazole (1.90 g, 8.48 mmol, 1.0 equiv.), THF (57 mL) were added to a 250-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, and n-BuLi (8.5 mL, 2.5 M soln, 1.5 equiv.) was added dropwise. The resulting solution was stirred at -78°C for 30 minutes, followed by the slow addition of dry ice (20.00 g), and the resulting solution was allowed to react for another 2 hours at -78°C with stirring. The reaction was then quenched by adding water / ice, and the aqueous layers were extracted and combined with 2×30 mL of ethyl acetate, and the pH of the solution was adjusted to 3 with HCl (3 M). The solid was collected by filtration to give 1 g (62.5%) of 1,3-dimethylindazole-5-carboxylic acid (acid F) as a white solid. LCMS: [M+H] + =191.

[0155] Preparation of acid H

[0156]

[0157] 2,3-Dimethylindazole-6-carboxylic acid methyl ester (H-2)

[0158] In a 50 mL pressure reactor, 6-bromo-2,3-dimethylindazole (H-1, 650.0 mg, 2.89 mmol, 1.0 equiv), CH3OH (6.5 mL), Pd(dppf)Cl2CH2Cl2 (117.9 mg, 0.14 mmol, 0.05 equiv), NaOAc (710.68 mg, 8.66 mmol, 3.0 equiv), CO (10 atm) were added. The resulting solution was stirred at 95 ° C for 24 hours. The resulting solution was diluted with 20 mL of H2O, and the resulting solution was extracted with 3×30 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×30 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated. LCMS: [M+H] + =205.

[0159] 2,3-Dimethylindazole-6-carboxylic acid (acid H)

[0160] In a 100-mL round-bottom flask, methyl 2,3-dimethylindazole-6-carboxylate (H-2, 700.0 mg, 3.43 mmol, 1.0 equiv), MeOH (21 mL), H2O (7 mL), sodium hydroxide (685.5 mg, 17.14 mmol, 5.0 equiv) were added, and the resulting solution was stirred at room temperature for 10 hours. The resulting mixture was concentrated and extracted with 2×50 mL of ethyl acetate, and then the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3 M), and the solid was collected by filtration to obtain 500 mg (76.7%) of 2,3-dimethylindazole-6-carboxylic acid (acid H) as a white solid. 1 H-NMR: (300MHz, DMSO-d6, ppm) δ12.81 (s, 1H), 8.17 (t, J = 1.2 Hz, 1H), 7.74 (dd, J = 8.7, 0.9 Hz, 1H), 7.49 (dd, J = 8.7, 1.4 Hz, 1H), 4.10 (s, 3H), 2.63 (s, 3H).

[0161] Preparation of Acid J

[0162]

[0163] 1-(4-Bromophenyl)-1-(pyridin-2-yl)ethanol (J-2)

[0164] To a stirred solution of dibromobenzene (10.0 g, 42.39 mmol, 1.0 equiv) in ether (200 mL) was added dropwise n-BuLi (16.96 mL, 42.39 mmol, 1.00 equiv) at -78 ° C under nitrogen atmosphere, and the resulting mixture was stirred at -78 ° C under nitrogen atmosphere for 30 minutes. A mixture of 2-acetylpyridine (J-1, 5.65 g, 46.63 mmol, 1.10 equiv) in 50 mL of ether was added dropwise at -78 ° C, and the resulting mixture was stirred at -78 ° C for another 30 minutes, and then allowed to slowly warm to room temperature. Saturated NH4Cl (aqueous solution) (100 mL) was added at 5 ° C to quench the reaction, and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (2:1) as eluent to give 1-(4-bromophenyl)-1-(pyridin-2-yl)ethanol (J-2, 4.5 g, 38.2%) as a yellow solid. LCMS: [M+1] + =278.

[0165] 2-[1-(4-Bromophenyl)vinyl]pyridine (J-3)

[0166] 1-(4-bromophenyl)-1-(pyridin-2-yl)ethanol (J-2, 1.10 g, 3.96 mmol, 1.00 equiv), DCM, triethylsilane (4.60 g, 39.55 mmol, 10.00 equiv) and TFA (9.02 g, 79.1 mmol, 20.0 equiv) were added to a 100-mL 3-necked round-bottom flask at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 48 hours and concentrated in vacuo. The resulting mixture was diluted with CH2Cl2 (50 mL), washed with 3×30 mL NaHCO3 (saturated), and the resulting organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to give 2-[1-(4-bromophenyl)vinyl]pyridine (J-3, 900 mg, 78.74%) as a light yellow oil. LCMS: [M+1] + =260.

[0167] Methyl 4-[1-(pyridin-2-yl)vinyl]benzoate (J-4)

[0168] 2-[1-(4-bromophenyl)vinyl]pyridine (J-3, 900 mg, 3.46 mmol, 1.00 equiv), MeOH (20 mL), NaOAc (851 mg, 10.38 mmol, 3.00 equiv) and Pd(dppf)Cl2 (253 mg, 0.346 mmol, 0.10 equiv) were added to a 30 mL pressure reactor at room temperature. The resulting mixture was stirred overnight under a CO (20 atm) atmosphere at 90°C, and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), the resulting mixture was washed with 1×30 mL of water, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give methyl 4-[1-(pyridin-2-yl)vinyl]benzoate (J-4, 660 mg, 74.94%) as a yellow solid. LCMS: [M+1] + =240

[0169] Methyl 4-[1-(pyridin-2-yl)ethyl]benzoate (J-5)

[0170] To a 50 mL round bottom flask at room temperature was added methyl 4-[1-(pyridin-2-yl)vinyl]benzoate (J-4, 660.0 mg, 2.76 mmol, 1.00 equiv), MeOH (20 mL) and Pd / C (530.0 mg, 10%). The reactants were stirred at room temperature and 1 atm H2(g) for 24 h, the resulting mixture was filtered, and the filter cake was washed with MeOH (2×20 mL). The filtrate was concentrated under reduced pressure to give methyl 4-[1-(pyridin-2-yl)ethyl]benzoate (J-5, 600 mg, 90%) as a black oil. LCMS: [M+1] + =242.

[0171] 4-[1-(Pyridin-2-yl)ethyl]benzoic acid (Acid J)

[0172] To a 50 mL round-bottom flask was added methyl 4-[1-(pyridin-2-yl)ethyl]benzoate (J-5, 600.0 mg, 2.49 mmol, 1.00 equiv) and MeOH (10 mL) at room temperature, and to the above mixture was added NaOH (198.92 mg, 4.97 mmol, 2.00 equiv) in H2O (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, and the resulting mixture was extracted with EtOAc (1×50 mL). The aqueous layer was acidified to pH 4 with 2M HCl. The resulting mixture was concentrated under reduced pressure to give 4-[1-(pyridin-2-yl)ethyl]benzoic acid (acid J, 700 mg, 86.71%) as a brown solid. LCMS: [M+1] + =228.

[0173] Preparation of Acid K

[0174]

[0175] In a 40-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (K-1, 0.97 g, 4.9 mmol, 1.00 equiv), dioxane (10 mL), H2O (10 mL), 2-bromo-5-methylpyrimidine (K-2, 0.85 g, 4.9 mmol, 1.00 equiv), palladium chloride; bis(triphenylphosphine) (0.34 g, 0.484 mmol, 0.10 equiv), sodium carbonate (1.58 g, 14.77 mmol, 3.0 equiv) were added. The resulting solution was stirred at 80° C. in an oil bath for 16 hours, and the reaction mixture was cooled. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL H2O. The resulting solution was extracted with 2×30 mL ethyl acetate, and the aqueous layers were combined. The pH value of the solution was adjusted to 3 with 3M HCl. The solid was collected by filtration to give 0.85 g (75%) of 2-fluoro-4-(5-methylpyrimidin-2-yl)benzoic acid (Acid K) as a brown solid. LCMS: [M+H] + =233.

[0176] Preparation of Acid O

[0177]

[0178] Methyl 4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzoate (O-2)

[0179] To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen was added a solution of methyl 4-(1H-pyrazol-4-yl)benzoate (O-1, 400.0 mg, 1.98 mmol, 1.00 equiv) in DMF (10 mL), 2-(2-bromoethoxy)oxane (537.7 mg, 2.57 mmol, 1.30 equiv) and cesium carbonate (1.3 g, 3.96 mmol, 2.00 equiv). The reaction was stirred at room temperature for 12 hours, and the resulting solution was diluted with 20 mL of H2O and extracted with 3×10 mL of ethyl acetate. The resulting mixture was washed with 2×10 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 400 mg (61.21%) of methyl 4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzoate (O-2) as a yellow solid. LCMS: [M+H] + =331.

[0180] 4-[1-[2-(Oxa-2-yloxy)ethyl]pyrazol-4-yl]benzoic acid (acid O)

[0181] A 20-mL glass bottle was charged with a solution of 4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzyl salt (O-2, 400.0 mg, 1.21 mmol, 1.00 equiv) in MeOH (10 mL), sodium hydroxide (193.70 mg, 4.844 mmol, 4.00 equiv), and H2O (5.00 mL). The resulting solution was stirred at room temperature for 16 hours and concentrated under vacuum, and the pH of the solution was adjusted to 2 with 2M HCl. The solid was collected by filtration to give 200 mg (52.22%) of 4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzoic acid (Acid O) as a white solid. LCMS: [M+H] + =317.

[0182] Preparation of acid P

[0183]

[0184] Methyl 4-(1-methylpyrazol-4-yl)benzoate (P-1)

[0185] To a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of methyl 4-(1H-pyrazol-4-yl)benzoate (O-1, 400.0 mg, 1.978 mmol, 1.00 equiv) in DMF (10 mL), MeI (365.00 mg, 2.572 mmol, 1.30 equiv), and Cs2CO3 (1.3 g, 3.956 mmol, 2 equiv) were added. The resulting solution was stirred at 60°C for 12 hours, the resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3×15 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 300 mg (70%) of methyl 4-(1-methylpyrazol-4-yl)benzoate (P-1) as a yellow solid. LCMS: [M+H] + =217.

[0186] A 20-mL glass bottle was charged with a solution of methyl 4-(1-methylpyrazol-4-yl)benzoate (P-1, 300.0 mg, 1.39 mmol, 1.00 equiv) in MeOH (10 mL), a solution of sodium hydroxide (221.96 mg, 5.549 mmol, 4.00 equiv) in H2O (5 mL). The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated in vacuo. 2M HCl was added to adjust the pH to 2-3 and the solid was collected by filtration to give 200 mg (71.3%) of 4-(1-methylpyrazol-4-yl)benzoic acid (acid P) as a white solid.

[0187] Preparation of acid R

[0188]

[0189] 2-Oxo-3H-1,3-benzoxazole-5-carboxylic acid methyl ester (R-2)

[0190] To a 20-mL glass bottle purged and maintained with a nitrogen inert atmosphere, a solution of methyl 3-amino-4-hydroxybenzoate (R-1, 1 g, 5.98 mmol, 1.00 equiv) in CH3CN (12 mL) and CDI (3.0 g, 17.95 mmol, 3.00 equiv) were added. The resulting solution was stirred at 80 ° C for 16 hours, and the resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 920 mg (79.62%) of methyl 2-oxo-3H-1,3-benzoxazole-5-carboxylate (R-2) as a white solid. LCMS: [M+H] + =194.

[0191] 2-Oxo-3H-1,3-benzoxazole-5-carboxylic acid (acid R)

[0192] A 12-mL glass vial was charged with a solution of methyl 2-oxo-3H-1,3-benzoxazole-5-carboxylate (200.00 mg, 1.035 mmol, 1.00 equiv) in MeOH (3 mL), a solution of sodium hydroxide (82.8 mg, 2.071 mmol, 2.00 equiv) in H2O (1 mL). The resulting solution was stirred at room temperature for 10 hours, the resulting mixture was concentrated in vacuo, and 2M HCl(aq) was added to adjust the pH to 2. The solid was collected by filtration to give 150 mg (81%) of 2-oxo-3H-1,3-benzoxazole-5-carboxylic acid (acid R) as a white solid. LCMS: [M+H] + =180.

[0193] Preparation of acid S

[0194]

[0195] 4-Methoxybut-2-yn-1-ol (S-2)

[0196] To a 250-mL 3-neck round bottom flask purged and maintained with a nitrogen inert atmosphere, 3-methoxy-propyne (S-1, 4.90 g, 69.909 mmol, 1.00 equiv) was added, followed by THF (100.00 mL) at -78°C. n-BuLi (33.60 mL, 83.880 mmol, 1.2 equiv) was added dropwise thereto while stirring at -78°C for 20 minutes. The resulting solution was stirred at -78°C for 1 hour. Paraformaldehyde (10.08 g, 111.855 mmol, 1.60 equiv) was added to the mixture at -78°C, and the resulting solution was stirred at room temperature for 20 hours. The reaction was then quenched by adding 50 mL NH4Cl (aqueous solution). The resulting solution was extracted with 2×100 mL ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:3) to obtain 3.4 g (48.58%) of yellow oily 4-methoxybut-2-yn-1-ol (S-2). GC-MS: (ES, m / z): M=100.

[0197] 1-Bromo-4-methoxybut-2-yne (S-3)

[0198] To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-methoxybut-2-yn-1-ol (S-2, 1.10 g, 10.987 mmol, 1.00 equiv), Et2O (20.00 mL, 192.791 mmol, 17.55 equiv), pyridine (0.20 mL, 2.485 mmol, 0.23 equiv) were added. PBr3 (1.19 g, 4.395 mmol, 0.40 equiv) was then added dropwise at 0°C with stirring. The resulting solution was stirred at 35°C for 1 hour, and then the reaction was quenched by adding 10 mL of NaCl (aqueous solution). The resulting solution was extracted with 2×30 mL of Et2O, and the organic layers were combined and concentrated to give 1.24 g (69.23%) of 1-bromo-4-methoxybut-2-yn (S-3) as a light yellow oil. GC-MS: [M+H] + =162.

[0199] 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylic acid methyl ester (S-4)

[0200] To a 100-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 1-bromo-4-methoxybut-2-yne (S-3, 1.20 g, 7.361 mmol, 1.34 equiv), 1H-indazole-5-carboxylic acid methyl ester (970.00 mg, 5.506 mmol, 1.00 equiv), KI (90.00 mg, 0.542 mmol, 0.10 equiv), K2CO3 (2.16 g, 15.629 mmol, 2.84 equiv), DMF (10.00 mL) were added. The resulting solution was stirred at 90 ° C for 8 hours and the solid was filtered off. The resulting mixture was concentrated and the residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 418 mg (29.39%) of solid 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylic acid methyl ester (S-4). LCMS: [M+H] + =259.

[0201] 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylate (acid S)

[0202] A 50-mL round-bottom flask was charged with methyl 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylate (S-4, 218.00 mg, 0.844 mmol, 1.00 equiv), LiOH (30.32 mg, 1.266 mmol, 1.50 equiv), MeOH (10.00 mL), and H2O (2.00 mL). The resulting solution was stirred at 50°C for 3 hours, and the resulting mixture was concentrated to give 207 mg (98.03%) of light yellow solid 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylate lithium (acid S). LCMS: [M+2H-Li]=245.

[0203] Preparation of Acid T

[0204]

[0205] Step 1: To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylic acid methyl ester (Example 27, 200.00 mg, 0.774 mmol, 1.00 equiv), MeOH (10.00 mL), PtO2 (50.00 mg, 0.220 mmol, 0.28 equiv) were added. The mixture was stirred at 40° C. under a hydrogen atmosphere (60 psi) for 12 hours, the catalyst was filtered and the resulting mixture was concentrated to give 157 mg (77.29%) of brown solid 1-(4-methoxybutyl)indazole-5-carboxylic acid methyl ester. LCMS: [M+H] + =263.

[0206] Step 2: In a 50-mL round-bottom flask, methyl 1-(4-methoxybutyl)indazole-5-carboxylate (160.00 mg, 0.610 mmol, 1.00 equiv), LiOH (21.91 mg, 0.915 mmol, 1.50 equiv), MeOH (5.00 mL), and H2O (1.00 mL) were added. The resulting solution was stirred at 50°C for 20 minutes, and the resulting mixture was concentrated to give 150 mg (96.74%) of lithium 1-(4-methoxybutyl)indazole-5-carboxylate as a white solid. LCMS: [M+2H-Li]=249.

[0207] Preparation of Acid U

[0208]

[0209] Methyl 4-[1-(pyridin-4-yl)ethyl]benzoate (U-2)

[0210] In a 100 mL round-bottom flask at room temperature, 4-acetylpyridine (U-1, 611.0 mg, 5.044 mmol, 1.00 equiv), dioxane (40.0 mL) and 4-toluenesulfonylhydrazide (1409 mg, 7.566 mmol, 1.50 equiv) were added. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. 4-(Methoxycarbonyl)phenylboronic acid (1007.6 mg, 5.6 mmol, 1.11 equiv) and K2CO3 (2091.2 mg, 15.131 mmol, 3.00 equiv) were added to the above mixture at 80°C. The resulting mixture was stirred at 110°C for another 4 hours and the mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (60 mL) and then 60 mL of water was added. The mixture was separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (3:2) to give methyl 4-[1-(pyridin-4-yl)ethyl]benzoate (U-2, 270 mg, 22.19%) as a yellow oil. LCMS: [M+1] + =242.

[0211] 4-[1-(Pyridin-4-yl)ethyl]benzoic acid (Acid U)

[0212] A solution of methyl 4-[1-(pyridin-4-yl)ethyl]benzoate (U-2, 250.00 mg, 1.036 mmol, 1.00 equiv), MeOH (4 mL) and NaOH (124.32 mg, 3.108 mmol, 3.00 equiv) in H2O (2 mL) was added to an 8 mL glass bottle at room temperature. The resulting mixture was stirred at room temperature for 4 hours and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL) and the aqueous layer was extracted with EtOAc (3×10 mL). The aqueous phase was collected and acidified to pH 5 with HCl (aqueous solution 1 M). The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under infrared light to give 4-[1-(pyridin-4-yl)ethyl]benzoic acid (acid U, 190 mg, 80.69%) as a yellow solid. LCMS: [M+1] + =228.

[0213] Preparation of Acid V

[0214] The preparation method was the same as acid U, except that U-1 was replaced by 3-acetylpyridine (1.00 g, 8.255 mmol, 1.00 equiv).

[0215] Preparation of Acid W

[0216]

[0217] To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, 5-bromo-1-methylpyrazole (500.18 mg, 3.107 mmol, 1.00 equiv), dioxane (5.00 mL), H2O (5.00 mL), 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (615.00 mg, 3.107 mmol, 1.00 equiv), Na2CO3 (987.81 mg, 9.320 mmol, 3.00 equiv), Pd(PPh3)2Cl2 (218.06 mg, 0.311 mmol, 0.10 equiv) were added. The resulting solution was stirred at 80°C for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 50 mL H2O, extracted with 2×30 mL ethyl acetate, and the aqueous layers were combined. The pH value of the solution was adjusted to 3 with HCl (3 mol / L). The solid was collected by filtration to give 600 mg (87.71%) of 2-fluoro-4-(2-methylpyrazol-3-yl)benzoic acid as a brown solid. LCMS: [M+H] + =221.

[0218] The acids in Table B below were prepared in the same manner as acid W, but using the acid designated W-1.

[0219] Table B

[0220]

[0221] Preparation of acid AC

[0222]

[0223] Step 1: To a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1H-indazole-5-carboxylic acid methyl ester (2.0 g, 11.35 mmol, 1.00 equiv), dioxane (40.00 mL), 4-iodopyridine (2.33 g, 11.366 mmol, 1.00 equiv), CuI (2.16 g, 11.342 mmol, 1.00 equiv), DMEDA (0.20 g, 2.269 mmol, 0.20 equiv), Cs2CO3 (11.10 g, 34.068 mmol, 3.00 equiv) were added. The resulting solution was stirred at 100° C. in an oil bath for 2 days, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 40 mL of H2O, extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.6 g (36.95%) of methyl 1-(pyridin-4-yl)indazole-5-carboxylate as an off-white solid. LCMS: [M+H] + =254.

[0224] Step 2: To a 100-mL glass bottle was added methyl 1-(pyridin-4-yl)indazole-5-carboxylate (1.60 g, 6.318 mmol, 1.00 equiv), CH3OH (32.00 mL), H2O (10.00 mL), and sodium hydroxide (1.26 g, 31.590 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 2×30 mL of ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3 mol / L). The solid was collected by filtration to give 350 mg (23.16%) of off-white solid 1-(pyridin-4-yl)indazole-5-carboxylic acid. LCMS: [M+H] + =240.

[0225] Preparation of acid AE

[0226] 6-Bromocinnoline (600.00 mg, 2.870 mmol, 1.00 equiv), MeOH (12.00 L), Pd(dppf)Cl2 (210.01 mg, 0.287 mmol, 0.10 equiv), TEA (871.30 mg, 8.611 mmol, 3.00 equiv), carbon monoxide (10 atm) were added to a 30-mL sealed tube. The resulting solution was stirred at 60°C in an oil bath overnight, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 3×20 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 600 mg (95.34%) of cinnoline-6-carboxylic acid methyl ester as a red solid. LCMS (PH-PUK): [M+H] + =189.

[0227] Preparation of Acid AF

[0228]

[0229] Step 1: To a 100-mL 3-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere, 1,2,3,4-tetrahydroquinoline-6-carboxylic acid methyl ester (350.0 mg, 1.830 mmol, 1.00 equiv.) and DMF (15.00 mL) were added. NaH (109.80 mg, 2.745 mmol, 1.50 equiv., 60%) was then added in batches at 0°C. CH3I (285.76 mg, 2.013 mmol, 1.10 equiv.) was added dropwise thereto while stirring at 0°C, and the resulting solution was stirred at 0°C to room temperature for 1 hour. The reaction was then quenched by adding 10 mL of water / ice, and the resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1) to obtain 260 mg (69.21%) of yellow solid 1-methyl-3,4-dihydro-2H-quinoline-6-carboxylic acid methyl ester. LCMS: [M+H] + =206.

[0230] Step 2: To a 50-mL round-bottom flask was added methyl 1-methyl-3,4-dihydro-2H-quinoline-6-carboxylate (260.0 mg, 1.27 mmol, 1.00 equiv), LiOH (60.7 mg, 2.53 mmol, 2.0 equiv), MeOH (10.0 mL), and H2O (5.0 mL). The resulting solution was stirred at 50 °C for 12 hours and the resulting mixture was concentrated. The reaction was then quenched by adding 20 mL of water and the pH of the solution was adjusted to 4 with citric acid. The solid was collected by filtration to give 207 mg (85.5%) of light yellow solid 1-methyl-3,4-dihydro-2H-quinoline-6-carboxylic acid. LCMS: [M+H] +=192.

[0231] Preparation of acid AG

[0232]

[0233] Step 1: To a 250-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added 1-(oxa-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (10.0 g, 35.95 mmol, 1.00 equiv), dioxane (100.0 mL), Pd2(dba)3 (1646.03 mg, 1.8 mmol, 0.05 equiv), potassium (peroxyphosphate), dipotassium (22893.12 mg, 107.852 mmol, 3.00 equiv), PCy3.HBF4 (661.92 mg, 1.798 mmol, 0.05 equiv), and methyl 4-bromobenzoate (11596.53 mg, 53.926 mmol, 1.50 equiv). The resulting solution was stirred at 80°C for 16 hours and the solid was filtered off. The resulting solution was diluted with 100 mL of H2O and extracted with 3×100 mL of ethyl acetate. The organic layers were combined to obtain 6 g (58.29%) of methyl 4-[1-(oxa-2-yl)pyrazol-4-yl]benzoate as a yellow oil. LCMS: [M+1] + =287.

[0234] Step 2: To a 50-mL 4-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, methyl 4-[1-(oxa-2-yl)pyrazol-4-yl]benzoate (400.00 mg, 1.397 mmol, 1.00 equiv), H2O (4.00 mL), MeOH (4.00 mL), sodium hydroxide (223.50 mg, 5.588 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated. The pH value of the solution was adjusted to 2-3 with HCL (1 mol / L). The solid was collected by filtration to give 300 mg (78.9%) of 4-[1-(oxa-2-yl)pyrazol-4-yl]benzoic acid as a white solid. LCMS: [M+1] + =273.

[0235] Preparation of Acid AH

[0236]

[0237] Step 1: 3-Bromo-1H-pyrazole (1.50 g, 10.206 mmol, 1.00 equiv), DCM (30.00 mL), dihydropyran (1.29 g, 15.336 mmol, 1.50 equiv), TsOH (0.05 g, 0.510 mmol, 0.05 equiv) were added to a 100-mL round-bottom flask. The resulting solution was stirred overnight at 80°C in an oil bath. The resulting solution was diluted with 50 mL of NaHCO3 (5%) and extracted with 3×30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2 g (84.8%) of 3-bromo-1-(oxa-2-yl)pyrazole as a brown oil. LCMS: [M+H] + =231.

[0238] Step 2: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (0.86 g, 4.327 mmol, 1.00 equiv), dioxane (12.00 mL), H2O (12.00 mL), 3-bromo-1-(oxa-2-yl)pyrazole (1.00 g, 4.327 mmol, 1.00 equiv), Na2CO3 (1.38 g, 13.02 mmol, 3.01 equiv), Pd(PPh3)2Cl2 (0.30 g, 0.427 mmol, 0.10 equiv), BINAP (0.54 g, 0.867 mmol, 0.20 equiv) were added. The resulting solution was stirred at 80°C in an oil bath for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 2×20 mL of ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3 mol / L). The solid was collected by filtration to give 1 g (62.38%) of 2-fluoro-4-[1-(oxa-2-yl)pyrazol-3-yl]benzoic acid as a white solid. LCMS: [M+H] + =291.

[0239] Preparation of Acid AI

[0240]

[0241] Step 1: To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-bromo-2-fluoro-5-methoxybenzaldehyde (1.00 g, 4.29 mmol, 1.00 equiv), acetone (43.00 mL), Jones reagent (10.3 mL) were added. The resulting solution was stirred in an ice / salt bath at 0°C for 4 hours. The resulting solution was diluted with 40 mL of H2O and extracted with 2×30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 0.7 g (65.5%) of 4-bromo-2-fluoro-5-methoxybenzoic acid as a brown solid. LCMS: [MH] + =247.

[0242] Step 2: To a 40-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 4-bromo-2-fluoro-5-methoxybenzoic acid (0.70 g, 2.811 mmol, 1.00 equiv), dioxane (20.0 mL), 1-(oxa-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.78 g, 2.804 mmol, 1.00 equiv), Pd2(dba)3 (0.13 g, 0.141 mmol, 0.05 equiv), PCy3.HBF4 (0.08 g, 0.217 mmol, 0.08 equiv), K3PO4 (1.79 g, 8.433 mmol, 3.00 equiv) were added. The resulting solution was stirred at 80° C. in an oil bath for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, and the resulting solution was extracted with 2×20 mL of ethyl acetate, and the aqueous layers were combined. The pH value of the solution was adjusted to 3 with HCl (3 mol / L). The solid was collected by filtration to obtain 600 mg (66.64%) of brown solid 2-fluoro-5-methoxy-4-[2-(oxa-2-yl)pyrazol-3-yl]benzoic acid. LCMS: [M+H] + =321.

[0243] Preparation of acid AJ

[0244]

[0245] Step 1: 5-bromo-3-methyl-1H-indazole (2.00 g, 9.48 mmol, 1.00 equiv), DHP (1.20 g, 14.214 mmol, 1.50 equiv), DCM (20.00 mL), TsOH (163.18 mg, 0.948 mmol, 0.10 equiv) were added to a 100-mL 3-neck round-bottom flask. The resulting solution was stirred at room temperature for 5 hours, and then the reaction was quenched by adding 50 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give 1.6 g (57.20%) of 5-bromo-3-methyl-1-(oxa-2-yl)indazole as a white solid. LCMS: [M+H] + =295.

[0246] Step 2: To a 100-mL pressure reactor, 5-bromo-3-methyl-1-(oxa-2-yl)indazole (1.60 g, 5.420 mmol, 1.00 equiv), TEA (1.65 g, 16.260 mmol, 3.00 equiv), Pd(dppf)Cl2 (793.22 mg, 1.084 mmol, 0.20 equiv), and MeOH (20.00 mL) were added. The flask was evacuated and flushed with nitrogen three times, and then flushed with CO (gas). The mixture was stirred at 60 ° C under a CO (0.3 MPa) atmosphere for 6 hours, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to obtain 1.25 g (84.07%) of 3-methyl-1-(oxa-2-yl)indazole-5-carboxylic acid methyl ester as a white solid. LCMS: [M+H] + =275.

[0247] Step 3: In a 50-mL round-bottom flask, methyl 3-methyl-1-(oxa-2-yl)indazole-5-carboxylate (600.0 mg, 2.187 mmol, 1.00 equiv), H2O (2.0 mL), MeOH (10.0 mL), LiOH (157.1 mg, 6.56 mmol, 3.00 equiv) were added. The resulting solution was stirred at 40°C for 12 hours, and the resulting mixture was concentrated to give 510 mg (87.58%) of lithium 3-methyl-1-(oxa-2-yl)indazole-5-carboxylate as a white solid. LCMS: [M+2H-Li]=275.

[0248] Preparation of Acid AK

[0249]

[0250] To a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1H-indazole-5-carboxylic acid methyl ester (2 g, 11.352 mmol, 1.00 equiv), K2CO3 (4.71 g, 34.056 mmol, 3.00 equiv), DMF (60.00 mL) were added. I2 (8.64 g, 34.056 mmol, 3.00 equiv) was then added in portions at 0°C. The resulting solution was stirred at room temperature for 16 hours, and then the reaction was quenched by adding 100 mL of NaHSO3 (aqueous solution). The solid was collected by filtration to give 2.9 g (84.57%) of 3-iodo-1H-indazole-5-carboxylic acid methyl ester as a yellow solid. LCMS: [M+H] + =387.

[0251] Step 2: In a 250-mL 3-neck round-bottom flask, 3-iodo-1H-indazole-5-carboxylic acid methyl ester (2.40 g, 7.945 mmol, 1.00 equiv), DHP (1.00 g, 11.918 mmol, 1.50 equiv), TsOH (273.63 mg, 1.589 mmol, 0.20 equiv), DCM (50.00 mL) were added. The resulting solution was stirred at room temperature for 5 hours, and then the reaction was quenched by adding 50 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate, and the organic layers were combined and concentrated to give 2.4 g (78.22%) of solid 3-iodo-1-(oxa-2-yl)indazole-5-carboxylic acid methyl ester. LCMS: [M+H] + =387.

[0252] Step 3: To a 100-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere were added 3-iodo-1-(oxa-2-yl)indazole-5-carboxylic acid methyl ester (1.40 g, 3.625 mmol, 1.00 equiv), cyclopropylboronic acid (0.62 g, 7.250 mmol, 2.00 equiv), Pd(PPh3)4 (418.91 mg, 0.363 mmol, 0.10 equiv), K3PO4 (3.0 8g, 14.500mmol, 4.00 equivalents), toluene (36.00mL), H2O (2.40mL). The resulting solution was stirred at 110°C for 16 hours and the solid was filtered out. The resulting mixture was concentrated and the residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to obtain 910mg (83.57%) of light brown solid 3-cyclopropyl-1-(oxa-2-yl)indazole-5-carboxylic acid methyl ester. LCMS: [M+H] + =301.

[0253] Step 4: To a 50-mL round bottom flask was added methyl 3-cyclopropyl-1-(oxa-2-yl)indazole-5-carboxylate (510.00 mg, 1.698 mmol, 1.00 equiv), NaOH (135.83 mg, 3.396 mmol, 2.00 equiv), MeOH (10.00 mL), H2O (2.00 mL). The resulting solution was stirred at room temperature for 12 hours and the resulting mixture was concentrated. The pH of the solution was adjusted to 4 with citric acid (aq.) and the solid was collected by filtration to give 400 mg (82.27%) of 3-cyclopropyl-1-(oxa-2-yl)indazole-5-carboxylic acid as a white solid. LCMS: [M+H] = 287.

[0254] Preparation of Acid AL

[0255]

[0256] Step 1: To a 250-mL 4-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, methyl 4-[1-(oxa-2-yl)pyrazol-4-yl]benzoate (6.00 g, 20.955 mmol, 1.00 equiv), DCM (60.00 mL), trifluoroacetic acid (8216.28 mg, 83.819 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated to give 4 g (94.40%) of methyl 4-(1H-pyrazol-4-yl)benzoate as a white solid. LCMS: [M+1] + =203.

[0257]

[0258] Step 2: In a 40-mL round-bottom flask, methyl 4-(1H-pyrazol-4-yl)benzoate (400.00 mg, 1.978 mmol, 1.00 equiv), DCE (10.00 mL), 2,2 (370.30 mg, 2.374 mmol, 1.20 equiv), Cu(AcO)2 (431.15 mg, 2.374 mmol, 1.20 equiv), cyclopropylboronic acid (424.80 mg, 4.945 mmol, 2.50 equiv) were added. The resulting solution was stirred at 70 °C for 3 hours. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of dichloromethane, and the organic layers were combined and concentrated to give 300 mg (62.60%) of methyl 4-(1-cyclopropylpyrazol-4-yl)benzoate as a yellow oil. LCMS: [M+1] + =243.

[0259]

[0260] Step 3: To a 50-mL 4-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, methyl 4-(1-cyclopropylpyrazol-4-yl)benzoate (300.00 mg, 1.238 mmol, 1.00 equiv), H2O (3.00 mL), MeOH (3.00 mL), sodium hydroxide (198.10 mg, 4.953 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated. The pH of the solution was adjusted to 2-3 with HCL (1 M). The solid was collected by filtration to give 150 mg (53.07%) of 4-(1-cyclopropylpyrazol-4-yl)benzoic acid as a white solid. LCMS: [M+1] + =229.

[0261] Preparation of Acid AM

[0262]

[0263] Step 1: In a 20-mL round-bottom flask, methyl 4-(1H-pyrazol-4-yl)benzoate (400.00 mg, 1.978 mmol, 1.00 equiv), CH3CN (4.00 mL), potassium fluoride (229.84 mg, 3.956 mmol, 2.00 equiv), diethyl bromodifluoromethylphosphonate (792.25 mg, 2.967 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 3 hours, and the resulting solution was diluted with 10 mL of H2O to give 400 mg (80.17%) of methyl 4-[1-(difluoromethyl)pyrazol-4-yl]benzoate as a yellow oil. LCMS: [M+1] + =253.

[0264] Step 2: To a 40-mL round-bottom flask, methyl 4-[1-(difluoromethyl)pyrazol-4-yl]benzoate (400.00 mg, 1.586 mmol, 1.00 equiv), H2O (4.00 mL), MeOH (4.00 mL), sodium hydroxide (253.73 mg, 6.344 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated. The pH of the solution was adjusted to 2-3 with HCL (1 M) and the solid was collected by filtration to give 260 mg (68.83%) of 4-[1-(difluoromethyl)pyrazol-4-yl]benzoic acid as a white solid. LCMS: [M+1] + =239.

[0265] Preparation of Acid AN

[0266]

[0267] Methyl 4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoate (AN-3)

[0268] In a 40-mL round-bottom flask, methyl 4-(1H-pyrazol-4-yl)benzoate (AN-1, 400.00 mg, 1.978 mmol, 1.00 equiv), cesium carbonate (1939.50 mg, 5.934 mmol, 3.0 equiv), DMF (10.00 mL), 2-bromoethyl methyl ether (AN-2, 412.41 mg, 2.967 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting solution was diluted with 10 mL of H2O, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3×10 ml of brine, and the resulting mixture was concentrated to give 400 mg (77.69%) of yellow oily methyl 4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoate (AN-3). LCMS: [M+1] + =261.

[0269] 4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoic acid (acid AN)

[0270] To a 40-mL round bottom flask, methyl 4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoate (400.00 mg, 1.537 mmol, 1.00 equiv), MeOH (4.00 mL), H2O (4.00 mL), sodium hydroxide (245.86 mg, 6.147 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated. The pH of the solution was adjusted to 2-3 with HCL (1 M) and the solid was collected by filtration to give 260 mg (68.70%) of 4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoic acid (acid AN) as a white solid. LCMS: [M+1] + =247.

[0271] Preparation of Acid AO

[0272] Prepared in the same manner as acid AN except that bromoacetonitrile was used instead of AN-2.

[0273] Preparation of acid AP

[0274]

[0275] Step 1: To a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 5-bromo-2-fluorobenzonitrile (5.5 g, 27.499 mmol, 1.00 equiv.), tetrahydrofuran (110.00 mL) were added. Bromo(cyclopropyl)magnesium (1 M in THF) (68.75 mL, 68.748 mmol, 2.50 equiv.) was added and the resulting solution was stirred at -78 °C for 2 hours. The resulting solution was allowed to react for an additional 30 minutes at 25 °C with stirring, then the reaction was quenched by adding 100 mL of HCl (10%) and stirred for an additional 6 hours. The resulting solution was extracted with 3×50 mL of ethyl acetate and the aqueous layers were combined. The resulting mixture was washed with 3×50 mL of brine and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:10) to give 3.3 g (49.37%) of off-white solid (5-bromo-2-fluorophenyl)(cyclopropyl)methanone. LCMS: [M+1] + =243.

[0276] Step 2: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, (5-bromo-2-fluorophenyl)(cyclopropyl)methanone (1.50 g, 6.171 mmol, 1.00 equiv), NH2OH.HCl (3001.77 mg, 0.042 mmol, 7.00 equiv), pyridine (15.00 mL, 186.353 mmol, 30.20 equiv) were added. The resulting solution was stirred at 115°C for 3 hours, and the pH value of the solution was adjusted to 3 with HCl (1 mol / L). The resulting solution was extracted with 3×50 mL of concentrated ethyl acetate to give 1.25 g (78.49%) of off-white solid (E)-N-[(5-bromo-2-fluorophenyl)(cyclopropyl)methylene]hydroxylamine. LCMS: [M+1] + =258.

[0277] Step 3: To a 50-mL pressure reactor, (E)-N-[(5-bromo-2-fluorophenyl)(cyclopropyl)methylene]hydroxylamine (1.25 g, 4.843 mmol, 1.00 equiv), TEA (1470.27 mg, 14.529 mmol, 3.00 equiv), Pd(dppf)Cl2 (354.38 mg, 0.484 mmol, 0.10 equiv), MeOH (20.00 mL), CO (20 atm) were added. The resulting solution was stirred at 80 °C for 12 hours and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:2) to give 850 mg (73.98%) of brown solid 3-[(1E)-cyclopropyl(hydroxyimino)methyl]-4-fluorobenzoic acid methyl ester. LCMS: [M+1] + =238.

[0278] Step 4: To a 20-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, methyl 3-[(1E)-cyclopropyl(hydroxyimino)methyl]-4-fluorobenzoate (450.00 mg, 1.897 mmol, 1.00 equiv), tetrahydrofuran (8 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1433.25 mg, 5.691 mmol, 3.00 equiv) were added. The resulting solution was stirred at 75 °C for 12 hours, and then the reaction was quenched by adding 20 mL of aqueous citric acid (5%). The resulting solution was extracted with 3×10 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:2) to give 140 mg (33.98%) of off-white solid methyl 3-cyclopropyl-1,2-benzoxazole-5-carboxylate. LCMS: [M+1] + =218.

[0279] Step 5: In a 20-mL glass bottle purged and maintained with a nitrogen inert atmosphere, methyl 3-cyclopropyl-1,2-benzoxazole-5-carboxylate (140.00 mg, 0.644 mmol, 1.00 equiv), H2O (1.00 mL), methanol (4.00 mL), sodium hydroxide (51.56 mg, 1.289 mmol, 2 equiv) were added. The resulting solution was stirred at 25°C for 2 hours, and the pH value of the solution was adjusted to 3 with HCl (37%). The resulting mixture was concentrated to give 220 mg (crude) of off-white solid 3-cyclopropyl-1,2-benzoxazole-5-carboxylic acid. LCMS: [M+1] + =204.

[0280] Preparation of Acid AR

[0281]

[0282] To a 100-mL 3-neck round-bottom flask, 1H-indazole-6-carboxylic acid methyl ester (4.00 g, 22.705 mmol, 1.00 equiv), K2CO3 (6275.83 mg, 45.410 mmol, 2.00 equiv), and DMF (100.00 mL) were added. I2 (8643.98 mg, 34.058 mmol, 1.50 equiv) was then added in batches at 0°C. The resulting solution was stirred at room temperature for 16 hours, and then the reaction was quenched by adding 100 mL of Na2S2O3 (aq). The resulting solution was extracted with 3×100 mL of ethyl acetate, and the organic layers were combined to give 7.4 g (crude) of yellow solid 3-iodo-1H-indazole-6-carboxylic acid methyl ester. LCMS: [M+H] + =303.

[0283] Step 2: To a 1-L 3-neck round bottom flask, methyl 3-iodo-1H-indazole-6-carboxylate (7.40 g, 24.498 mmol, 1.00 equiv), K2CO3 (10.16 g, 73.494 mmol, 3.00 equiv), and DMF (740.00 mL) were added dropwise with stirring at 0°C. The resulting solution was stirred at room temperature for 10 hours, the solid was filtered out, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to obtain 5.34 g (68.96%) of off-white solid methyl 3-iodo-1-methylindazole-6-carboxylate. LCMS: [M+H] + =317.

[0284] Step 3: To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, methyl 3-vinyl-1-methylindazole-6-carboxylate (500.00 mg, 2.312 mmol, 1.00 equiv), trifluoro(vinyl)-14-borane, potassium salt (1238.90 mg, 0.000 mmol, 4.00 equiv), toluene (10.00 mL), H2O (2.00 mL), K3PO4 (1963.25 mg, 9.248 mmol, 4.00 equiv), Pd(PPh3)4 (267.19 mg, 0.231 mmol, 0.10 equiv) were added. The resulting solution was stirred in an oil bath at 110°C for 16 hours and the solid was filtered off. The resulting mixture was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:2) to obtain 240 mg (32.8%) of methyl 3-iodo-1-methylindazole-6-carboxylate as a white solid. LCMS: [M+H] + =217.

[0285] Step 4: To a 100-mL 3-neck round-bottom flask, methyl 3-vinyl-1-methylindazole-6-carboxylate (750.00 mg, 3.468 mmol, 1.00 equiv), H2O (4.00 mL), CH3CN (20.00 mL), NaIO4 (1483.71 mg, 6.936 mmol, 2.00 equiv), RuCl3.H2O (78.19 mg, 0.347 mmol, 0.10 equiv) were added. The resulting solution was stirred at room temperature for 10 hours, and then the reaction was quenched by adding 100 mL of Na2S2O3 (aqueous solution). The resulting solution was extracted with 3×30 mL of dichloromethane, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to give 240 mg (31.7%) of methyl 3-formyl-1-methylindazole-6-carboxylate as a brown solid. LCMS: [M+H] + =219.

[0286] Step 5: To a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-formyl-1-methylindazole-6-carboxylic acid methyl ester (240.00 mg, 1.100 mmol, 1.00 equiv.) and DCM (20.00 mL) were added. DAST (709.13 mg, 4.399 mmol, 4.00 equiv.) was then added dropwise with stirring at 0°C. The resulting solution was stirred at room temperature for 10 hours, and then the reaction was quenched by adding 20 mL of water / ice. The resulting solution was extracted with 2×20 mL of dichloromethane, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 180 mg (68.1%) of 3-(difluoromethyl)-1-methylindazole-6-carboxylic acid methyl ester as a white solid. LCMS: [M+H] + =241.

[0287] Step 6: In a 50-mL round-bottom flask, methyl 3-(difluoromethyl)-1-methylindazole-6-carboxylate (180.00 mg, 0.749 mmol, 1.00 equiv), MeOH (10.00 mL), H2O (10.00 mL), NaOH (59.94 mg, 1.498 mmol, 2.00 equiv) were added. The resulting solution was stirred at room temperature for 6 hours and the resulting mixture was concentrated. The reaction was then quenched by adding 10 mL of water. The pH of the solution was adjusted with citric acid (aqueous solution). The solid was collected by filtration to give 150 mg (88.50%) of 3-(difluoromethyl)-1-methylindazole-6-carboxylic acid as a white solid. LCMS: [M+H] + =227.

[0288] Preparation of acid AS

[0289]

[0290] To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 3-iodo-1-methylindazole-6-carboxylic acid methyl ester (1.00 g, 3.164 mmol, 1.00 equivalent), cyclopropylboronic acid (815.25 mg, 9.492 mmol, 3.00 equivalent), Pd(PPh3)4 (365.57 mg, 0.316 mmol, 0.10 equivalent), toluene (20.00 mL), H2O (2.00 mL), K3PO4 (2.69 g, 12.656 mmol, 4.00 equivalent) were added. The resulting solution was stirred at 110 ° C for 16 hours in an oil bath, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to obtain 590 mg (81%) of yellow solid 3-cyclopropyl-1-methylindazole-6-carboxylic acid methyl ester. LCMS: [M+H] + =231.

[0291]

[0292] To a 50-mL round-bottom flask, methyl 3-cyclopropyl-1-methylindazole-6-carboxylate (590.00 mg, 2.56 mmol, 1.00 equiv), LiOH (184.08 mg, 3.00 equiv), MeOH (10.00 mL), and H2O (2.00 mL) were added. The resulting solution was stirred at room temperature for 6 hours, the resulting mixture was concentrated, and the pH value of the solution was adjusted to 2-3 with citric acid (aqueous solution). The solid was collected by filtration to give 450 mg of 3-cyclopropyl-1-methylindazole-6-carboxylic acid as a white solid. LCMS: [M+H] + =217.

[0293] Preparation of acid AT

[0294]

[0295] Step 1: To a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 2-amino-benzonitrile (11.00 g, 93.111 mmol, 1.00 equiv.), tetrahydrofuran (220 mL) were added. Ethylmagnesium bromide (2 mol / L in Et2O solution) (139.67 mL, 279.33 mmol, 3.00 equiv.) was added and the resulting solution was stirred at -10 °C for 30 minutes. The resulting solution was reacted at 25 °C for another 12 hours under stirring, and then the reaction was quenched by adding 300 mL of HCl (10%). The resulting solution was extracted with 3×100 mL of ethyl acetate, and the aqueous layers were combined. The resulting mixture was washed with 3×100 mL of brine, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:10) to give 11 g (79.19%) of light yellow solid 1-(2-aminophenyl)propan-1-one. LCMS: [M+1] + =150.

[0296] Step 2: To a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1-(2-aminophenyl)propan-1-one (11.0 g, 73.730 mmol, 1.00 equiv), TEA (22.38 g, 221.190 mmol, 3.00 equiv), DCM (220.00 mL), acetyl chloride (8.68 g, 110.595 mmol, 1.50 equiv) were added, and the resulting solution was stirred at 25 ° C for 3 hours. The reaction was then quenched by adding 600 mL of water / ice. The resulting solution was extracted with 3×500 mL of ethyl acetate, and the aqueous layers were combined. The resulting mixture was washed with 3×400 mL of brine and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:10) to give 10 g (70.9%) of brown solid N-(2-propionylphenyl)acetamide. LCMS: [M+1] + =192.

[0297] Step 3: To a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, N-(2-propionylphenyl)acetamide (10.0 g, 52.293 mmol, 1.00 equiv), DMF (150.00 mL), NBS (11168.79 mg, 62.752 mmol, 1.20 equiv) were added. The resulting solution was stirred at 40°C overnight, and the resulting solution was extracted with 3×150 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×150 mL of brine, and the resulting mixture was concentrated to give 13 g (92.03%) of solid N-(4-bromo-2-propionylphenyl)acetamide. LCMS: [M+1] + =270.

[0298] Step 4: To a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, N-(4-bromo-2-propionylphenyl)acetamide (5.50 g, 0.020 mmol, 1.00 equiv), THF (60.00 mL), H2O (12.00 mL) and HCl (12.00 mL) were added. The resulting solution was stirred at 70°C for 1 hour. The resulting mixture was concentrated to give 5.8 g (crude) of brown solid 1-(2-amino-5-bromophenyl)propan-1-one hydrochloride. LCMS: [M+1] + =228.

[0299] Step 5: To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1-(2-amino-5-bromophenyl)propan-1-one (5.00 g, 21.921 mmol, 1.00 equiv), H2O (24.00 mL, 222.033 mmol), HCl (37%) (12.00 mL, 0.058 mmol) and sodium nitrite (1.81 g, 26.305 mmol, 1.20 equiv) were added. The resulting solution was stirred at 25°C for 30 minutes and the resulting solution was allowed to react at 100°C for another 10 hours with stirring. The reaction mixture was cooled to 25°C using a water / ice bath. The solid was collected by filtration to give 2.8 g (53.43%) of solid 6-bromo-3-methylcinnoline-4-ol. LCMS: [M+1] + =239.

[0300] Step 6: To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 6-bromo-3-methylcinnoline-4-ol (2.8 g, 11.76 mmol, 1.00 equiv.) and POCl3 (20 mL) were added. The resulting solution was stirred at 100°C for 2 hours, and the resulting mixture was concentrated to give 2.8 g (92.84%) of brown solid 6-bromo-4-chloro-3-methylcinnoline. LCMS: [M+1] + =257.

[0301] Step 7: To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 6-bromo-4-chloro-3-methylcinnoline (2.80 g, 10.873 mmol, 1.00 equiv), ethanol (56 mL), NH2NH2.H2O (10.89 g, 217.460 mmol, 20.00 equiv) were added. The resulting solution was stirred at 80 ° C for 3 days, and then the reaction was quenched by adding 200 mL of water / ice. The solid was collected by filtration to give 2.3 g (83.58%) of brown solid 6-bromo-4-hydrazino-3-methylcinnoline. LCMS: [M+1] + =253.

[0302] Step 8: To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 6-bromo-4-hydrazine-3-methylcinnoline (2.30 g, 9.087 mmol, 1.00 equiv), water (40.00 mL) and dioxo(sulfinyl)copper (2.90 mg, 18.174 mmol, 2.00 equiv) were added. The resulting solution was stirred at 100 ° C for 2 hours, and then the reaction was quenched by adding 100 mL of water / ice. The pH value of the solution was adjusted to 8 with NaOH (1 mol / L), and the resulting solution was extracted with 3×50 mL of concentrated ethyl acetate. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:3) to give 1 g (49.33%) of off-white solid 6-bromo-3-methylcinnoline. LCMS: [M+1] + =223.

[0303] Step 9: To a 50-mL pressure reactor, 6-bromo-3-methylcinnoline (500.00 mg, 2.241 mmol, 1.00 equiv), methanol (10.00 mL), Pd(dppf)Cl2 (164.00 mg, 0.224 mmol, 0.10 equiv), TEA (680.43 mg, 6.723 mmol, 3.00 equiv) and carbon monoxide (20 atm) were added. The resulting solution was stirred at 80 °C for 16 hours and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:3) to give 400 mg (88.3%) of 3-methylcinnoline-6-carboxylic acid methyl ester as an off-white solid. LCMS: [M+1] + =203.

[0304] Step 10: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, methyl 3-methylcinnoline-6-carboxylate (400.00 mg, 1.978 mmol, 1.00 equiv), methanol (10.00 mL), water (2.00 mL) and sodium hydroxide (158.24 mg, 3.96 mmol, 2.00 equiv) were added. The resulting solution was stirred at 25 °C for 16 hours, and the pH of the solution was adjusted to 3 with HCl (37%). The resulting mixture was concentrated to give 400 mg (crude) of 3-methylcinnoline-6-carboxylic acid as an off-white solid. LCMS: [M+1] + =189.

[0305] Preparation of acid AU

[0306]

[0307] Step 1: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, methyl 2-chloroquinoline-6-carboxylate (1.20 g, 5.414 mmol, 1.00 equiv), dioxane (24.00 mL), BocNH2 (0.95 g, 8.110 mmol, 1.50 equiv), BINAP (0.34 g, 0.541 mmol, 0.10 equiv), Cs2CO3 (5.29 g, 16.242 mmol, 3.00 equiv) and Pd2(dba)3 (0.25 g, 0.271 mmol, 0.05 equiv) were added. The resulting solution was stirred at 100° C. in an oil bath for 20 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 700 mg (63.9%) of methyl 2-aminoquinoline-6-carboxylate as a brown solid. LCMS: [M+H] + =303.

[0308] Step 2: In a 100-mL round-bottom flask, methyl 2-aminoquinoline-6-carboxylate (700.00 mg, 3.462 mmol, 1.00 equiv), DCM (21.00 mL), Boc2O (1511.01 mg, 6.92 mmol, 2.00 equiv), Et3N (1050.9 mg, 10.385 mmol, 3.00 equiv), DMAP (84.58 mg, 0.692 mmol, 0.20 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, and the resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 1.5 g (69.76%) of methyl 2-[bis(tert-butoxycarbonyl)amino]quinoline-6-carboxylate as a brown solid. LCMS: [M+H] + =403.

[0309] Step 3: In a 100-mL round-bottom flask, methyl 2-[bis(tert-butoxycarbonyl)amino]quinoline-6-carboxylate (1.50 g, 3.727 mmol, 1.00 equiv), CH3OH (30.00 mL), H2O (10.00 mL), and sodium hydroxide (0.45 g, 11.251 mmol, 3.02 equiv) were added. The resulting solution was stirred at room temperature for 6 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 2×20 mL of ethyl acetate, the aqueous layers were combined, and the pH of the solution was adjusted to 3 with HCl (3 M). The solid was collected by filtration to give 800 mg (62.18%) of 2-[(tert-butoxycarbonyl)amino]quinoline-6-carboxylic acid as a brown solid. LCMS: [M+H] + =289.

[0310] Preparation of Acid AV

[0311]

[0312] Step 1: To a 50-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, methyl 3-formyl-4-nitrobenzoate (1.10 g, 5.26 mmol, 1.00 equiv), AcOH (5.50 mL), EtOH (5.50 mL), Fe (881.10 mg, 15.78 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 3 hours and the solid was filtered out. The resulting mixture was concentrated and the residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to give 700 mg (74.28%) of yellow solid methyl 4-amino-3-formylbenzoate. LCMS: [M+1] + =180.

[0313] Step 2: Into an 8-mL round-bottom flask, methyl 4-amino-3-formylbenzoate (700.00 mg, 3.907 mmol, 1.00 equiv) and urea (1173.13 mg, 19.534 mmol, 5.00 equiv) were added. The resulting solution was stirred at 145 °C for 16 hours and diluted with 10 mL of H2O. The solid was collected by filtration to give 400 mg (50.14%) of methyl 2-oxo-1H-quinazoline-6-carboxylate as a yellow solid. LCMS: [M+1] + =205.

[0314] Step 3: To an 8-mL round-bottom flask, 2-oxo-1H-quinazoline-6-carboxylic acid methyl ester (400.00 mg, 1 equivalent) and phosphorus oxychloride (1.00 mL) were added, and the resulting solution was stirred at 100°C for 1 hour. The resulting mixture was concentrated to give 250 mg (57.32%) of yellow solid 2-chloroquinazoline-6-carboxylic acid methyl ester. LCMS: [M+1] + =223.

[0315] Step 4: To an 8-mL round-bottom flask, methyl 2-chloroquinazoline-6-carboxylate (140.00 mg, 0.629 mmol, 1.00 equiv), ACN (2.00 mL), potassium carbonate (262.63 mg, 1.887 mmol, 3.0 equiv), and 1-(2,4-dimethoxyphenyl)benzylamine (157.72 mg, 0.943 mmol, 1.50 equiv) were added. The resulting solution was stirred at 80 °C for 20 hours, diluted with 10 mL of H2O, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to obtain 120 mg (54.00%) of light yellow solid methyl 2-[[(2,4-dimethoxyphenyl)methyl]amino]quinazoline-6-carboxylate. LCMS: [M+1] + =354.

[0316] Step 5: Into an 8-mL round-bottom flask, methyl 2-[[(2,4-dimethoxyphenyl)methyl]amino]quinazoline-6-carboxylate (120.00 mg, 0.340 mmol, 1.00 equiv), MeOH (2.00 mL), H2O (2.00 mL), sodium hydroxide (54.33 mg, 1.358 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting mixture was concentrated, and the pH value of the solution was adjusted to 1-2 with HCL (1 mol / L). The solid was collected by filtration to give 90 mg (78.10%) of 2-[[(2,4-dimethoxyphenyl)methyl]amino]quinazoline-6-carboxylic acid as a white solid. LCMS: [M+1] + =340.

[0317] Preparation of Acid AW

[0318]

[0319] Step 1: To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, methyl 3-iodo-1-methylindazole-6-carboxylate (1.00 g, 3.164 mmol, 1.00 equiv), tert-butyl carbamate (1111.82 mg, 0.000 mmol, 3.00 equiv), Pd2(dba)3 (289.69 mg, 0.316 mmol, 0.10 equiv), Xantphos (366.10 mg, 0.633 mmol, 0.20 equiv), Cs2CO3 (4123.02 mg, 12.656, 4.00 equiv) and dioxane (20.00 mL) were added. The resulting solution was stirred in an oil bath at 100° C. for 20 hours, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:2) to obtain 850 mg of brown solid 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-6-carboxylic acid methyl ester. LCMS: [M+H] + =306.

[0320] Step 2: To a 50-mL round-bottom flask, methyl 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-6-carboxylate (400.00 mg, 1.310 mmol, 1.00 equiv), LiOH (94.12 mg, 3.930 mmol, 3.00 equiv), MeOH (20.00 mL) and H2O (5.00 mg) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting mixture was concentrated, and the pH of the solution was adjusted to 2-3 with citric acid (aqueous solution). The solid was collected by filtration to give 280 mg (73.37%) of 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-6-carboxylic acid as an off-white solid. LCMS: [M+H] + =292.

[0321] Preparation of Acid AX

[0322]

[0323] Step 1: To a 250-mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-amino-3-nitrophenol (10.00 g, 64.882 mmol, 1.00 equiv), dimethylformamide (100.00 mL), t-BuOK (7.28 g, 64.882 mmol, 1 equiv) were added. The resulting solution was stirred in a water / ice bath at 0°C for 0.5 h, and BnBr (11.10 g, 64.882 mmol, 1 equiv) was added to the flask. The resulting solution was stirred at room temperature for 4 h, and the resulting solution was diluted with 200 mL of NH4Cl. The solid was collected by filtration to give 8 g (50.48%) of brown solid 4-(benzyloxy)-2-nitroaniline. LCMS: [M+H]+ =245.

[0324] Step 2: To a 100-mL 3-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere, 4-(benzyloxy)-2-nitroaniline (2.00 g, 8.188 mmol, 1.00 equiv), CH3OH (40.00 mL), stannous chloride (4.71 g, 24.579 mmol, 3.00 equiv) were added. The resulting solution was stirred in an oil bath at 80 ° C for 16 hours, and the resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give 1.5 g (75.40%) of brown solid 4-(benzyloxy)benzene-1,2-diamine. LCMS: [M+H] + =215.

[0325] Step 3: To a 40-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 4-(benzyloxy)benzene-1,2-diamine (800.00 mg, 3.734 mmol, 1.00 equiv.), methyl 2-glycolate (8.00 mL), LiBr (64.85 mg, 0.747 mmol, 0.2 equiv.) were added, and the resulting solution was stirred in an oil bath at 80° C. for 12 hours. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 500 mg (44.89%) of brown solid [5-(benzyloxy)-1H-1,3-benzodiazol-2-yl]methanol. LCMS: [M+H] + =255.

[0326] Step 4: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, [5-(benzyloxy)-1H-1,3-benzodiazol-2-yl]methanol (500.00 mg, 1.966 mmol, 1.00 equiv), acetone (20.00 mL), H2O (5.00 mL), NaOH (165.15 mg, 4.129 mmol, 2.10 equiv), KMnO4 (466.11 mg, 2.949 mmol, 1.50 equiv) were added. The resulting solution was stirred at 100°C in an oil bath for 2 hours, and the reaction mixture was cooled. The resulting mixture was concentrated in vacuo, and the resulting solution was diluted with 30 mL of H2O. The solid was filtered off. The resulting solution was extracted with 2×20 mL of ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3M). The solid was collected by filtration to give 260 mg (49.29%) of 5-(benzyloxy)-1H-1,3-benzodiazole-2-carboxylic acid as a brown solid. LCMS: [M+H] + =269.

[0327] Preparation of Acid AY

[0328]

[0329] Step 1: To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 2-amino-4-nitroaniline (5.00 g, 32.650 mmol, 1.00 equiv), HCl (6M) (50.00 mL), glycolic acid (2.48 g, 32.650 mmol, 1.00 equiv) were added. The resulting solution was stirred in an oil bath at 100 ° C for 3 hours, and the resulting solution was extracted with 2×50 mL of ethyl acetate and the aqueous layers were combined. The pH value of the solution was adjusted to pH 8 with NaHCO3. The solid was collected by filtration to give 4 g (63.42%) of brown solid (5-nitro-1H-1,3-benzodiazol-2-yl)methanol. LCMS: [M+H] + =194.

[0330] Step 2: To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, (5-nitro-1H-1,3-benzodiazol-2-yl)methanol (4.00 g, 20.708 mmol, 1.00 equiv), H2O (60.00 mL), NaOH (1.74 g, 0.044 mmol, 2.10 equiv), KMnO4 (4.91 g, 31.069 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 2 hours, and the resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 2×40 mL of ethyl acetate, and the aqueous layers were combined. The solid was filtered off. The pH of the solution was adjusted to 3 with HCl (3 M). The solid was collected by filtration to give 3.5 g (81.59%) of brown solid 5-nitro-1H-1,3-benzodiazol-2-carboxylic acid. LCMS: [M+H] + =208.

[0331] Step 3: To a 50-mL pressure reactor purged and maintained with a nitrogen inert atmosphere, 5-nitro-1H-1,3-benzodiazole-2-carboxylic acid (3.25 g, 15.689 mmol, 1.00 equiv), CH3OH (32 mL), Pd / C (2.00 g, 18.827 mmol, 1.20 equiv), H2 (10 atm) were added. The resulting solution was stirred at room temperature for 4 hours and the solid was filtered off. The resulting mixture was concentrated in vacuo to give 2.3 g (82.75%) of 5-amino-1H-1,3-benzodiazole-2-carboxylic acid as a light brown solid. LCMS: [M+H] + =178.

[0332] Step 4: In a 100-mL round-bottom flask, 5-amino-1H-1,3-benzodiazole-2-carboxylic acid (2.30 g, 12.982 mmol, 1.00 equiv), DCM (23.00 mL), H2O (23.00 mL), Boc2O (5.67 g, 25.980 mmol, 2.00 equiv), NaHCO3 (3.27 g, 38.947 mmol, 3 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting solution was diluted with 30 mL of H2O, extracted with 3×30 mL of dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2.3 g (63.9%) of brown solid 5-[(tert-butoxycarbonyl)amino]-1H-1,3-benzodiazole-2-carboxylic acid. LCMS: [M+H] + =278.

[0333] Preparation of acid BA

[0334]

[0335] To a 50-mL pressure reactor, 6-bromo-1-chloroisoquinoline (2.00 g, 8.247 mmol, 1.00 equiv), TEA (4.17 g, 0.040 mmol, 5.00 equiv), and MeOH (20.00 mL) were added. The resulting solution was filled with CO (gas) to an internal pressure of 0.3 MPa, and then stirred at 60°C for 16 hours. The solid was filtered off and the resulting mixture was concentrated to give 1.52 g (75.15%) of off-white solid 1,6-dimethylisoquinoline-1,6-dicarboxylate. LCMS: [M+H] + =246.

[0336] Step 2: To a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1,6-dimethylisoquinoline-1,6-dicarboxylate (1.52 g, 6.198 mmol, 1.00 equiv), MeOH (30.00 mL), CaCl2 (687.90 mg, 6.198 mmol, 1.00 equiv), NaBH4 (281.39 mg, 7.438 mmol, 1.20 equiv) were added. The resulting solution was stirred at 0°C for 3 hours, then the reaction was quenched by adding 10 mL of water / ice, and the solid was filtered off. The resulting solution was extracted with 2×30 mL of ethyl acetate, and the organic layers were combined and concentrated to give 1.2 g (89.13%) of off-white solid 1-(hydroxymethyl)isoquinoline-6-carboxylic acid methyl ester. LCMS: [M+H] + =218.

[0337] Step 3: In a 100-mL 3-necked round-bottom flask, methyl 1-(hydroxymethyl)isoquinoline-6-carboxylate (300.00 mg, 1.381 mmol, 1.00 equiv), DCM (20.00 mL), TsOH (23.78 mg, 0.138 mmol, 0.10 equiv), and DHP (232.34 mg, 2.762 mmol, 2.00 equiv) were added. The resulting solution was stirred at room temperature for 40 hours, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give 400 mg (96.11%) of methyl 1-[(oxa-2-yloxy)methyl]isoquinoline-6-carboxylate as a brown solid. LCMS: [M+H] + =302.

[0338] Step 4: In a 50-mL round-bottom flask, methyl 1-[(oxa-2-yloxy)methyl]isoquinoline-6-carboxylate (400.00 mg, 1.327 mmol, 1.00 equiv), NaOH (106.18 mg, 2.654 mmol, 2.00 equiv), THF (10.00 mL), and H2O (10.00 mL) were added. The resulting solution was stirred at room temperature for 10 hours, and the pH value of the solution was adjusted to 2-3 with citric acid (aqueous solution). The solid was collected by filtration to give 253 mg (66.34%) of 1-[(oxa-2-yloxy)methyl]isoquinoline-6-carboxylic acid as a white solid. LCMS: [M+H] + =288.

[0339] Preparation of acid BB

[0340]

[0341] Step 1: To a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 6-bromo-3-methyl-1H-indazole (1.00 g, 4.738 mmol, 1.00 equiv), DHP (478.25 mg, 5.686 mmol, 1.20 equiv), DCM (10.00 mL) and TsOH (81.59 mg, 0.474 mmol, 0.10 equiv) were added. The resulting solution was stirred at room temperature for 5 hours, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to give 1.2 g (85.80%) of 6-bromo-3-methyl-1-(oxa-2-yl)indazole as a white solid. LCMS: [M+H] + =295.

[0342] Step 2: In a 50-mL pressure reactor, 6-bromo-3-methyl-1-(oxa-2-yl)indazole 3-methyl-1-(oxa-2-yl)indazole-6-carboxylic acid methyl ester (1.20 g, 4.374 mmol, 1.00 equiv), TEA (2.21 g, 0.022 mmol, 5 equiv), MeOH (20.00 mL), Pd(dppf)Cl2CH2Cl2 (0.36 g, 0.000 mmol, 0.1 equiv) were added. The resulting solution was stirred at 80° C. for 12 hours under 0.3 MPa CO (gas) atmosphere, and the solid was filtered out. The resulting mixture was concentrated, and the residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to obtain 900 mg (69.70%) of 3-methyl-1-(oxa-2-yl)indazole-6-carboxylate in 6-bromo-3-methyl-1-(oxa-2-yl)indazole as a white solid. LCMS: [M+H] + =275.

[0343] Step 3: To a 50-mL round-bottom flask, methyl 3-methyl-1-(oxa-2-yl)indazole-6-carboxylate (400.00 mg, 1.458 mmol, 1.00 equiv), MeOH (10.00 mL), H2O (2.00 mL, 0.111 mmol), LiOH (69.84 mg, 2.916 mmol, 2.00 equiv) were added. The resulting solution was stirred in an oil bath at 40 °C for 12 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 10 mL of water, and the pH of the solution was adjusted to 2-3 with citric acid (aqueous solution). The solid was collected by filtration to give 260 mg (68.50%) of off-white solid 3-methyl-1-(oxacyclohexane-2-yl)indazole-6-carboxylic acid. LCMS: [M+H] + =261.

[0344] Preparation of acid BC

[0345]

[0346] Step 1: To a 50-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 6-bromo-1H-indole-3-carboxaldehyde (2.00 g, 8.926 mmol, 1.00 equiv), THF (20.00 mL), LAH (914.73 mg, 24.101 mmol, 2.70 equiv) were added. The resulting solution was stirred at room temperature for 6 hours, and the reaction mixture was cooled to 0-5 ° C using a water / ice bath. The resulting solution was diluted with 20 mL of H2O, and the resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to give 1 g (53.3%) of brown solid 6-bromo-3-methyl-1H-indole. LCMS: [M+1] + =210.

[0347] Step 2: In a 50-mL round-bottom flask, 6-bromo-3-methyl-1H-indole (1.00 g, 4.760 mmol, 1.00 equiv), MeOH (10.00 mL), TEA (1445.06 mg, 14.281 mmol, 3.00 equiv), Pd(dppf)Cl2 (174.15 mg, 0.238 mmol, 0.05 equiv) and CO were added. The resulting solution was stirred at 120 °C for 16 hours and the solid was filtered off. The resulting mixture was concentrated to give 700 mg (77.72%) of 3-methyl-1H-indole-6-carboxylic acid methyl ester as a brown solid. LCMS: [M+1] + =190.

[0348] Step 3: To an 8-mL round-bottom flask, methyl 3-methyl-1H-indole-6-carboxylate (400.00 mg, 2.114 mmol, 1.00 equiv), H2O (1.00 mL), MeOH (1.00 mL), sodium hydroxide (169.11 mg, 4.228 mmol, 2.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, and the pH of the solution was adjusted to 2-3 with HCL (1 M). The solid was collected by filtration to give 300 mg (81.01%) of 3-methyl-1H-indole-6-carboxylic acid as a white solid. LCMS: [M+1] + =176.

[0349] Preparation of acid BE

[0350]

[0351] Step 1: Into a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 4-bromo-1-(2-methoxyethyl)pyrazole (1.00 g, 4.88 mmol, 1.00 equiv), 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (1158.48 mg, 5.85 mmol, 1.20 equiv), Pd(dppf)Cl2 (356.83 mg, 0.488 mmol, 0.10 equiv), K3PO4 (3105.50 mg, 14.63 mmol, 3.00 equiv), dioxane (20.00 mL) were added. The resulting solution was stirred at 100° C. for 5 hours, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column using ethyl acetate / hexane (1:3) to obtain 1.2 g (88.42%) of methyl 2-fluoro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoate as a brown solid. LCMS: [M+1] + =279.

[0352]

[0353] Step 2: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, methyl 2-fluoro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoate (1.20 g, 4.31 mmol, 1.00 equiv), sodium hydroxide (344.95 mg, 0.008 mol, 2.00 equiv), MeOH (12.00 mL) and H2O (3.00 mL) were added. The resulting solution was stirred at 25°C for 16 hours, and the pH of the solution was adjusted to 3 with HCl (37%). The resulting mixture was concentrated to give 1.7 g (crude) of 2-fluoro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoic acid as an off-white solid. LCMS: [M+1] + =265.

[0354] Preparation of acid BG

[0355] To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 5-bromopyridine-2-carboxylic acid methyl ester (1.00 g, 4.629 mmol, 1.00 equiv), imidazole (630.26 mg, 9.258 mmol, 2.00 equiv), CuI (88.16 mg, 0.463 mmol, 0.1 equiv), 1,10-phenanthroline (166.83 mg, 0.926 mmol, 0.20 equiv), K2CO3 (1919.22 mg, 13.887 mmol, 3.00 equiv) and DMF (20.00 mL) were added. The resulting solution was stirred at 75 ° C for 3 days and the solid was collected by filtration. The resulting solid was diluted with 20 mL of water, the pH of the solution was adjusted to 5 with HCl (1 M), and the resulting mixture was concentrated. The crude product was purified by recrystallization from MeOH to give 400 mg (crude) of 5-(imidazol-1-yl)pyridine-2-carboxylic acid as an off-white solid. LCMS: [M+1] + =204.

[0356] Preparation of acid BH

[0357] To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-iodo-1-(triphenylmethyl)imidazole (1.00 g, 2.292 mmol, 1.00 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylic acid methyl ester (0.90 g, 0.003 mmol, 1.50 equiv), Pd(dppf)Cl2 (167.71 mg, 0.229 mmol, 0.10 equiv), K2CO3 (1.58 g, 11.432 mmol, 4.99 equiv), dioxane (20.00 mL), H2O (5.00 mL) were added. The resulting solution was stirred at room temperature for 20 hours, the solid was filtered off, and then the reaction was quenched by adding 30 mL of water. The resulting solution was extracted with 3×20 mL of ethoxyethane, and the aqueous layers were combined. The pH of the solution was adjusted to 3 with citric acid (aqueous solution). The solid was collected by filtration to give 352 mg (35.59%) of 5-[1-(triphenylmethyl)imidazol-4-yl]pyridine-2-carboxylic acid as a brown solid. LCMS: [M+H]=432.

[0358] Preparation of acid BN

[0359]

[0360] Step 1: To a 50-mL pressure reactor purged and maintained with an inert atmosphere of nitrogen was added 6-bromoisoquinolin-1-amine (1.20 g, 5.379 mmol, 1.00 equiv), CH3OH (24.00 mL), Pd(dppf)Cl2 (0.39 g, 0.000 mmol, 0.10 equiv), NaOAc (1.77 g, 21.576 mmol, 4.01 equiv) and CO (10 atm). The resulting solution was stirred in an oil bath at 80°C for 16 hours and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 3×30 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×30 mL of brine, the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1) to obtain 0.9 g (82.7%) of methyl 1-aminoisoquinoline-6-carboxylate as a pale yellow solid. LCMS: [M+H] + =203.

[0361] Step 2: In a 100-mL 3-necked round-bottom flask, methyl 1-aminoisoquinoline-6-carboxylate (0.90 g, 4.45 mmol, 1.00 equiv), DCM (18.00 mL), Boc2O (2.43 g, 11.13 mmol, 2.50 equiv), TEA (1.80 g, 17.80 mmol, 4.00 equiv), DMAP (0.05 g, 0.45 mmol, 0.10 equiv) were added. The resulting solution was stirred at room temperature for 10 hours, and the resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×30 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to obtain 1 g (55.8%) of methyl 1-[bis(tert-butoxycarbonyl)amino]isoquinoline-6-carboxylate as a brown oil. LCMS: [M+H] + =403.

[0362] Step 3: In a 100-mL round-bottom flask, methyl 1-[bis(tert-butoxycarbonyl)amino]isoquinoline-6-carboxylate (1.00 g, 2.49 mmol, 1.00 equiv), CH3OH (20.00 mL), H2O (7.00 mL), and NaOH (0.30 g, 7.501 mmol, 3.02 equiv) were added. The resulting solution was stirred at room temperature for 16 hours. The resulting solution was diluted with 20 mL of H2O, and the resulting mixture was concentrated in vacuo, and the pH value of the solution was adjusted to 3 with HCl (3 mol / L). The resulting mixture was concentrated in vacuo to give 1 g (139.59%) of light yellow solid 1-[(tert-butoxycarbonyl)amino]isoquinoline-6-carboxylic acid. LCMS: [M+H] + =289.

[0363] Preparation of acid BO

[0364]

[0365] Step 1: To a 250-mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-bromo-2-fluorobenzonitrile (10.0 g, 50 mmol, 1.00 equiv), t-BuOH (100.00 mL), NH2NH2.H2O (7.51 g, 150.02 mmol, 3.00 equiv) were added. The resulting solution was stirred in an oil bath at 110°C for 12 hours and the reaction mixture was cooled. The solid was collected by filtration to give 6.5 g (61.3%) of 6-bromo-1H-indazole-3-amine as a white solid. LCMS: [M+H] + =212.

[0366] Step 2: In a 100-mL pressure reactor, 6-bromo-1H-indazole-3-amine (6.50 g, 30.65 mmol, 1.00 equiv), CH3OH (65 mL), Pd(dppf)Cl2 (2.24 g, 3.07 mmol, 0.10 equiv), triethylamine (9.31 g, 91.959 mmol, 3.00 equiv) and CO (10 atm) were added. The resulting solution was stirred in an oil bath at 80°C for 16 hours, and the resulting mixture was concentrated. The resulting solution was diluted with 100 mL of H2O, and the resulting solution was extracted with 3×60 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×60 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 3.5 g (59.7%) of 3-amino-1H-indazole-6-carboxylic acid methyl ester as a brown solid. LCMS: [M+H] + =192.

[0367] Step 3: In a 250-mL 3-neck round bottom flask, methyl 3-amino-1H-indazole-6-carboxylate (3.50 g, 18.31 mmol, 1.00 equiv), DCM (70.0 mL), Boc2O (11.99 g, 54.94 mmol, 3.00 equiv), triethylamine (7.41 g, 73.226 mmol, 4 equiv), DMAP (0.22 g, 1.831 mmol, 0.1 equiv) were added. The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 60 mL of H2O, extracted with 3×60 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×60 mL of brine, the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:3) to obtain 3 g (41.9%) of brown solid 6-methyl 3-[(tert-butoxycarbonyl)amino]indazole-1,6-dicarboxylic acid 1-tert-butyl ester. LCMS: [M+H] + =492.

[0368] Step 4: To a 100-mL round-bottom flask, 1-tert-butyl 6-methyl 3-[(tert-butoxycarbonyl)amino]indazole-1,6-dicarboxylate (3.00 g, 7.67 mmol, 1.00 equiv), CH3OH (60.00 mL), H2O (20.00 mL), and NaOH (0.92 g, 23.002 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O, and the pH of the solution was adjusted to 3 with HCl (3 M). The resulting mixture was concentrated in vacuo to give 2 g of brown solid 1-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)amino]indazole-6-carboxylic acid. LCMS: [MH] + =376.

[0369] Preparation of acid BP

[0370]

[0371] Step 1: To a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1H-indazole-6-carboxylic acid methyl ester (2.00 g, 11.352 mmol, 1.00 equiv), DMF (40.00 mL), K2CO3 (3.14 g, 22.704 mmol, 2.00 equiv) were added. The resulting solution was stirred at 0°C in an ice / salt bath, and then I2 (24.32 g, 17.021 mmol, 1.50 equiv) was added to the flask. The resulting solution was allowed to react at room temperature with stirring for 16 hours, and the resulting solution was diluted with 80 mL Na2S2O3. The solid was collected by filtration to give 3 g (87.48%) of 3-iodo-1H-indazole-6-carboxylic acid methyl ester as a yellow solid. LCMS: [M+H] + =303.

[0372]

[0373] Step 2: To a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, methyl 3-iodo-1H-indazole-6-carboxylate (3.00 g, 9.93 mmol, 1.00 equiv), DCE (60.00 mL), cyclopropylboronic acid (1.71 g, 19.86 mmol, 2.00 equiv), Cu(OAc)2 (1.80 g, 9.93 mmol, 1.00 equiv), 2-(pyridin-2-yl)pyridine (1.55 g, 9.92 mmol, 1.00 equiv) were added. The resulting solution was stirred at 70°C in an oil bath for 10 hours, and the resulting solution was diluted with 90 mL of H2O. The resulting solution was extracted with 3×60 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 2×60 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:5) to obtain 1 g (29.43%) of brown solid 1-cyclopropyl-3-iodoindazole-6-carboxylic acid methyl ester. LCMS: [M+H] + =343.

[0374]

[0375] Step 3: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, methyl 1-cyclopropyl-3-iodoindazole-6-carboxylate (900.0 mg, 2.63 mmol, 1.00 equiv), dioxane (18.0 mL), tert-butyl carbamate (616.32 mg, 5.26 mmol, 2.00 equiv), Pd2(dba)3 (240.88 mg, 0.263 mmol, 0.10 equiv), XantPhos (304.41 mg, 0.53 mmol, 0.20 equiv), Cs2CO3 (2571.24 mg, 7.89 mmol, 3.00 equiv) were added. The resulting solution was stirred at 100° C. for 20 hours in an oil bath, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to obtain 190 mg (21.80%) of yellow solid 3-[(tert-butoxycarbonyl)amino]-1-cyclopropylindazole-6-carboxylic acid methyl ester. LCMS: [M+H] + =332.

[0376]

[0377] Step 4: In a 100-mL round-bottom flask, methyl 3-[(tert-butoxycarbonyl)amino]-1-cyclopropylindazole-6-carboxylate (190.00 mg, 0.573 mmol, 1.00 equiv), CH3OH (3.80 mL), H2O (1.30 mL), and lithium hydroxide (41.20 mg, 1.720 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 12 hours. The resulting solution was diluted with 10 mL of H2O, and the resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to 3 with HCl (3M), and the resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 150 mg (82.4%) of light yellow solid 3-[(tert-butoxycarbonyl)amino]-1-cyclopropylindazole-6-carboxylic acid. LCMS: [M+H] + =318.

[0378] Preparation of acid BQ

[0379]

[0380] Step 1: To an 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-6-carboxylic acid methyl ester (200.00 mg, 0.66 mmol, 1.00 equiv), CH3I (139.46 mg, 0.983 mmol, 1.50 equiv), Cs2CO3 (533.55 mg, 1.64 mmol, 2.50 equiv) and DMF (3.00 mL) were added. The resulting solution was stirred at 25 ° C overnight, and then the reaction was quenched by adding 10 mL of ice / salt. The resulting solution was extracted with 3×5 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:3) to give 120 mg (57.36%) of brown solid 3-[(tert-butoxycarbonyl)(methyl)amino]-1-methylindazole-6-carboxylic acid methyl ester. LCMS: [M+1] + =320.

[0381] Step 2: To an 8-mL glass bottle purged and maintained with an inert atmosphere of nitrogen was added methyl 3-[(tert-butoxycarbonyl)(methyl)amino]-1-methylindazole-6-carboxylate (120.00 mg, 0.376 mmol, 1.00 equiv), lithium hydroxide (18.00 mg, 0.752 mmol, 2.00 equiv), MeOH (1.20 mL) and H2O (0.30 mL). The resulting solution was stirred at 25°C for 12 hours and the resulting mixture was concentrated to give 110 mg (95.88%) of 3-[(tert-butoxycarbonyl)(methyl)amino]-1-methylindazole-6-carboxylic acid as an off-white solid. LCMS: [M+1] + =306.

[0382] Preparation of acid BR

[0383]

[0384] Step 1: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, a solution of methyl 3-iodo-1-methylindazole-6-carboxylate (800 mg, 2.53 mmol, 1.00 equiv) in dioxane (20 mL), dimethylamine (2.53 mL, 5.06 mmol, 2.00 equiv), Pd2(dba)3 (23.18 mg, 0.025 mmol, 0.01 equiv), XantPhos (14.64 mg, 0.025 mmol, 0.01 equiv), Cs2CO3 (2473.81 mg, 7.59 mmol, 3.00 equiv) were added. The resulting solution was stirred at 100° C. for 12 hours and the resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1) to obtain 400 mg (67.8%) of yellow solid 3-(dimethylamino)-1-methylindazole-6-carboxylic acid methyl ester. LCMS: [M+H] + =234.

[0385] Step 2: To a 40-mL glass bottle, a solution of methyl 3-(dimethylamino)-1-methylindazole-6-carboxylate (400.00 mg, 1.715 mmol, 1.00 equiv) in MeOH (10 mL) and a solution of lithium hydroxide (82.14 mg, 3.430 mmol, 2.00 equiv) in H2O (5 mL) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated in vacuo, and the pH was adjusted to 2 using HCl (1 M). The crude product was purified by Flash-Prep-HPLC high performance liquid chromatography using C18 silica gel to obtain 200 mg (53.20%) of yellow solid 3-(dimethylamino)-1-methylindazole-6-carboxylic acid. LCMS: 220 [M+H] + .

[0386] Preparation of acid BT

[0387]

[0388] Step 1: To a 250-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-bromo-3-methyl-1H-pyrazole (5.00 g, 31.06 mmol, 1.00 equiv.), DCM (100.00 mL), DHP (3.92 g, 46.584 mmol, 1.50 equiv.), TsOH (0.27 g, 1.568 mmol, 0.05 equiv.) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting solution was diluted with 100 mL of H2O, extracted with 3×100 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 2×100 mL of brine, the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 6.5 g of a brown oily 4-bromo-5-methyl-1-(oxa-2-yl)pyrazole. LCMS: [M+H] + =245.

[0389] Step 2: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, 4-(methoxycarbonyl)phenylboronic acid (1.50 g, 8.34 mmol, 1.00 equiv), dioxane (24.00 mL), 4-bromo-3-methyl-1-(oxa-2-yl)pyrazole (2.04 g, 8.32 mmol, 1.00 equiv), Pd(dppf)Cl2 (0.61 g, 0.834 mmol, 0.10 equiv), K3PO4 (5.31 g, 25.02 mmol, 3.00 equiv) were added. The resulting solution was stirred in an oil bath at 100° C. for 5 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was extracted with 3×30 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×30 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1) to obtain 1.3 g of brown solid methyl 4-[3-methyl-1-(oxa-2-yl)pyrazol-4-yl]benzoate. LCMS: [M+H] + =301.

[0390] Step 3: To a 100-mL round-bottom flask, methyl 4-[3-methyl-1-(oxa-2-yl)pyrazol-4-yl]benzoate (1.30 g, 4.328 mmol, 1.00 equiv), CH3OH (26.00 mL), H2O (9.00 mL), and sodium hydroxide (0.52 g, 12.984 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with 2×20 mL of ethyl acetate, the aqueous layers were combined, and the pH value of the solution was adjusted to 3 with HCl (3 M). The solid was collected by filtration to give 0.9 g (72.6%) of 4-[3-methyl-1-(oxa-2-yl)pyrazol-4-yl]benzoic acid as a white solid. LCMS: [M+H] + =287.

[0391] Preparation of acid BU

[0392]

[0393] Step 1: To a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, THF (12.00 mL), methyl 3-amino-4-(methylamino)benzoate (600.00 mg, 3.33 mmol, 1.00 equiv.), CDI (1619.62 mg, 9.99 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 70 ° C for 4 hours and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 400 mg (58.26%) of white solid 1-methyl-2-oxo-3H-1,3-benzodiazole-5-carboxylic acid methyl ester. LCMS: [M+1] + =207.

[0394] Step 2: To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 1-methyl-2-oxo-3H-1,3-benzodiazole-5-carboxylic acid methyl ester (200.00 mg, 0.97 mmol, 1.00 equiv), dimethylformamide (4.00 mL), Cs2CO3 (632.04 mg, 1.940 mmol, 2.00 equiv), MeI (206.51 mg, 1.46 mmol, 1.50 equiv) were added. The resulting solution was stirred at 25 ° C for 18 hours, and then the reaction was quenched by adding 15 mL of water / ice. The resulting solution was extracted with 3×4 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3×4 mL of brine to give 180 mg (84.27%) of light brown solid 1,3-dimethyl-2-oxo-1,3-benzodiazole-5-carboxylic acid methyl ester. LCMS: [M+1] + =221.

[0395] Step 3: To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, methyl 1,3-dimethyl-2-oxo-1,3-benzodiazole-5-carboxylate (180.00 mg, 0.817 mmol, 1.00 equiv), sodium hydroxide (65.38 mg, 1.634 mmol, 2.00 equiv), MeOH (1.60 mL) and H2O (0.40 mL) were added. The resulting solution was stirred at 25°C for 16 hours, and the pH of the solution was adjusted to 3 with HCl (37%). The resulting mixture was concentrated to give 250 mg (crude) of brown solid 1,3-dimethyl-2-oxo-1,3-benzodiazole-5-carboxylic acid. LCMS: [M+1] + =207.

[0396] Preparation of acid BW

[0397]

[0398] Step 1: To a stirred solution of methylhydrazine﹒sulfuric acid (7.21 g, 49.998 mmol, 5 equiv) and K2CO3 (11.06 g, 79.996 mmol, 8 equiv) in EtOH (60.00 mL) at 5°C in a nitrogen atmosphere, methylhydrazine﹒sulfuric acid (7.21 g, 49.998 mmol, 5 equiv) was added. The resulting mixture was stirred at 80°C in a nitrogen atmosphere overnight, and the mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with 3×20 mL of water. The resulting organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:3) to give 5-bromo-1-methylindazole-3-amine (1.1 g, 48.66%) as a yellow solid. LCMS: [M+1] + =226.

[0399]

[0400] Step 2: NaHMDS (2 mol / L, 5.67 mL, 11.345 mmol, 2.70 equiv) was added dropwise to a stirred solution of 5-bromo-1-methylindazole-3-amine (0.95 g, 4.202 mmol, 1.00 equiv) and di-tert-butyl dicarbonate (2.29 g, 10.505 mmol, 2.50 equiv) in THF (30.00 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 0°C for 4 hours in a nitrogen atmosphere and the reaction was quenched with water at 0°C. The mixture was allowed to warm to room temperature and the resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by titration using hexane / ethyl acetate = 50 / 1 (50 mL) to obtain tert-butyl N-(5-bromo-1-methylindazol-3-yl)-N-(tert-butoxycarbonyl)carbamate (1.5 g, 66.99%) as a pale yellow solid. LCMS: [M+1] + =426.

[0401]

[0402] Step 3: At room temperature, tert-butyl N-(5-bromo-1-methylindazol-3-yl)-N-(tert-butoxycarbonyl)carbamate (500.0 mg, 1.173 mmol, 1.00 equiv), Pd(dppf)Cl2 (85.82 mg, 0.117 mmol, 0.10 equiv), MeOH (10.00 mL) and triethylamine (593.40 mg, 5.865 mmol, 5.00 equiv) were added to a 30 mL pressure reactor. The resulting mixture was stirred overnight at 110 ° C in a CO (10 atm) atmosphere, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to give methyl 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-5-carboxylate (290 mg, 80.98%) as a yellow solid. LCMS: [M+1] + =306.

[0403]

[0404] Step 4: To a 25 mL round-bottom flask was added methyl 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-5-carboxylate (290.00 mg, 0.950 mmol, 1.00 equiv), MeOH (5.00 mL), water (2.00 mL) and NaOH (151.95 mg, 3.800 mmol, 4.00 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (15 mL). The mixture was acidified to pH 5 with HCl (1 M aqueous solution). The precipitated solid was collected by filtration and washed with water (2×10 mL). The resulting solid was dried under infrared light to give 3-[(tert-butoxycarbonyl)amino]-1-methylindazole-5-carboxylic acid (138 mg, 49.88%) as a light yellow solid. LCMS: [M+1] + =292.

[0405] Preparation of acid BY

[0406]

[0407] Step 1: To a 100-mL 3-neck round-bottom flask purged and maintained with inert nitrogen, a solution of 7-bromo-3-chloroisoquinoline (1.00 g, 4.124 mmol, 1.00 equiv) in THF (20 mL) was added. Then n-BuLi (0.58 mL, 6.157 mmol, 1.49 equiv) was added dropwise under stirring at -78°C, and DMF (0.60 g, 8.209 mmol, 1.99 equiv) was added dropwise under stirring at -78°C. The resulting solution was stirred at -78°C for 30 minutes, and the resulting solution was allowed to react for another hour under stirring at room temperature, and then the reaction was quenched by adding 10 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:5) to obtain 230 mg (29.11%) of yellow solid 3-chloroisoquinoline-7-carbaldehyde. LCMS: [M+H] + =192.

[0408]

[0409] Step 2: To a 100-mL 3-neck round bottom flask purged and maintained with inert nitrogen, a solution of 3-chloroisoquinoline-7-carbaldehyde (230.00 mg, 1.200 mmol, 1.00 equiv) in dioxane (5 mL), tert-butyl carbamate (421.86 mg, 3.600 mmol, 3.00 equiv), Xantphos (69.45 mg, 0.120 mmol, 0.10 equiv), Pd2(dba)3 (109.92 mg, 0.120 mmol, 0.10 equiv), Cs2CO3 (782.20 mg, 2.400 mmol, 2.00 equiv) were added. The resulting solution was stirred at 100° C. for 16 hours, the resulting solution was diluted with 100 mL of H2O and extracted with 3×20 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of brine, the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1) to obtain 100 mg (30.59%) of light yellow solid N-(7-formylisoquinolin-3-yl)carbamic acid tert-butyl ester. LCMS: [M+H] + =273.

[0410]

[0411] Step 3: To an 8-mL glass bottle purged and maintained with inert nitrogen, a solution of tert-butyl N-(7-formylisoquinolin-3-yl)carbamate (100.00 mg, 0.367 mmol, 1.00 equiv) in DMF (2 mL), CH3I (104.25 mg, 0.734 mmol, 2 equiv), K2CO3 (101.51 mg, 0.734 mmol, 2 equiv) was added. The resulting solution was stirred at room temperature for 12 hours, and the resulting solution was diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 3×10 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 52 mg (49.45%) of tert-butyl N-(7-formylisoquinolin-3-yl)-N-methylcarbamate as a yellow solid. LCMS: [M+H] + =287.

[0412]

[0413] Step 4: To an 8-mL glass vial, tert-butyl N-(7-formylisoquinolin-3-yl)-N-methylcarbamate (52.00 mg, 0.182 mmol, 1.00 equiv) in CH3CN (5 mL), KMnO4 (71.75 mg, 0.455 mmol, 2.50 equiv), KOH (30.57 mg, 0.546 mmol, 3.00 equiv) in H2O (5 mL) were added. The resulting solution was stirred at room temperature for 12 hours and the pH was adjusted to 3-4 using citric acid (3 mol / L). The resulting solution was extracted with 2×20 mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated in vacuo to give 21 mg (38.25%) of 3-[(tert-butoxycarbonyl)(methyl)amino]isoquinoline-7-carboxylic acid as a yellow solid. LCMS: [M+H] + =303.

[0414] Preparation of acid CA

[0415]

[0416] Step 1: In a 50-mL round-bottom flask, 5-bromo-3-methyl-1H-indazole (1.00 g, 4.738 mmol, 1.00 equiv), 3-iodooxetane (1.05 g, 0.000 mmol, 1.20 equiv), Cs2CO3 (3087.43 mg, 9.476 mmol, 2.00 equiv), and DMF (20.00 mL) were added. The resulting solution was stirred in an oil bath at 100 ° C for 2 hours, the solid was filtered out, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to obtain 907 mg (71.66%) of white solid 5-bromo-3-methyl-1-(oxetane-3-yl)indazole. LCMS: [M+H] = 267.

[0417]

[0418] Step 2: 5-bromo-3-methyl-1-(oxetane-3-yl)indazole (700.00 mg, 2.620 mmol, 1.00 equiv), Pd(dppf)Cl2CH2Cl2 (213.47 mg, 0.262 mmol, 0.10 equiv), triethylamine (1325.83 mg, 0.000 mmol, 5.00 equiv), MeOH (20.00 mL) were added to a 50-mL pressure reactor. The resulting solution was stirred at room temperature under CO (3.0 MPa) atmosphere for 16 hours, the solid was filtered out, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 380 mg (58.88%) of brown solid 3-methyl-1-(oxetane-3-yl)indazole-5-carboxylic acid methyl ester. LCMS: [M+H] = 247.

[0419]

[0420] Step 3: In a 50-mL round-bottom flask, methyl 3-methyl-1-(oxetane-3-yl)indazole-5-carboxylate (380.00 mg, 1.543 mmol, 1.00 equiv), LiOH (147.81 mg, 6.172 mmol, 4.00 equiv), MeOH (10.00 mL), H2O (2.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated, and then the reaction was quenched by adding 10 mL of water / ice, and the pH value of the solution was adjusted to 3 with citric acid (aqueous solution). The solid was collected by filtration to give 323 mg (90.13%) of 3-methyl-1-(oxetane-3-yl)indazole-5-carboxylic acid as a white solid. LCMS: [M+H] = 233.

[0421] Preparation of acid CB

[0422]

[0423] Step 1: In a 50-mL round-bottom flask, 3-hydroxythietane 1,1-dioxide (600.00 mg, 4.912 mmol, 1.00 equiv), MsCl (675.26 mg, 5.894 mmol, 1.20 equiv), DCM (5.00 mL), TEA (1491.26 mg, 14.736 mmol, 3.00 equiv) were added, and the resulting solution was stirred at room temperature for 1 hour. In a 50-mL round-bottom flask, crude thietane 1,1-dioxide 3-methanesulfonate, 5-bromo-3-methyl-1H-indazole (933.14 mg, 4.421 mmol, 0.90 equiv), Cs2CO3 (4801.67 mg, 14.736 mmol, 3.00 equiv), DMF (5.00 mL) were added in DCM. The resulting solution was stirred at room temperature for 16 hours, and then the reaction was quenched by adding 50 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated to give 820 mg (52.96%) of light brown solid 3-(5-bromo-3-methyl-1H-indazol-1-yl)thietane 1,1-dioxide. LCMS: [M+H]=315.

[0424]

[0425] Step 2: To a 50-mL pressure reactor, 3-(5-bromo-3-methyl-1H-indazol-1-yl)thietane 1,1-dioxide (500.00 mg, 1.586 mmol, 1.00 equiv), TEA (802.61 mg, 7.930 mmol, 5.00 equiv), MeOH (10.00 mL), Pd(dppf)Cl2CH2Cl2 (129.23 mg, 0.159 mmol, 0.10 equiv) were added. The resulting solution was stirred at 100°C for 3 hours under a CO (3 MPa) atmosphere, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:3) to give 360 ​​mg (77.10%) of brown solid 1-(1,1-dioxidothietane-3-yl)-3-methyl-1H-indazole-5-carboxylic acid methyl ester. LCMS: [M+H]=295.

[0426]

[0427] Step 3: To a 50-mL round-bottom flask, methyl 1-(1,1-dioxidothiacyclobutane-3-yl)-3-methylindazole-5-carboxylate (360.00 mg, 1.223 mmol, 1.00 equiv), LiOH (58.58 mg, 2.446 mmol, 2.00 equiv), MeOH (10.00 mL), and H2O (2.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated, and the pH value of the solution was adjusted to 3 with citric acid (aqueous solution). The solid was collected by filtration to give 247 mg (72.05%) of 1-(1,1-dioxidothiacyclobutane-3-yl)-3-methylindazole-5-carboxylic acid as a white solid. LCMS: [M+H] = 281.

[0428] Preparation of Acid CC

[0429]

[0430] Step 1: In a 100-mL 3-neck round-bottom flask, 5-bromo-3-methyl-1H-indazole (1.00 g, 4.74 mmol, 1.00 equiv), diethyl bromodifluoromethylphosphonate (1265.06 mg, 1.00 equiv), MeCN (35.00 mL), KF (550.52 mg, 9.476 mmol, 2.00 equiv) were added. The resulting solution was stirred at room temperature for 3 hours, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 1.0 g (80.84%) of 5-bromo-1-(difluoromethyl)-3-methylindazole as a white solid. LCMS: [M+H] = 261.

[0431]

[0432] Step 2: To a 50-mL pressure reactor, 5-bromo-1-(difluoromethyl)-3-methylindazole (550.00 mg, 2.107 mmol, 1.00 equiv), triethylamine (1065.89 mg, 0.000 mmol, 5.00 equiv), MeOH (20.00 mL), Pd(dppf)Cl2.CH2Cl2 (171.62 mg, 0.211 mmol, 0.10 equiv) were added. The resulting solution was stirred at 105°C for 16 hours under a CO (3.0 MPa) atmosphere, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 420 mg (83.00%) of brown solid 1-(difluoromethyl)-3-methylindazole-5-carboxylic acid methyl ester. LCMS: [M+H] = 241.

[0433]

[0434] Step 3: To a 50-mL round-bottom flask, methyl 1-(difluoromethyl)-3-methylindazole-5-carboxylate (420.00 mg, 1.748 mmol, 1.00 equiv), MeOH (10.00 mL), H2O (1.00 mL), LiOH (125.62 mg, 5.24 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated, and the pH value of the solution was adjusted to 3 with citric acid (aqueous solution). The solid was collected by filtration to give 343 mg (86.73%) of 1-(difluoromethyl)-3-methylindazole-5-carboxylic acid as a light brown solid. LCMS: [M+H] = 227.

[0435] Preparation of acid CE

[0436]

[0437] Step 1: In a 50-mL pressure reactor, 5-bromo-6-fluoro-3-methyl-1H-indazole (550.0 mg, 2.4 mmol, 1.00 equiv), MeOH (20.0 mL), Pd(dppf)Cl2 (175.7 mg, 0.24 mmol, 0.10 equiv), TEA (971.9 mg, 9.61 mmol, 4.00 equiv) and CO (10 atm) were added. The resulting solution was stirred at 80 °C for 16 hours and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 50 mL of H2O, the resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3×20 mL of brine, the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 280 mg (56%) of methyl 6-fluoro-3-methyl-1H-indazole-5-carboxylate as an orange solid. LCMS: [M+H] + =209.

[0438] Step 2: To a 50-mL round-bottom flask, add methyl 6-fluoro-3-methyl-1H-indazole-5-carboxylate (280.0 mg, 1.35 mmol, 1.00 equiv), CH3OH (9.00 mL), H2O (3.00 mL), and sodium hydroxide (161.38 mg, 4.0 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 16 hours, and the resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 2×20 mL of ethyl acetate, and the aqueous layers were combined. The pH value of the solution was adjusted to 3 with HCl (3 mol / L). The solid was collected by filtration to give 210 mg of off-white solid 6-fluoro-3-methyl-1H-indazole-5-carboxylic acid. LCMS: [M+H] + =195.

[0439] Preparation of acid CF

[0440]

[0441] Step 1: To a 250-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-bromo-2,6-difluorobenzaldehyde (5.5 g, 24.89 mmol, 1.00 equiv), tetrahydrofuran (110.0 mL), MeMgBr (in Et2O) (20.70 mL, 62.2 mmol, 2.50 equiv) were added and the resulting solution was stirred at -75 °C for 30 minutes. The resulting solution was allowed to react for an additional 2.5 hours with stirring at room temperature, and then the reaction was quenched by adding 300 mL of water / ice. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3×100 mL of brine. The resulting solution was concentrated to give 5.5 g (93.23%) of 1-(3-bromo-2,6-difluorophenyl)ethanol as a light yellow oil. LCMS: [M+1] + =237.

[0442]

[0443] Step 2: To a 250-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1-(3-bromo-2,6-difluorophenyl)ethanol (5.50 g, 23.202 mmol, 1.00 equiv), DCM (110.0 mL), DMP (14.76 g, 34.80 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 18 hours, and then the reaction was quenched by adding 250 mL of saturated Na2S2O3. The resulting solution was extracted with 3×100 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×100 ml of saturated NaHCO3 and then with 2×100 mL of brine. The resulting mixture was concentrated. The residue was loaded onto a silica gel column with PE / THF (1:3) to give 5.5 g (100%) of 1-(3-bromo-2,6-difluorophenyl)ethanone as a light yellow oil. LCMS: [M+1] + =235.

[0444]

[0445] Step 3: To a 250-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 1-(3-bromo-2,6-difluorophenyl)ethanone (5.50 g, 23.40 mmol, 1.00 equiv), DME (110.0 mL), NH2NH2.H2O (11.7 g, 0.23 mmol, 10.00 equiv) were added. The resulting solution was stirred at 90 ° C for 12 hours, and then the reaction was quenched by adding 500 mL of water / ice. The solid was collected by filtration, and the residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give 670 mg (12.50%) of off-white solid 5-bromo-4-fluoro-3-methyl-1H-indazole. LCMS: [M+1] + =229.

[0446]

[0447] Step 4: To a 50-mL sealed tube, 5-bromo-4-fluoro-3-methyl-1H-indazole (600.0 mg, 2.62 mmol, 1.00 equiv), Pd(dppf)Cl2 (383 mg, 0.52 mmol, 0.20 equiv), TEA (795.20 mg, 7.86 mmol, 3.00 equiv), MeOH (20.00 mL), CO (5 atm) were added. The resulting solution was stirred at 80 ° C for 16 hours and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give 450 mg (83%) of brown solid 4-fluoro-3-methyl-1H-indazole-5-carboxylic acid methyl ester. LCMS: [M+1] + =209.

[0448]

[0449] Step 5: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, methyl 4-fluoro-3-methyl-1H-indazole-5-carboxylate (450.00 mg, 2.161 mmol, 1.00 equiv), caustic soda (172.90 mg, 4.323 mmol, 2.00 equiv), MeOH (8.00 mL), H2O (2.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the pH value of the solution was adjusted to 3 with HCl (37%). The resulting mixture was concentrated to give 600 mg (crude) of brown solid 4-fluoro-3-methyl-1H-indazole-5-carboxylic acid. LCMS: [M+1] + =195.

[0450] Preparation of acid CH

[0451]

[0452] Step 1: To a 50-mL round-bottom flask, 3-oxo-2,4-dihydro-1,4-benzoxazine-7-carboxylic acid (CAS: 214848-62-1, 500.0 mg, 2.59 mmol, 1.00 equiv), MeI (808.32 mg, 5.696 mmol, 2.20 equiv), K2CO3 (1073.26 mg, 7.767 mmol, 3.00 equiv), and DMF (10.00 mL) were added. The resulting solution was stirred at room temperature for 10 hours, the solid was filtered off, and the resulting mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2) to give 373 mg (65%) of yellow solid 4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylic acid methyl ester. LCMS: [M+H] + =222.

[0453] Step 2: To a 100-mL round-bottom flask, methyl 4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylate (373.00 mg, 1.686 mmol, 1.00 equiv), NaOH (134.88 mg, 3.372 mmol, 2.00 equiv), MeOH (5.00 mL) and H2O (1.00 mL, 0.056 mmol, 0.03 equiv) were added. The resulting solution was stirred at room temperature for 5 hours, the resulting mixture was concentrated, and the pH of the solution was adjusted to 5 with citric acid. The solid was collected by filtration to give 277 mg (79.3%) of 4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylic acid as an off-white solid. LCMS: [M+H] + =208.

[0454] Preparation of Acid CI

[0455]

[0456] Step 1: To a 50-mL pressure reactor, 7-bromo-2H-isoquinolin-1-one (200.00 mg, 0.893 mmol, 1.00 equiv), MeOH (5.0 mL), TEA (270.98 mg, 2.678 mmol, 3 equiv), Pd(dppf)Cl2 (32.66 mg, 0.045 mmol, 0.05 equiv) were added, followed by CO (5 atm). The resulting solution was stirred at 120°C for 3 hours and the solid was filtered off. The resulting mixture was concentrated to give 120 mg (66.16%) of methyl 1-oxo-2H-isoquinoline-7-carboxylate as a brown solid. LCMS: [M+1] + =204.

[0457]

[0458] Step 2: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added methyl 1-oxo-2H-isoquinoline-7-carboxylate (120.0 mg, 0.591 mmol, 1.00 equiv), H2O (3.0 mL), MeOH (3.0 mL) and sodium hydroxide (94.5 mg, 2.362 mmol, 4.00 equiv). The resulting solution was stirred at room temperature for 12 hours, the resulting mixture was concentrated, and the pH of the solution was adjusted to 2-3 with 1M HCl. The solid was collected by filtration to give 80 mg (72%) of 1-oxo-2H-isoquinoline-7-carboxylic acid as a light yellow solid. LCMS: [M+1] + =190.

[0459] Preparation of acid CJ

[0460]

[0461] Step 1: In a 40-mL round-bottom flask, 4-bromobenzeneacetonitrile (1.10 g, 5.611 mmol, 1.00 equiv), paraformaldehyde (556 mg, 6.172 mmol, 1.10 equiv), and PPA (6.5 g, 56.1 mmol, 10.00 equiv) were added. The resulting solution was stirred at 160°C for 24 hours, the resulting solution was diluted with 20 mL of H2O, and the pH value of the solution was adjusted to 7-8 with 1 M NaHCO3. The resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to obtain 600 mg (47%) of yellow solid 7-bromo-2,4-dihydro-1H-isoquinolin-3-one. LCMS: [M+1] + =226.

[0462]

[0463] Step 2: To a 50-mL round-bottom flask, 7-bromo-2,4-dihydro-1H-isoquinolin-3-one (600.0 mg, 2.65 mmol, 1.00 equiv), MeOH (12.0 mL), TEA (805.7 mg, 7.962 mmol, 3.00 equiv), Pd(dppf)Cl2 (97 mg, 0.133 mmol, 0.05 equiv), CO (5-atm) were added. The resulting solution was stirred at 120°C for 16 hours and the solid was filtered. The resulting mixture was concentrated to give 450 mg (82.62%) of dark brown solid 3-oxo-2,4-dihydro-1H-isoquinoline-7-carboxylic acid methyl ester. LCMS: [M+1] + =206.

[0464]

[0465] Step 3: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, methyl 3-oxo-2,4-dihydro-1H-isoquinoline-7-carboxylate (450.0 mg, 2.19 mmol, 1.00 equiv), MeOH (9 mL), H2O (9 mL), sodium hydroxide (350.83 mg, 8.77 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was washed with 1×20 ml of DCM. The solid was filtered off to give 200 mg (47.71%) of 3-oxo-2,4-dihydro-1H-isoquinoline-7-carboxylic acid as a white solid. LCMS: [M+1] + =192.

[0466] Preparation of acid CK

[0467]

[0468] 2-Oxo-1H-quinoline-6-carboxylic acid methyl ester (CK-2)

[0469] To a 50-mL pressure reactor, 6-bromo-1H-quinolin-2-one (CK-1, 2.00 g, 8.926 mmol, 1.00 equiv), CH3OH (20.00 mL), Pd(dppf)Cl2 (0.65 g, 0.888 mmol, 0.10 equiv), TEA (3.61 g, 35.675 mmol, 4.00 equiv), CO (10 atm) were added. The resulting solution was stirred at 80°C in an oil bath for 16 hours, the resulting mixture was concentrated in vacuo, and the resulting solution was diluted with 40 mL of H2O. The resulting solution was extracted with 3×30 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.9 g (73.45%) of methyl 2-oxo-1H-quinoline-6-carboxylate (CK-2) as a red solid. LCMS: [M+H] + =204.

[0470] 2-Oxo-1H-quinoline-6-carboxylic acid (acid CK)

[0471] To a 100-mL round-bottom flask, methyl 2-oxo-1H-quinoline-6-carboxylate (1.90 g, 9.351 mmol, 1.00 equiv), CH3OH (38.00 mL), H2O (12.00 mL), sodium hydroxide (1.12 g, 28.002 mmol, 2.99 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting mixture was concentrated in vacuo, and the resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 2×20 mL of ethyl acetate and the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3 M). The solid was collected by filtration to give 1.2 g (67.84%) of 2-oxo-1H-quinoline-6-carboxylic acid (acid CK) as a red solid. LCMS: [M+H] + =190.

[0472] Preparation of acid CL

[0473]

[0474] Step 1: To a 100-mL 4-neck round bottom flask, a solution of methyl 3-cyano-4-fluorobenzoate (2.00 g, 11.164 mmol, 1.00 equiv) in DMF (30 mL), potassium carbonate (4662.45 mg, 33.491 mmol, 3.00 equiv), CH3NH2HCl (2261.28 mg, 33.492 mmol, 3.00 equiv) was added. The resulting solution was stirred at room temperature for 12 hours, and then the reaction was quenched by adding 100 mL of water / ice. The solid was collected by filtration to give 1800 mg (84.77%) of methyl 3-cyano-4-(methylamino)benzoate as a white solid. LCMS: [M+H] + =191.

[0475]

[0476] Step 2: To a 250-mL pressure reactor purged and maintained with an inert atmosphere of nitrogen was added a solution of methyl 3-cyano-4-(methylamino)benzoate (1800.00 mg, 9.464 mmol, 1.00 equiv) in MeOH (50 mL), Pd / C (500.00 mg, 4.698 mmol, 0.50 equiv), Boc2O (6196.22 mg, 28.391 mmol, 3 equiv). H2 (g) was introduced and the resulting solution was stirred at room temperature for 5 h, the solid was filtered, and the resulting mixture was concentrated in vacuo to give 1.67 g (59.95%) of methyl 3-[[(tert-butyloxycarbonyl)amino]methyl]-4-(methylamino)benzoate as a yellow solid. LCMS: [M+H] + =295.

[0477]

[0478] Step 3: To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added methyl 3-[[(tert-butyloxycarbonyl)amino]methyl]-4-(methylamino)benzoate (1.67 g, 5.67 mmol, 1.00 equiv), hydrogen chloride in ethyl acetate (2M) (20 mL). The resulting solution was stirred at room temperature for 5 hours and the solid was collected by filtration to give 1.1 g (84.05%) of methyl 3-(aminomethyl)-4-(methylamino)benzoate hydrochloride as a yellow solid. LCMS: [M+H] + =19.

[0479]

[0480] Step 4: To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of methyl 3-(aminomethyl)-4-(methylamino)benzoate hydrochloride (1100.00 mg, 4.768 mmol, 1.00 equiv) in THF (10 mL), triethylamine (1447.51 mg, 14.304 mmol, 3.00 equiv), CDI (1159.76 mg, 7.152 mmol, 1.50 equiv) was added. The resulting solution was stirred at room temperature for 5 hours, and then the reaction was quenched by adding 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to give 680 mg (64.8%) of 1-methyl-2-oxo-3,4-dihydroquinazoline-6-carboxylic acid methyl ester as a white solid. LCMS: [M+H] + =221.

[0481]

[0482] Step 5: To a 20-mL glass bottle purged and maintained with an inert atmosphere of nitrogen, a solution of methyl 1-methyl-2-oxo-3,4-dihydroquinazoline-6-carboxylate (680.00 mg, 3.09 mmol, 1.00 equiv) in MeOH (5 mL) and a solution of sodium hydroxide (247.00 mg, 6.18 mmol, 2.00 equiv) in H2O (5 mL) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting mixture was concentrated in vacuo, and the pH was adjusted to 2-3 using HCl (1 M). The solid was collected by filtration to give 510 mg (80.10%) of 1-methyl-2-oxo-3,4-dihydroquinazoline-6-carboxylic acid as a white solid. LCMS: [M+H] + =207.

[0483] Preparation of acid CM

[0484] To an 8-mL round-bottom flask, methyl 3-oxo-2H-isoquinoline-7-carboxylate (CAS: 1416713-96-6, 100.0 mg, 0.492 mmol, 1.00 equiv), H2O (1 mL), MeOH (1 mL), sodium hydroxide (78.7 mg, 1.97 mmol, 4.00 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting solution was diluted with 10 mL of H2O, and the pH of the solution was adjusted to 2-3 with 1M HCl. The solid was collected by filtration to give 70 mg (75%) of 3-oxo-2H-isoquinoline-7-carboxylic acid as a white solid. LCMS: [M+1] + =190.

[0485] Preparation of Acid CN

[0486] The preparation method is similar to that of acid CK, except that CK-1 is replaced by 6-bromoquinolin-2(1H)-one. LCMS: [M+1] + =190.

[0487] Table C describes the amines used below and the synthetic schemes are described in the specification.

[0488] Table C

[0489]

[0490]

[0491] Synthesis of amine D

[0492]

[0493] 2-[[6-Chloro-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (D.2)

[0494] To a solution of 6-chloro-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridine (1.30 g, 5.21 mmol, 1 eq) in THF (30 mL) at 0°C was added NaH (D.1, 625 mg, 15.6 mmol, 60 wt% dispersible oil, 3 eq). After stirring at 0°C for 1 hour, SEM-Cl (868 mg, 5.21 mmol, 0.921 ml, 1 eq) was added at 0°C. The resulting mixture was stirred at 25°C for 3 hours, the reaction mixture was quenched by adding H2O (10 ml), and the mixture was extracted with EtOAc (10 ml×3). The combined organic layers were washed with brine (10 ml×2), dried over Na2SO4 and filtered. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient 1:0 to 2:1) to afford 2-[[6-chloro-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridin-1-yl]methoxy]ethyl-trimethylsilane.

[0495] N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenylmethanimine (D.3)

[0496] A mixture of 2-[[6-chloro-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridin-1-yl]methoxy]ethyl-trimethylsilane (D.1, 0.600 g, 1.58 mmol, 1 eq), diphenylmethanimine (429 mg, 2.37 mmol, 0.397 mL, 1.5 eq), Pd2(dba)3 (145 mg, 0.158 mmol, 0.1 eq), BINAP (98 mg, 0.16 mmol, 0.1 eq) and t-BuONa (303 mg, 3.16 mmol, 2 eq) in toluene (15 mL) was degassed and purged with N2 (3X). The mixture was stirred at 110° C. for 4 hours under N2 atmosphere, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenyl-methylimine.

[0497] 2-[[(2S)-2-Methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]-pyridin-6-amine (Amine D)

[0498] HCl (10 mL) was added to a solution of N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-yl]-1,1-diphenyl-formimine (D.2, 0.900 g, 1.72 mmol, 1 equivalent) in THF (10 mL). The mixture was stirred at 25 ° C for 1 hour, and water (15 mL) and EtOAc (15 mL) were added to the reaction mixture. The layers were separated, and the aqueous phase was adjusted to pH = 9-10 by adding 1N NaOH aqueous solution, and the aqueous layer was extracted with EtOAc (15 ml × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-6-amine.

[0499] Synthesis of amine E

[0500]

[0501] 6-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (E.2)

[0502] To a solution of 2,5-dibromopyridin-3-amine (5.00 g, 19.9 mmol, 1 eq.) in DMF (120 mL) was added TEA (8.84 g, 87.3 mmol, 12.2 mL, 4.4 eq.), PPh3 (4.58 g, 17.5 mmol, 0.88 eq.), Pd(OAc)2 (980 mg, 4.37 mmol, 0.22 eq.) and 2-oxopropionic acid (4.63 g, 52.6 mmol, 3.71 mL, 2.65 eq.). The mixture was stirred at 100 °C for 12 h, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O (50 mL) and EtOAc (50 mL). The solid was filtered and dried to obtain 6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid. 1 H-NMR: 400MHz, DMSO-d6: δ12.17 (br s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.17 (d, J = 1.0 Hz, 1H).

[0503] 6-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (E.3)

[0504] To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (4.00 g, 16.6 mmol, 1 eq) in MeOH (30 mL) and DCM (30 mL) was added TMSCHN2 (2 M, 32.61 mL) dropwise. The mixture was stirred at 25 °C for 2 hours, and acetic acid (3 mL) was added to the mixture. The reaction mixture was filtered and the solution was concentrated under reduced pressure to obtain methyl 6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylate. 1 H-NMR: 400MHz, DMSO-d6: δ12.36(br s,1H),8.53(d,J=2.0Hz,1H),8.03(d,J=1.4Hz,1H),7.25(s,1H),3.92(s,3H)

[0505] (6-Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (E.4)

[0506] At 0 ° C, to a mixture of LiAlH4 (565 mg, 14.9 mmol, 2 eq.) in THF (25 mL), 6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (1.90 g, 7.45 mmol, 1 eq.) was added. The mixture was warmed to 25 ° C and stirred at 25 ° C for 1 hour, and the reaction mixture was cooled to 0 ° C. NaOH aqueous solution (20 mL, 10%) and H2O (30 mL) were added, the mixture was stirred at 0 ° C for 0.5 hours, the mixture was filtered and extracted with EtOAc (20 mL×3). The organic layer was dried over Na2SO4 and filtered, and the solution was concentrated under reduced pressure to obtain (6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol. LCMS: M+H + :149.0

[0507] 6-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (E.5)

[0508] To a solution of (6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (1.55 g, 6.83 mmol, 1 eq.) in DCM (100 mL) was added Dess-Martin (8.69 g, 20.5 mmol, 3 eq.). The mixture was stirred at 25 °C for 12 hours, the reactant was diluted with saturated aqueous NaHCO3 (50 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The solution was concentrated under reduced pressure to obtain 6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde. 1H-NMR: 400MHz, DMSO-d6: δ10.00(s,1H),8.59(d,J=2.0Hz,1H),8.09(d,J=1.3Hz,1H),7.55(s,1H)

[0509] 6-Bromo-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridine (E.6)

[0510] To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (1.59 g, 7.07 mmol, 1 eq.) in DCE (20 mL) was added (2S)-2-methylpyrrolidine (602 mg, 7.07 mmol, 1 eq.) and AcOH (424 mg, 7.07 mmol, 0.404 mL, 1 eq.). After stirring at 25 °C for 0.5 h, NaBH(OAc)3 (2.99 g, 14.1 mmol, 2 eq.) was added. The mixture was stirred at 25 °C for 11.5 h, the reaction mixture was diluted with saturated aqueous NaHCO3, and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered, and the solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient 1 / 0 to 0 / 1) to afford 6-bromo-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridine.

[0511] 2-[[6-Bromo-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-b]pyridin-1-yl]methoxy]-ethyl-trimethyl-silane (E.7)

[0512] To a solution of 6-bromo-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridine (0.400 g, 1.36 mmol, 1 eq) in THF (10 mL) was added NaH (163 mg, 4.08 mmol, 60 wt% dispersible oil, 3 eq) at 0°C. After stirring at 0°C for 1 hour, SEM-Cl (227 mg, 1.36 mmol, 0.241 mL, 1 eq) was added. The mixture was stirred at 0°C for 2 hours, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered, and the solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient 1 / 0 to 1 / 2) to obtain 2-[[6-bromo-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane. LCMS: M+H + :426.2

[0513] N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-6-yl]-1,1-diphenylmethanimine (E.8)

[0514] A mixture of 2-[[6-bromo-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-b]pyridin-1-yl]methoxy]ethyl-trimethylsilane (0.200 g, 0.471 mmol, 1 eq), diphenylmethanimine (128 mg, 0.707 mmol, 0.119 mL, 1.5 eq), Pd2(dba)3 (43 mg, 0.047 mmol, 0.1 eq), BINAP (29 mg, 0.047 mmol), t-BuONa (91 mg, 0.94 mmol, 2 eq) in toluene (4 mL) was stirred at 110 °C under microwave irradiation for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient 1 / 0 to 0 / 1) to obtain N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-6-yl]-1,1-diphenylmethanimine.

[0515] 2-[[(2S)-2-Methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-6-amine (Amine E)

[0516] To a solution of N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-6-yl]-1,1-diphenylmethanimine (0.140 g, 0.267 mmol, 1 equivalent) in THF (5 mL) was added aqueous HCl solution (1 M, 140 mL). The mixture was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (5 mL) and extracted with EtOAc (15 mL). The aqueous layer was adjusted to pH = 8 with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (15 mL×2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and filtered. The solution was concentrated under reduced pressure to obtain 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridin-6-amine. LCMS: M+H + :361.2.

[0517] Synthesis of amine F

[0518]

[0519] 3,6-Dichloro-N-[(4-methoxyphenyl)methyl]pyridazin-4-amine (F.2)

[0520] A mixture of 3,4,6-trichloropyridazine (3 g, 16.36 mmol, 1 equivalent), PMBNH2 (2.24 g, 16.36 mmol, 2.12 mL, 1 equivalent), K2CO3 (2.26 g, 16.36 mmol, 1 equivalent) in MeCN (30 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 95 ° C. for 4 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to obtain a white solid compound 3,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridazine-4-amine (4 g, 85% purity). 1 H-NMR: (400MHz, CDCl3, ppm): δ7.30 (d, J = 3.89Hz, 2H), 6.97 (d, J = 8.53Hz, 2H), 6.58 (s, 1H), 5.42 (br s, 1H), 4.38 (d, J = 5.27Hz, 2H), 3.87 (s, 3H).

[0521] 6-Chloro-3-(3,3-diethoxyprop-1-ynyl)-N-[(4-methoxyphenyl)methyl]pyridazin-4-amine (F.3)

[0522] A mixture of 3,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridazin-4-amine (1 g×4, 3.52 mmol, 1 eq), 3,3-diethoxyprop-1-yne (473.63 mg×4, 3.70 mmol, 529.78 uL, 1.05 eq), Pd(PPh3)2Cl2 (74.11 mg×4, 105.58 umol, 0.03 eq), TEA (1.78 g×4, 17.60 mmol, 2.45 mL, 5 eq) and CuI (40.22 mg×4, 211.16 umol, 0.06 eq) in MeCN (7 mL) was degassed and purged with N2, and then the mixture was stirred under microwave at 65°C for 5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give 6-chloro-3-(3,3-diethoxyprop-1-ynyl)-N-[(4-methoxyphenyl)methyl]pyridazin-4-amine (3.6 g, crude) as a brown oil, which was used directly in the next step without further purification.

[0523] 3-Chloro-6-(diethoxymethyl)-5-[(4-methoxyphenyl)methyl]pyrrolo[3,2-c]pyridazine (F.4)

[0524] To a solution of 6-chloro-3-(3,3-diethoxyprop-1-ynyl)-N-[(4-methoxyphenyl)methyl]pyridazine-4-amine (2.8 g, 4.47 mmol, 1 equivalent) in anhydrous DMF (20 mL) was added CuI (170.26 mg, 893.98 umol, 0.2 equivalent). The reaction mixture was heated to 130 ° C for 12 hours, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 3 / 1) to give a brown oily compound 3-chloro-6-(diethoxymethyl)-5-[(4-methoxyphenyl)methyl]pyrrolo[3,2-c]pyridazine (0.9 g, crude product).

[0525] 3-Chloro-5-[(4-methoxyphenyl)methyl]pyrrolo[3,2-c]pyridazine-6-carbaldehyde (F.5)

[0526] A mixture of 3-chloro-6-(diethoxymethyl)-5-[(4-methoxyphenyl)methyl]pyrrolo[3,2-c]pyridazine (0.9 g, 2.39 mmol, 1 eq.), TsOH.H2O (683.25 mg, 3.59 mmol, 1.5 eq.) in THF (10 mL) and H2O (2 mL) was stirred at 45° C. for 1 hour. The mixture was poured into NaHCO3 (50 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a brown solid compound 3-chloro-5-[(4-methoxyphenyl)methyl]pyrrolo[3,2-c]pyridazine-6-carbaldehyde (0.8 g, crude).

[0527] 3-Chloro-5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazine (F.6)

[0528] To a solution of 3-chloro-5-[(4-methoxyphenyl)methyl]pyrrolo[3,2-c]pyridazine-6-carbaldehyde (950 mg, 1.57 mmol, 1 eq) and (2S)-2-methylpyrrolidine (160.85 mg, 1.89 mmol, 1.2 eq) in DCE (20 mL) was added AcOH (94.53 mg, 1.57 mmol, 90.03 uL, 1 eq). The mixture was stirred at 15 °C for 0.5 h, and NaBH(OAc)3 (667.30 mg, 3.15 mmol, 2 eq) was added to the solution. The mixture was stirred at 15 °C for 12 h, and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give a brown oily compound 3-chloro-5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazine (800 mg, crude). 1 H-NMR: (400MHz, DMSO-d6, ppm): δ7.94 (s, 1H), 7.01 (d, J = 8.63Hz, 2H), 6.94-6. 83(m,3H),5.52(s,2H),4.04-3.99(m,1H),3.70(s,3H),3.42(d,J=14.13Hz,1H ),2.84-2.76(m,1H),2.46-2.39(m,1H),2.17(q,J=8.67Hz,1H),1.94-1.90(m, 1H), 1.67-1.53 ​​(m, 2H), 1.33 (dq, J=12.07, 8.15Hz, 1H), 1.03 (d, J=6.00Hz, 3H).

[0529] N-[5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazin-3-yl]-1,1-diphenylmethanimine (F.7)

[0530] A mixture of 3-chloro-5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazine (850 mg, 2.29 mmol, 1 eq), diphenylmethanimine (498.44 mg, 2.75 mmol, 461.51 uL, 1.2 eq), tBuONa (440.50 mg, 4.58 mmol, 2 eq) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium, dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (207.76 mg, 229.19 umol, 0.1 eq) in THF (20 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 100°C under N2 atmosphere for 5 hours, and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give a brown oily compound N-[5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazine-3-yl]-1,1-diphenyl-methanimine (crude, 0.5 g). 1 H-NMR: (400MHz, DMSO-d6, ppm) δ7.76-7.68(m,2H),7.61-7.55(m,1H),7.54-7.48(m,2H) ,7.31-7.18(m,4H),7.10-7.05(m,2H),6.89-6.77(m,4H),6.65(s,1H),5.32(s,2H),3.9 5(d,J=13.88Hz,1H),3.71-3.68(m,1H),2.80-2.72(m,1H),2.42-2.37(m,1H),2.18-2.0 7(m,1H),1.94-1.88(m,1H),1.61-1.52(m,2H),1.38-1.26(m,1H),1.03(d,J=5.88Hz,3H)

[0531] 5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazin-3-amine (amine F)

[0532] A mixture of N-[5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazine-3-yl]-1,1-diphenylmethanimine (400 mg, 775.72 umol, 1 equivalent) in HCl (4 mL) and THF (4 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 15 ° C for 0.5 hours under N2 atmosphere. H2O (20 mL) and EtOAc (10 mL) were added to the mixture, and the organic phase was separated. The aqueous phase was basified using NaHCO3 to adjust pH = 8. The aqueous layer was extracted with EtOAc (15 mL × 3), and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown solid compound 5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazine-3-amine (0.27 g, 553.15 umol, 71.31% yield, 72% purity). The crude product can be used directly in the next step without further purification. LCMS: [M+H] + =352.

[0533] Synthesis according to the examples of the present application

[0534] Preparation of Example 1

[0535]

[0536] 3-Methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-6-carboxamide (1-1)

[0537] To an 8-mL glass vial purged and maintained with an inert atmosphere of nitrogen was added 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 170.0 mg, 0.471 mmol, 1.0 equiv), 3-methyl-1,2-benzoxazole-6-carboxylic acid (acid A, CAS: 478169-72-1, 91.9 mg, 0.52 mmol, 1.10 equiv), EDCI (135.6 mg, 0.71 mmol, 1.5 equiv) and pyridine (2.0 mL). The resulting solution was stirred at 50° C. for 12 hours and then quenched by adding 8 mL of water / ice. The resulting solution was extracted with 3×3 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3×3 mL of brine, and the resulting mixture was concentrated to obtain 280 mg (crude) of brown liquid 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-6-carboxamide (1-1). LCMS: [M+1]+=520.

[0538] (S)-3-methyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzo[d]isoxazole-6-carboxamide (Example 1)

[0539] Into an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-6-carboxamide (1-1, 280.0 mg, 0.54 mmol, 1.0 equiv), TFA (2.0 mL, 50 equiv), DCM (2.0 mL) were added. The resulting solution was stirred at 25° C. for 12 hours, and the resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3·H2O) and acetonitrile (Phase B from 12% to 34% in 7 minutes); detector, UV 254nm. 40.9mg (19.5%) of off-white solid (S)-3-methyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzo[d]isoxazole-6-carboxamide (Example 1) was obtained. LCMS: [M+1] + =390. 1H-NMR (300MHz, methanol-d4, ppm): δ8.57(d,J=1.0Hz,1H),8.26–8.19(m,2H),8.04–7.90(m,2H),6.55(s,1H),4.19(d,J=14.1Hz,1H),3.61(d, J=14.1Hz,1H),3.08(s,1H),2.65(s,4H),2.45(d,J=10.5Hz,1H),2.07(m,1H),1.77(d,J=8.7Hz,2H),1.52(s,1H),1.25(d,J=6.3Hz,3H).

[0540] The following Examples in Table D were prepared in a similar manner to Example 1 above using amine D and appropriate reagents and conditions.

[0541] Table D

[0542]

[0543]

[0544] Preparation of Example 2

[0545]

[0546] To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 150.0 mg, 0.42 mmol, 1.0 equiv), pyridine (3.00 mL), 3-methyl-1,2-benzoxazole-5-carboxylic acid (81.1 mg, 0.46 mmol, 1.10 equiv), EDCI (119.6 mg, 0.62 mmol, 1.5 equiv) were added. The resulting solution was stirred at room temperature for 24 hours, and the resulting mixture was concentrated and diluted with H2O. The resulting solution was extracted with 3×20 mL of ethyl acetate, the organic layers were combined, and the resulting mixture was washed with 2×20 mL of brine. The resulting mixture was concentrated to obtain 300 mg (crude) of brown solid 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-5-carboxamide. LCMS: [M+H] + =520.

[0547]

[0548] To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-5-carboxamide (300.00 mg, 0.577 mmol, 1.00 equiv), DCM (3.00 mL), TFA (3 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated. The pH value of the solution was adjusted to 8 with Et2NH, and the crude product (110 mg) was purified by Prep-HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 25% to 50% in 7 minutes); detector, UV254nm. 47.3 mg (21.04%) of white solid 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-5-carboxamide was obtained. LCMS: [M+H]+=390. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.57 (d, J=1.0Hz, 1H), 8.52–8.46 (m, 1H), 8.27 (dd, J=8.8 ,1.8Hz,1H),8.21(t,J=1.0Hz,1H),7.74(dd,J=8.8,0.8Hz,1H),6.55(s,1H),4.19(d,J= 13.9Hz,1H),3.62(d,J=14.0Hz,1H),3.09(m,1H),2.67(s,3H),2.63(s,1H),2.46(m,1H) ,2.08(m,1H),1.80(s,1H),1.88–1.71(m,2H),1.62–1.43(m,1H),1.25(d,J=6.1Hz,3H).

[0549] The following Examples in Table E were prepared in a similar manner to Example 2 above using amine D and appropriate reagents and conditions.

[0550] Table E

[0551]

[0552]

[0553] Preparation of Example 3

[0554]

[0555] To a 50-mL round-bottom flask, 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 150.0 mg, 0.42 mmol, 1.0 equiv), 2-methyl-1,3-benzoxazole-5-carboxylic acid (CAS: 90322-32-0, 81.07 mg, 0.458 mmol, 1.10 equiv), EDCI (119.6 mg, 0.62 mmol, 1.5 equiv), and pyridine (1.5 mL) were added. The resulting solution was stirred at 50°C for 1 hour, then quenched by adding 5 mL of water, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined and concentrated to give 300 mg (crude) of brown solid 2-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,3-benzoxazole-5-carboxamide. LCMS: [M+H] + =506.

[0556]

[0557] To a 50-mL round-bottom flask, 2-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,3-benzoxazole-5-carboxamide (300.0 mg, crude), TFA (0.50 mL), and DCM (0.50 mL) were added. The resulting solution was stirred at room temperature for 2 hours, and the resulting mixture was concentrated. The crude product (100 mg) was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 32% to 63% in 7 minutes); detector, UV 254nm. 33.6 mg (21% for two steps) of light brown solid 2-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,3-benzoxazole-5-carboxamide were obtained. LCMS: [M+H] + =390. 1H-NMR: (300MHz, CD3OD-d4, ppm): δ8.54(d,J=1.0Hz,1H),8.30(d,J=1.8Hz,1H),8.20(d,J=1 .1Hz,1H),8.05(dd,J=8.5,1.8Hz,1H),7.72(d,J=8.6Hz,1H),6.51(s,1H),4.13(d,J=13.9H z,1H),3.53(d,J=13.9Hz,1H),3.04-3.00(m,1H),2.70(s,3H),2.63–2.47(m,1H),2.36(q,J =9.0Hz,1H),2.13–1.95(m,1H),1.76-1.70(m,2H),1.59–1.40(m,1H),1.22(d,J=6.1Hz,3H).

[0558] The following Examples in Table F were prepared in a similar manner to Example 3 above using amine D and appropriate reagents and conditions.

[0559] Table F

[0560]

[0561]

[0562] Preparation of Example 10

[0563]

[0564] 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 111 mg, 0.308 mmol, 1.00 equiv), 4-[1-(pyridin-2-yl)ethyl]benzoic acid (100 mg, 0.308 mmol, 1.00 equiv), pyridine (3.00 mL) and EDCI (89 mg, 0.462 mmol, 1.50 equiv) were added to an 8 mL glass bottle at room temperature. The resulting mixture was stirred at 50 ° C. under a nitrogen atmosphere for 6 hours, and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was washed with 3×20 mL brine, and the organic layer was dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to give brown oily N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(pyridin-2-yl)ethyl]benzamide (100 mg, 48.43%). LCMS: [M+1] +=570.

[0565]

[0566] N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(pyridin-2-yl)ethyl]benzamide (100.01 mg, 0.175 mmol, 1.00 equiv), DCM (2.00 mL) and TFA (2.00 mL) were added to an 8 mL glass bottle at room temperature. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (3 mL). The mixture was basified to pH 9 with ammonium hydroxide and then purified by Prep-HPLC under the following conditions (column: XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 20mL / min; gradient: from 44B to 66B in 7 minutes, 220nm). A white solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(pyridin-2-yl)ethyl]benzamide (24.7mg, 35.8%) was obtained. LCMS: [M+1] + =440. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.55 (s, 1H), 8.51–8.49 (m, 1H), 8.20 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7. 82-7.76(m,1H),7.48(d,J=8.4Hz,2H),7.39(d,J=8.1Hz,1H),7.30-7.26(m,1H),6.56(s,1H),4.43( q,J=7.2Hz,1H),4.22(d,J=14.1Hz,1H),3.66(d,J=14.1Hz,1H),3.12–3.09(m,1H),2.75-2.65(m,1H ),2.56-2.46(m,1H),2.13-2.06(m,1H),1.88–1.71(m,5H),1.63–1.44(m,1H),1.26(d,J=6.3Hz,3H).

[0567] Preparation of Example 14

[0568]

[0569] To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 124.22 mg, 0.345 mmol, 1.00 equiv), pyridine (2.5 mL), 2-fluoro-4-(5-methylpyrimidin-2-yl)benzoic acid (80.0 mg, 0.345 mmol, 1.00 equiv), EDCI (99.06 mg, 0.517 mmol, 1.50 equiv) were added. The resulting solution was stirred at 50° C. in an oil bath for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, and the resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 200 mg (70.5%) of 2-fluoro-4-(5-methylpyrimidin-2-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)benzamide as a brown oil. LCMS: [M+H] + =575.

[0570]

[0571] To an 8-mL glass bottle, 2-fluoro-4-(5-methylpyrimidin-2-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)benzamide (200 mg, 0.348 mmol, 1.00 equiv), DCM (2.0 mL), TFA (2.0 mL) were added. The resulting solution was stirred at room temperature for 6 hours, and the resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to 8 with Et2NH. The crude product (100 mg) was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 25% to 50% in 7 minutes); detector, UV 254nm. 38.3 mg (24.76%) of yellow solid 2-fluoro-4-(5-methylpyrimidin-2-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide were obtained. LCMS: [M+H] + =445. 1H-NMR: (300MHz, methanol-d4, ppm) δ8.77 (d, J = 0.8Hz, 2H), 8.54 (d, J = 1.0Hz, 1H), 8.39 (dd ,J=8.2,1.5Hz,1H),8.34–8.23(m,2H),8.05(t,J=7.9Hz,1H),6.56(s,1H),4.21(d,J =13.9Hz,1H),3.65(d,J=14.0Hz,1H),3.11(m,1H),2.68(s,1H),2.48(d,J=9.7Hz,1 H),2.41(s,3H),2.15–2.02(m,1H),1.80(m,2H),1.54(m,1H),1.26(d,J=6.1Hz,3H). 19 F-NMR: (300 MHz, methanol-d4, ppm): δ-115.236.

[0572] Preparation of Example 16

[0573]

[0574] To an 8-mL sealed tube, 3-oxo-2,4-dihydro-1,4-benzoxazine-7-carboxylic acid (CAS: 214848-62-1, 35.36 mg, 0.183 mmol, 1.10 equiv), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 60.00 mg, 0.166 mmol, 1.00 equiv), EDCI (47.85 mg, 0.249 mmol, 1.50 equiv) and pyridine (1.00 mL) were added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated, and the resulting solution was extracted with 2×20 mL of ethyl acetate. The organic layers were combined to obtain 200 mg (crude) of light brown solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-oxo-2,4-dihydro-1,4-benzoxazine-7-carboxamide. LCMS: [M+H]+=536.

[0575]

[0576] To an 8-mL sealed tube, N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolidin[3,2-c]pyridin-6-yl)-3-oxo-2,4-dihydro-1,4-benzoxazine-7-carboxamide (200.0 mg, 0.373 mmol, 1.00 equiv), TFA (0.5 mL), DCM (0.5 mL) were added. The resulting solution was stirred at room temperature for 2 hours and the resulting mixture was concentrated. The pH of the solution was adjusted to 7 with NaHCO3(aq.) and the solid was collected by filtration. The crude product (100 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150m; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 15% to 45% in 7 minutes); detector, UV 254nm. 21.7 mg (17.3% in two steps) of brown solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolidin[3,2-c]pyridin-6-yl)-3-oxo-2,4-dihydro-1,4-benzoxazine-7-carboxamide was obtained. LCMS: (ES, m / z): [M+H] + =389. 1 H-NMR: (300MHz, DMSO-d6, ppm): δ11.33(s,1H),10.96(s,1H),10.33(s,1H),8.50(s,1H), 8.18(d,J=1.2Hz,1H),7.77–7.64(m,2H),6.97(d,J=8.2Hz,1H),6.36(s,1H),4.65(s,2H), 4.01(d,J=13.9Hz,1H),3.40(d,J=13.8Hz,1H),2.89(d,J=6.4Hz,1H),2.43(q,J=6.9Hz,1 H), 2.19 (q, J = 8.8Hz, 1H), 1.93-1.90 (m, 1H), 1.63 (d, J = 8.1Hz, 1H), 1.10 (d, J = 6.0Hz, 3H).

[0577] Preparation of Example 17

[0578]

[0579] To an 8-mL sealed tube, 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 145.00 mg, 0.402 mmol, 1.00 equiv), 4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylic acid (99.98 mg, 0.483 mmol, 1.20 equiv), EDCI (115.63 mg, 0.603 mmol, 1.50 equiv) and pyridine (5.00 mL) were added. The resulting solution was stirred in an oil bath at 50° C. for 20 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 20 mL of water, the resulting solution was extracted with 2×20 mL of ethyl acetate, the organic layers were combined and concentrated to give 200 mg (crude) of brown oily 4-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-oxo-2H-1,4-benzoxazine-7-carboxamide. LCMS: [M+H]+=550.

[0580]

[0581] To a 50-mL round-bottom flask, 4-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-oxo-2H-1,4-benzoxazine-7-carboxamide (200.00 mg, 0.364 mmol, 1.00 equiv), TFA (2 mL), DCM (1 mL) were added. The resulting solution was stirred at room temperature for 10 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 20 mL of water, and the pH of the solution was adjusted to 7 with NaHCO3 (aq.). The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The crude product (130 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 27% to 60% in 7 minutes); detector, UV 254nm. 25.1 mg (12.41% in two steps) of light brown solid 4-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-oxo-2H-1,4-benzoxazine-7-carboxamide was obtained. LCMS: [M+H] + =420. 1H-NMR: (300MHz, DMSO-d6, ppm): δ8.54(d,J=1.0Hz,1H),8.18(t,J=1.0Hz,1H),7.77(dd,J=8.4,2.1Hz,1 H),7.66(d,J=2.0Hz,1H),7.31(d,J=8.5Hz,1H),6.52(s,1H),4.72(s,2H),4.14(d,J=13.9Hz,1H),3.54( d,J=13.9Hz,1H),3.44(s,3H),3.37(s,3H),3.04(t,J=6.7Hz,1H),2.55-2.50(m,1H),2.37-2.30(m,1H), 2.05(t,J=6.8Hz,1H), 1.76(dd,J=10.4,4.7Hz,2H), 1.52(dd,J=18.7,9.4Hz,1H), 1.23(d,J=6.1Hz,3H).

[0582] Preparation of Example 20

[0583]

[0584] To a 40-mL glass bottle, a solution of 4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzoic acid (120.00 mg, 0.379 mmol, 1.00 equiv) in pyridine (10 mL), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 136.77 mg, 0.379 mmol, 1.00 equiv) and EDCI (109.07 mg, 0.569 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 5 hours and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of EA and the resulting mixture was washed with 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 100 mg (40.01%) of N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2)-c]pyridin-6-yl)-4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzamide as a yellow oil. LCMS: 659.

[0585]

[0586] To a 20-mL glass vial was added a solution of N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-[1-[2-(oxa-2-yloxy)ethyl]pyrazol-4-yl]benzamide (100.0 mg, 0.152 mmol, 1.00 equiv) in DCM (5 mL) and TFA (2.00 mL, 26.926 mmol, 177.42 equiv). The resulting solution was stirred at room temperature for 5 hours and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3.H2O) and acetonitrile (Phase B from 29% to 46% in 7 minutes); detector, UV 254nm. 23mg of white solid 4-[1-(2-hydroxyethyl)pyrazol-4-yl]-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide was obtained. LCMS: [M+H] + =445. 1 H-NMR: (300MHz, methanol-d4, ppm): δ8.55 (d, J=1.0Hz, 1H), 8.25–8.14 (m, 2H), 8.07– 7.96(m,3H),7.81–7.71(m,2H),6.52(s,1H),4.31(m,2H),4.15(d,J=13.9Hz,1H ),3.95(m,2H),3.55(d,J=13.9Hz,1H),3.05(s,1H),2.57(m,1H),2.39(m,1H),2 .05(m,1H),1.77(s,1H),1.86–1.69(m,2H),1.51(s,1H),1.24(d,J=6.1Hz,3H).

[0587] Preparation of Example 21

[0588]

[0589] To a 20-mL glass bottle, a solution of 4-(1-methylpyrazol-4-yl)benzoic acid (100.00 mg, 0.495 mmol, 1.00 equiv) in pyridine (10 mL), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 178.32 mg, 0.495 mmol, 1.00 equiv), EDCI (142.20 mg, 0.742 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting solution was diluted with 20 mL of EA. The resulting mixture was washed with 3×10 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. 150 mg (crude) of yellow oily 4-(1-methylpyrazol-4-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)benzamide was obtained. LCMS: [M+H]+=545.

[0590]

[0591] To a 20-mL glass bottle, 4-(1-methylpyrazol-4-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)benzamide (150.00 mg, 0.275 mmol, 1.00 equiv), DCM (5.00 mL, 78.650 mmol, 285.64 equiv), TFA (5.00 mL, 0.044 mmol, 0.16 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3.H2O) and acetonitrile (Phase B from 33% to 55% in 7 minutes); detector, UV 254nm. 26mg of white solid 4-(1-methylpyrazol-4-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide was obtained. LCMS: [M+H] + =415. 1H-NMR: (300MHz, methanol-d4, ppm) δ8.59(s,1H),8.25(s,1H),8.11(s,1H),8.07–7.97(m ,2H),7.95(d,J=0.8Hz,1H),7.79–7.70(m,2H),6.63(s,1H),4.30(d,J=13.9Hz,1H) ,3.97(s,3H),3.79(d,J=14.0Hz,1H),3.19(m,1H),2.85(s,1H),2.68(s,1H),2.64 (s,1H),2.15(m,7.3Hz,1H),1.86(m,2H),1.68–1.49(m,1H),1.30(d,J=6.2Hz,3H).

[0592] The following Examples in Table G were prepared in a similar manner to Example 21 above using amine D and appropriate reagents and conditions.

[0593] Table G

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601] Preparation of Example 23

[0602]

[0603] Into an 8-mL round-bottom flask, 3-oxo-2H-isoquinoline-7-carboxylic acid (60.00 mg, 0.317 mmol, 1.00 equiv), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 114.37 mg, 0.317 mmol, 1.00 equiv), DMF (2.00 mL), HATU (180.90 mg, 0.476 mmol, 1.5 equiv) and DIEA (163.97 mg, 1.269 mmol, 4 equiv) were added. The resulting solution was stirred at room temperature for 15 hours, the resulting solution was diluted with 10 mL of H2O, extracted with 3×10 mL of ethyl acetate, the organic layers were combined, and the resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated to give 80 mg (47.43%) of yellow oily N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2)-c]pyridin-6-yl)-3-oxo-2H-isoquinoline-7-carboxamide. LCMS: [M+1]+=532.

[0604]

[0605] Into an 8-mL round-bottom flask, N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-oxo-2H-isoquinoline-7-carboxamide (60.00 mg, 0.113 mmol, 1.00 equiv), DCM (2.00 mL), TFA (55.30 mg, 0.564 mmol, 5.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting solution was diluted with 10 mL of H2O, extracted with 3×10 mL of dichloromethane, and the organic layers were combined and concentrated. The crude product was purified by preparative HPLC under the following conditions: chromatographic column: HPHC18, 50×3.0 mm, 2.6 um; mobile phase A: water / 0.05% NH3.H2O, mobile phase B: acetonitrile; flow rate: 1.2 mL / min; gradient: from 5% B to 100% B in 1.1 minutes, maintained for 0.7 minutes), detector, UV 254 nm. 19 mg (42%) of white solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-oxo-2H-isoquinoline-7-carboxamide was obtained. LCMS: M+1] + =402. 1H-NMR: (300MHz, methanol-d4, ppm): δ11.40–11.33(m,1H),10.56(s,1H),9.02(s,1H),8.74(d,J=1.7Hz ,1H),8.53(s,1H),8.26(s,1H),8.14(dd,J=8.9Hz,1H),7.77(d,J=8.9Hz,1H),6.95(s,1H),6.37 (s,1H),4.02(d,J=13.9Hz,1H),3.41(d,J=13.9Hz,1H),2.88(s,1H),2.47–2.37(m,1H),2.20(m, 1H), 1.92 (d, J = 11.6Hz, 1H), 1.63 (d, J = 8.2Hz, 3H), 1.35 (d, J = 9.0Hz, 1H), 1.11 (d, J = 6.0Hz, 3H).

[0606] Preparation of Example 24

[0607]

[0608] To a 12-mL glass bottle purged and maintained with a nitrogen inert atmosphere, a solution of 2-oxo-3H-1,3-benzoxazole-5-carboxylic acid (100.0 mg, 0.558 mmol, 1.00 equiv) in pyridine (5 mL), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 201.29 mg, 0.558 mmol, 1.00 equiv), EDCI (160.53 mg, 0.837 mmol, 1.50 equiv) was added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of DCM, and the resulting mixture was washed with 2×10 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 150 mg (51.50%) of brown crude N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2)-c]pyridin-6-yl)-2-oxo-3H-1,3-benzoxazole-5-carboxamide. LCMS: [M+H]+=522.

[0609]

[0610] To a 10-mL glass vial purged and maintained with an inert atmosphere of nitrogen was added a solution of N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-2-oxo-3H-1,3-benzoxazole-5-carboxamide (150.00 mg, 0.288 mmol, 1.00 equiv, crude) in DCM (2 mL) and TFA (2 mL). The resulting solution was stirred at room temperature for 16 hours and the resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3.H2O) and acetonitrile (phase B from 15% to 55% in 7 minutes); detector, UV 254nm. 2mg of white solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-oxo-3H-1,3-benzoxazole-5-carboxamide was obtained. LCMS: [M+H] + =392. 1 H-NMR: (300MHz, DMSO-d6, ppm): δ11.34(s,1H),10.50(s,1H),8.51(s,1H),8.18(s,1H),7.84(d,J=9.9Hz,1H),7.75(s,1H),7.38(d,J=8.3 Hz,1H),6.37(s,1H),4.01(d,J=14.0Hz,1H),2.87(s,1H),2.43(d,J=6.4Hz,1H),2.20(d,J=8.9Hz,1H),1.64(s,2H),1.10(d,J=6.0Hz,3H).

[0611] The following Examples in Table H were prepared in a similar manner to Example 24 above using amine D and appropriate reagents and conditions.

[0612] Table H

[0613]

[0614]

[0615] Preparation of Example 27

[0616]

[0617] To an 8-mL sealed tube, lithium 1-(4-methoxybut-2-yn-1-yl)indazole-5-carboxylate (87.42 mg, 0.350 mmol, 1.40 equiv), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 90.00 mg, 0.250 mmol, 1.00 equiv), HATU (170.83 mg, 0.450 mmol, 1.80 equiv), DIPEA (96.78 mg, 0.750 mmol, 3.00 equiv), DMF (1.00 mL, 12.922 mmol, 51.77 equiv) were added. The resulting solution was stirred at room temperature for 20 hours, and then the reaction was quenched by adding 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate, and the organic layers were combined and concentrated to obtain 200 mg (crude) of brown solid 1-(4-methoxybut-2-yn-1-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide. LCMS: [M+H]=587.

[0618]

[0619] To a 50-mL round-bottom flask, 1-(4-methoxybut-2-yn-1-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide (200.00 mg, 0.341 mmol, 1.00 equiv), CF3COOH (1.00 mL), DCM (2.00 mL) were added. The resulting solution was stirred at room temperature for 2 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 10 mL of water, and the pH of the solution was adjusted to 7 with NaHCO3 (aqueous solution). The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The crude product (120 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 41% to 54% in 7 minutes); detector, UV254nm. 12.2 mg (12% in two steps) of light brown solid 1-(4-methoxybut-2-yn-1-yl)-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide was obtained. LCMS: [M+H] + =457.1 H-NMR: (300MHz, methanol-d4, ppm): δ8.59–8.50 (m, 2H), 8.28–8.18 (m, 2H), 8.12 (dd, J = 8.9, 1.7 Hz, 1H), 7.82 (dd, J = 8.8, 1.1 Hz, 1H), 6.52 (s, 1H), 5.41 (t, J = 2.0 Hz, 2H), 4.20–4. 09(m,3H),3.53(d,J=13.9Hz,1H),3.11–2.98(m,1H),2.61–2.48(m,1H),2.41-2.30(m ,1H),2.11–1.99(m,1H),1.76-1.70(m,2H),1.60–1.44(m,1H),1.24(d,J=6.1Hz,3H).

[0620] The following Examples in Table I were prepared in a similar manner to Example 27 above using amine D and appropriate reagents and conditions.

[0621] Table I

[0622]

[0623] Preparation of Example 29

[0624]

[0625] To an 8-mL glass vial at room temperature was added 4-[1-(pyridin-4-yl)ethyl]benzoic acid (83.20 mg, 0.366 mmol, 1.20 equiv), pyridine (2.50 mL) and EDCI (87.72 mg, 0.458 mmol, 1.50 equiv). To the above mixture was added 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 110.00 mg, 0.305 mmol, 1.00 equiv). The resulting mixture was stirred at 50°C for another 6 hours, and the resulting mixture was concentrated under reduced pressure to give a brown oily N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(pyridin-4-yl)ethyl]benzamide (260 mg, crude product). The crude product was used directly in the next step without further purification. LCMS: [M+1]+=570.

[0626]

[0627] To a 20 mL glass bottle was added N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(pyridin-4-yl)ethyl]benzamide (240.00 mg, 0.421 mmol, 1.00 equiv, 50%), DCM (4.00 mL) and CF3COOH (4.00 mL) at room temperature. The resulting mixture was stirred at room temperature overnight and the resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (3 mL) and the mixture was basified to pH 10 with ammonium hydroxide. The crude product was purified by preparative HPLC under the following conditions (chromatographic column: XBridge Prep C18OBD column, 5um, 19×150mm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 20mL / min; gradient: from 25B to 50B in 7 minutes, 220nm) to obtain N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(pyridin-4-yl)ethyl]benzamide (60mg, 64.82%) as a white solid. LCMS: [M+1] + =440. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.53 (d, J = 0.9Hz, 1H), 8.47–8.45 (m, 2H), 8.19 (s, 1H), 7.98 (d, J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),7.39-7.37(m,2H),6.51(s,1H),4.35(q,J=7.2Hz,1H),4 .14(d,J=13.8Hz,1H),3.53(d,J=13.8Hz,1H),3.07–3.00(m,1H),2.55-2.53(m,1H),2.37(q, J=9.0Hz,1H),2.06-2.00(m,1H),1.79-1.72(m,5H),1.53-1.49(m,1H),1.23(d,J=6.0Hz,3H).

[0628] The following Examples in Table J were prepared in a similar manner to Example 29 above using amine D and appropriate reagents and conditions.

[0629] Table J

[0630]

[0631] Preparation of Example 37

[0632]

[0633] To an 8-mL glass bottle, 1-(pyridin-4-yl)indazole-5-carboxylic acid (70.00 mg, 0.293 mmol, 1.00 equiv), pyridine (2.00 mL), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 105.51 mg, 0.293 mmol, 1.00 equiv), EDCI (84.14 mg, 0.439 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O, extracted with 3×15 mL of ethyl acetate, the organic layers were combined, and the resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 150 mg (76.11%) of N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2)-c]pyridin-6-yl)-1-(pyridin-4-yl)indazole-5-carboxamide as a brown oil. LCMS: [M+H]+=582.

[0634]

[0635] Into an 8-mL glass bottle, N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolidin[3,2-c]pyridin-6-yl)-1-(pyridin-4-yl)indazole-5-carboxamide (150.00 mg, 0.258 mmol, 1 eq), DCM (2.00 mL), CF3COOH (2.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated in vacuo, and the pH of the solution was adjusted to 8 with Et2NH. The crude product (110 mg) was purified by Prep-HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 31% to 48% in 7 minutes); detector, UV 254nm. 38.1 mg (32.73%) of white solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-1-(pyridin-4-yl)indazole-5-carboxamide was obtained. LCMS: [M+H] + =452. 1H-NMR: (300MHz, methanol-d4, ppm) δ8.74–8.72(m,2H),8.62–8.55(m,3H),8.23(m,3H),8.04–8.02(m,2H),6.53(s,1H),4.15(d,J=13.9Hz,1 H),3.54(d,J=13.9Hz,1H),3.05(m,1H),2.56(m,1H),2.38(m,1H),2.05(m,1H),1.76(m,2H),1.60–1.45(m,1H),1.24(d,J=6.1Hz,3H).

[0636] The following Examples in Table K were prepared in a similar manner to Example 37 above using amine D and appropriate reagents and conditions.

[0637] Table K

[0638]

[0639]

[0640]

[0641] Preparation of Example 40

[0642]

[0643] Into an 8-mL sealed tube, 1-methyl-3,4-dihydro-2H-quinoline-6-carboxylic acid (50.00 mg, 0.261 mmol, 1.00 equiv), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 94.28 mg, 0.261 mmol, 1.00 equiv), pyridine (1.00 mL), EDCI (75.19 mg, 0.392 mmol, 1.50 equiv) were added. The resulting solution was stirred in an oil bath at 50° C. for 12 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 20 mL of water, the resulting solution was extracted with 2×20 mL of ethyl acetate, the organic layers were combined and concentrated to give 150 mg (crude) of light brown solid 1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolidin[3,2-c]pyridin-6-yl)-3,4-dihydro-2H-quinoline-6-carboxamide. LCMS: [M+H]+=534.

[0644]

[0645] To a 50-mL round-bottom flask, 1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3,4-dihydro-2H-quinoline-6-carboxamide (150.0 mg, 0.281 mmol, 1.00 equiv), CF3COOH (1.0 mL), DCM (5.0 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 20 mL of water, and the pH of the solution was adjusted to 8 with NaHCO3 (aq.). The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The crude product (120 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150 mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 50% to 75% in 7 minutes); detector, UV 254 nm. 25.7 mg (22% in two steps) of light brown solid 1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,4-dihydro-2H-quinoline-6-carboxamide was obtained. LCMS: [M+H]+=404. 1 H-NMR: (300MHz, methanol-d4, ppm): δ8.50(d,J=1.0Hz,1H),8.17(t,J=1.0Hz,1H),7.73(dd,J=8.7,2. 4Hz,1H),7.60(d,J=2.4Hz,1H),6.66(d,J=8.7Hz,1H),6.48(s,1H),4.12(d,J=13.8Hz,1H),3.50 (d,J=13.9Hz,1H),3.43–3.35(m,2H),3.00(s,4H),2.84(t,J=6.3Hz,2H),2.58-2.44(m,1H),2. 42-2.29(m,1H),2.11-1.94(m,3H),1.84-1.66(m,2H),1.58-1.39(m,1H),1.22(d,J=6.1Hz,3H).

[0646] Preparation of Example 42

[0647]

[0648] To an 8-mL round-bottom flask were added 2-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 264.83 mg, 0.734 mmol, 1.00 equiv), pyridine (2.00 mL), EDCI (563.20 mg, 2.938 mmol, 4.00 equiv), and 4-[1-(oxa-2-yl)pyrazol-4-yl]benzoic acid (200.00 mg, 0.734 mmol, 1.00 equiv). The resulting solution was stirred at room temperature for 4 hours, diluted with 10 mL of H2O, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined and concentrated to give 100 mg (22.14%) of yellow oily N-(2-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2)-c]pyridin-6-yl)-4-[1-(oxa-2-yl)pyrazol-4-yl]benzamide. LCMS: [M+1]+=615.

[0649]

[0650] Into an 8-mL round-bottom flask, N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-[1-(oxa-2-yl)pyrazol-4-yl]benzamide (100.00 mg, 0.163 mmol, 1.00 equiv), DCM (2.00 mL), CF3COOH (79.71 mg, 0.813 mmol, 5.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting solution was diluted with 10 mL of H2O, and the pH value of the solution was adjusted to 7-8 with NaHCO3 (1 mol / L). The resulting solution was extracted with 3×10 mL of ethyl acetate, and the organic layers were combined and concentrated. The crude product was purified by preparative HPLC under the following conditions: chromatographic column: HPHC18, 50×3.0 mm, 2.6 um; mobile phase A: water / 0.05% NH3.H2O, mobile phase B: acetonitrile; flow rate: 1.2 mL / min; gradient: from 5% B to 100% B in 1.1 minutes, maintained for 0.7 minutes), detector, UV 254 nm. 8.6 mg (13.20%) of white solid N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-4-yl)benzamide was obtained. LCMS: [M+1] + =401. 1H-NMR: (300MHz, methanol-d4, ppm): δ13.01(s,1H),11.35(s,1H),10.40(s,1H),8.52( d,J=1.1Hz,1H),8.21(d,J=7.3Hz,3H),8.06(d,J=8.4Hz,2H),7.79–7.70(m,2H), 6.37(s,1H),4.01(d,J=13.9Hz,1H),3.40(d,J=13.8Hz,1H),2.88(s,1H),2.43(m ,1H),2.20(m,1H),1.92(m,1H),1.64(s,2H),1.37(s,1H),1.11(d,J=6.0Hz,3H).

[0651] Preparation of Example 43

[0652]

[0653] To an 8-mL glass bottle, 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 104.93 mg, 0.291 mmol, 1.00 equiv), pyridine (2.10 mL), 2-fluoro-4-(1H-pyrazol-3-yl)benzoic acid (prepared according to step 2 of Example 43 above, 60.00 mg, 0.291 mmol, 1.00 equiv), and EDCI (83.68 mg, 0.437 mmol, 1.50 equiv) were added. The resulting solution was stirred at 50° C. in an oil bath for 6 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 15 mL of H2O, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 160 mg (81.41%) of 2-fluoro-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolidin[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-3-yl)benzamide as a brown oil. LCMS: [M+H]+=549.

[0654]

[0655] To an 8-mL glass bottle, 2-fluoro-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-3-yl)benzamide (160.00 mg, 0.292 mmol, 1 eq), DCM (2.00 mL), CF3COOH (2.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated in vacuo, and the pH of the solution was adjusted to 8 with Et2NH. The crude product (90 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 36% to 59% in 7 minutes); detector, UV 254nm. 25.8 mg (21.14%) of light yellow solid 2-fluoro-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1H-pyrazol-3-yl)benzamide was obtained. LCMS: [M+H] + =419. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.53 (d, J=1.0Hz, 1H), 8.31 (s, 1H), 8.02 (t, J= 8.0Hz,1H),7.76(d,J=12.2Hz,3H),6.85(d,J=2.4Hz,1H),6.54(s,1H),4.17( d,J=14.0Hz,1H),3.60(d,J=30.3Hz,1H),3.06(s,1H),2.59(s,1H),2.42(d,J =9.4Hz,1H),1.77(d,J=8.1Hz,2H),1.61–1.48(m,1H),1.25(d,J=6.1Hz,3H). 19 F-NMR: (300 MHz, methanol-d4, ppm) δ-115.077.

[0656] Preparation of Example 53

[0657]

[0658] To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 3-cyclopropyl-1,2-benzoxazole-5-carboxylic acid (54.10 mg, 0.266 mmol, 1.20 equiv), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (amine D, 80.00 mg, 0.222 mmol, 1.00 equiv), EDCI (63.80 mg, 0.333 mmol, 1.5 equiv), pyridine (3.00 mL) were added. The resulting solution was stirred at 25 ° C for 12 hours, and then the reaction was quenched by adding 15 mL of water / ice. The resulting solution was extracted with 3×10 mL of ethyl acetate, the organic layers were combined, and the resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated to give 100 mg (crude) of 3-cyclopropyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl])methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-5-carboxamide as a brown oil. LCMS: [M+1]+=546.

[0659]

[0660] Into a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 3-cyclopropyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-5-carboxamide (100.00 mg, 0.183 mmol, 1.00 equiv), CF3COOH (2.00 mL), DCM (2.00 mL) were added. The resulting solution was stirred at 25° C. for 16 hours, and the resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3.H2O) and acetonitrile (Phase B from 41% to 66% in 7 minutes); detector, UV 254nm. 24mg (31.52%) of light yellow solid 3-cyclopropyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2-benzoxazole-5-carboxamide was obtained. LCMS: [M+1] +=416. H-NMR: (300MHz, methanol-d4, ppm): δ8.57(s,1H),8.51(s,1H),8.26(d,J=6.9Hz,1H),8.20(s,1H)7.73(d,J=8.7Hz,1H),6.53(s,1H),4.15(d,J=1 3.8Hz,1H),3.54(d,J=13.8Hz,1H),3.05(s,1H),2.57(s,1H),2.46-2.33(m,2H),2.04(s,1H),1.77(s,2H),1.52(s,2H),1.28–1.22(m,7H).

[0661] The following Examples in Table L were prepared in a similar manner to Example 53 above using amine D and appropriate reagents and conditions.

[0662] Table L

[0663]

[0664]

[0665] Preparation of Example 69

[0666]

[0667] To an 8-mL round-bottom flask, 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-indole-6-carboxamide (Example 61, 40.00 mg, 0.103 mmol, 1.00 equiv), hydrogen chloride (1.00 mL), DMSO (2.00 mL) were added. H2O (1.00 mL) was then added dropwise over 5 minutes with stirring at ℃, and the resulting solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated, and the resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 3×10 mL of dichloromethane, and the organic layers were combined and concentrated. The crude product was purified by preparative HPLC under the following conditions: chromatographic column: HPHC18, 50×3.0 mm, 2.6 um; mobile phase A: water / 0.05% NH3.H2O, mobile phase B: acetonitrile; flow rate: 1.2 mL / min; gradient: from 5% B to 100% B in 1.1 minutes, maintained for 0.7 minutes), detector, UV 254 nm. This gave 12.5 mg (30.01%) of white solid 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-2-oxo-1,3-indoline-6-carboxamide. LCMS: [M+1] + =404.1 H-NMR: (300MHz, methanol-d4, ppm): δ8.54(d,J=1.0Hz,1H),8.19(d,J=1.0Hz,1H ),7.70(dd,J=7.7,1.7Hz,1H),7.54–7.41(m,2H),6.52(s,1H),4.14(d,J=1 4.0Hz,1H),3.53(d,J=13.9Hz,1H),3.04(s,1H),2.59–2.48(m,1H),2.37( m,1H),2.11–1.96(m,1H),1.75(m,2H),1.50(s,3H),1.23(d,J=6.1Hz,3H).

[0668] Preparation of Example 87

[0669]

[0670] To an 8-mL sealed tube, tert-butyl N-[1-methyl-6-[(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)carbamoyl]indazol-3-yl]carbamate (200.00 mg, 0.316 mmol, 1.00 equiv), DCM (5.00 mL), ZnBr2 (213.18 mg, 0.947 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, then the reaction was quenched by adding 20 mL of water, and the pH of the solution was adjusted to 8 with NaHCO3(aq). The solid was filtered, and the resulting solution was extracted with 2×30 mL of ethyl acetate, and the organic layers were combined and concentrated. 156 mg (crude) of brown solid 3-amino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide was obtained. LCMS: [M+H]=534.

[0671]

[0672] To a 50-mL round-bottom flask was added 3-amino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide (150.00 mg, 0.281 mmol, 1.00 equiv), acetic acid (20.25 mg, 0.337 mmol, 1.20 equiv), DMF (10.00 mL), HATU (160.28 mg, 0.422 mmol, 1.50 equiv). The resulting solution was stirred at room temperature for 6 hours and then quenched by adding 20 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated to obtain 200 mg (crude) of brown solid 3-acetylamino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide. LCMS: [M+H]=576.

[0673]

[0674] To a 50-mL round-bottom flask, 3-acetylamino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide (200.00 mg, 1 eq., crude), CF3COOH (10.00 mL), and DCM (10.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated. The reaction was then quenched by adding 10 mL of water. The pH of the solution was adjusted to 9 with NaHCO3(aq). The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The crude product (110 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Shield RP18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 19% to 44% in 7 minutes); detector, UV 254nm. 22.4 mg (18% in two steps) of light brown solid 3-acetylamino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide was obtained. LCMS: [M+H]=446. 1H-NMR (300MHz, methanol-d4, ppm): δ8.56 (d, J=1.0Hz, 1H), 8.26–8.16 (m, 2H), 7.96 (d, J=8.6Hz, 1H),7.73(dd,J=8.6,1.4Hz,1H),6.52(s,1H),4.14(d,J=14.3Hz,1H),4.11(s,3H),3.53(d ,J=14.0Hz,1H),3.11-2.98(m,1H),2.63-2.46(m,1H),2.44-2.31(m,1H),2.26(s,3H),2. 13-1.98(m,1H),1.77(s,2H),1.86–1.68(m,1H),1.59–1.41(m,1H),1.23(d,J=6.1Hz,3H).

[0675] Preparation of Example 94

[0676]

[0677] To a 50-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added methoxyacetaldehyde (51.41 mg, 0.692 mmol, 4.00 equiv), 3-amino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide (Example 87, Step 2, 70.00 mg, 0.173 mmol, 1.00 equiv), DCE (5.00 mL), NaBH(AcO)3 (367.69 mg, 1.730 mmol, 10.00 equiv). The resulting solution was stirred at room temperature for 12 hours, and then the reaction was quenched by adding 10 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane, and the organic layers were combined and concentrated. The crude product (40 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge ShieldRP18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 20% to 45% in 7 minutes); detector, UV 254nm. 9.4 mg (11.74%) of light brown solid 3-[(2-methoxyethyl)amino]-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide was obtained. LCMS: [M+H]=462. 1H-NMR (300MHz, methanol-d4, ppm): δ8.56(d,J=1.0Hz,1H),8.23(t,J=1.0Hz,1H),8.02–7.95(m,1H),7.83(dd,J =8.4,0.8Hz,1H),7.57(dd,J=8.4,1.5Hz,1H),6.52(s,1H),4.14(d,J=13.8Hz,1H),3.92(s,3H),3.70(t,J =5.5Hz,2H),3.62-3.48(m,3H),3.43(s,3H),3.05(t,J=6.7Hz,1H),2.60-2.48(m,1H),2.37(q,J=9.0Hz, 1H), 2.12-1.99 (m, 1H), 1.77 (dd, J=11.1, 5.7Hz, 2H), 1.52 (dd, J=17.3, 9.9Hz, 1H), 1.23 (d, J=6.1Hz, 3H).

[0678] Preparation of Example 95

[0679]

[0680] To a 50-mL round-bottom flask was added 3-amino-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide (Example 87, Step 1, 95 mg, 0.178 mmol, 1.00 equiv), 1-ethoxy-2,2-difluoroethanol (44.89 mg, 0.000 mmol, 2.00 equiv), DCM (6.00 mL), and CF3COOH (40.59 mg, 0.356 mmol, 2.00 equiv). NaBH(AcO)3 (377.22 mg, 1.780 mmol, 10.00 equiv) was then added in portions at 0°C, and the resulting solution was stirred at 0°C for 1 hour, then quenched by adding 10 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated to give 120 mg (crude) of brown solid 3-[(2,2-difluoroethyl)amino]-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide. LCMS: [M+H]=598.

[0681]

[0682] To an 8-mL sealed tube, 3-[(2,2-difluoroethyl)amino]-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide (120.00 mg), CF3COOH (1.00 mL), and DCM (1.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated. The pH value of the solution was adjusted to 8 with NaHCO3 (aqueous solution). The resulting solution was extracted with 2×20 mL of ethyl acetate, and the organic layers were combined and concentrated. The crude product (100 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Shield RP18 OBD column, 5um, 19×150 mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (phase B from 26% to 50% in 7 minutes); detector, UV 254 nm. 19.1 mg (23% in two steps) of light brown solid 3-[(2,2-difluoroethyl)amino]-1-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-6-carboxamide was obtained. LCMS: [M+H]=468. 1 H-NMR (300MHz, methanol-d4, ppm): δ8.55(d,J=1.0Hz,1H),8.23(t,J=1.0Hz,1H),7.99(t,J=1.1Hz,1H),7.8 2(dd,J=8.4,0.8Hz,1H),7.58(dd,J=8.5,1.4Hz,1H),6.52(s,1H),6.14(t,J=4.4Hz,1H),4.14(d,J=13 .9Hz,1H),3.93(s,3H),3.84-3.67(m,2H),3.53(d,J=13.9Hz,1H),3.10-2.98(m,1H),2.61-2.47(m,1 H),2.43-2.29(m,1H),2.13-1.95(m,1H),1.85-1.68(m,2H),1.58-1.41(m,1H),1.23(d,J=6.1Hz,3H). 19 F-NMR (PH-PUK): (300 MHz, methanol-d4, ppm): 124.1-124.2 (s, 2F).

[0683] Preparation of Example 99

[0684]

[0685] To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 3-methylimidazo[1,5-a]pyridine-7-carboxylic acid (80.00 mg, 0.454 mmol, 1.00 equiv), pyridine (4.00 mL), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-amine (163.74 mg, 0.454 mmol, 1.00 equiv), EDCI (130.58 mg, 0.681 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O, extracted with 3×10 mL of ethyl acetate, the organic layers were combined, and the resulting mixture was washed with 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 100 mg (42.5%) of 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolidin[3,2-c]pyridin-6-yl)imidazo[1,5-a]pyridine-7-carboxamide as a brown oil. LCMS: [M+H]+=519.

[0686]

[0687] To a 50-mL round-bottom flask, 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)imidazo[1,5-a]pyridine-7-carboxamide (100.00 mg, 1 eq), DCM (3.00 mL), CF3COOH (3.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 4 mL of DMF. The pH of the solution was adjusted to 8 with NH3 / H2O. The crude product (80 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Shield RP18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 25% to 45% in 7 minutes); detector, UV 254nm. 31.3 mg (41.80%) of white solid 3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)imidazo[1,5-a]pyridine-7-carboxamide was obtained. LCMS: [M+H] + =389. 1H-NMR: (300MHz, methanol-d4, ppm) δ8.56(d,J=1.0Hz,1H),8.30(t,J=1.5Hz,1H),8.18(t,J=1.0Hz ,1H),8.15–8.07(m,1H),7.62(d,J=0.9Hz,1H),7.25(dd,J=7.5,1.8Hz,1H),6.53(s,1H),4. 16(d,J=13.9Hz,1H),3.57(d,J=13.8Hz,1H),3.11–3.00(m,1H),2.72(s,3H),2.59(m,1H),2 .41(m,1H),2.15–1.97(m,1H),1.83–1.70(m,2H),1.60–1.42(m,1H),1.24(d,J=6.1Hz,3H).

[0688] Preparation of Example 41

[0689]

[0690] Step 1: In a 100-mL round-bottom flask, 3-bromo-1H-pyrazole (1.50 g, 10.206 mmol, 1.00 equiv), DCM (30.00 mL), dihydropyran (1.29 g, 15.336 mmol, 1.50 equiv), TsOH (0.05 g, 0.510 mmol, 0.05 equiv) were added. The resulting solution was stirred overnight at 80° C. in an oil bath, and the resulting solution was diluted with 50 mL of NaHCO 3 (5%), extracted with 3×30 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2 g (84.8%) of 3-bromo-1-(oxa-2-yl)pyrazole as a brown oil. LCMS: [M+H]+=231.

[0691] Step 2: Into a 40-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (0.86 g, 4.327 mmol, 1.00 equiv), dioxane (12.00 mL), H2O (12.00 mL), 3-bromo-1-(oxa-2-yl)pyrazole (1.00 g, 4.327 mmol, 1.00 equiv), Na2CO3 (1.38 g, 13.02 mmol, 3.01 equiv), Pd(PPh3)2Cl2 (0.30 g, 0.427 mmol, 0.10 equiv), BINAP (0.54 g, 0.867 mmol, 0.20 equiv) were added. The resulting solution was stirred in an oil bath at 80°C for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 30 mL of H2O, extracted with 2×20 mL of ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to 3 with HCl (3 mol / L). The solid was collected by filtration to give 1 g (62.38%) of 2-fluoro-4-[1-(oxa-2-yl)pyrazol-3-yl]benzoic acid as a white solid. LCMS: [M+H]+=291.

[0692] Step 3: To an 8-mL glass vial purged and maintained with an inert atmosphere of nitrogen was added 2-fluoro-4-[1-(oxa-2-yl)pyrazol-3-yl]benzoic acid (Acid AH, 100.00 mg, 0.344 mmol, 1.00 equiv), DMF (2.50 mL), HATU (157.18 mg, 0.413 mmol, 1.20 equiv), DIEA (89.04 mg, 0.689 mmol, 2.00 equiv), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-b]pyridin-6-amine (Amine E, 124.21 mg, 0.344 mmol, 1.00 equiv). The resulting solution was stirred at room temperature for 16 hours, and the resulting solution was diluted with 15 mL of H2O, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 4×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 200 mg (76.18%) of brown solid 2-fluoro-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-b]pyridin-6-yl)-4-[1-(oxa-2-yl)pyrazol-3-yl]benzamide. LCMS: [M+H]+=633.

[0693] Step 4: To an 8-mL glass bottle, 2-fluoro-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-b]pyridin-6-yl)-4-[1-(oxa-2-yl)pyrazol-3-yl]benzamide (200.00 mg, 0.316 mmol, 1.00 equiv), DCM (2.00 mL), CF3COOH (2 mL) were added. The resulting solution was stirred at room temperature for 16 hours, the resulting mixture was concentrated in vacuo, and the pH of the solution was adjusted to 8 with Et2NH. The crude product (100 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 30% to 55% in 7 minutes); detector, UV254nm. 26 mg (19.66%) of white solid 2-fluoro-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]ethyl]-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-(1H-pyrazol-3-yl)benzamide was obtained. LCMS: [M+H] + =419. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.44–8.14(m,2H),7.87(t,J=7.6Hz,1H),7.80( s,1H),7.74(d,J=13.1Hz,2H),6.83(d,J=2.4Hz,1H),6.53(s,1H),4.18(d,J= 13.9Hz,1H),3.58(d,J=14.0Hz,1H),3.09–3.00(m,1H),2.57(m,1H),2.39(m, 1H), 2.14–1.97 (m, 1H), 1.78 (m, 2H), 1.60–1.45 (m, 1H), 1.24 (d, J = 6.1Hz, 3H). 19 F-NMR: (300 MHz, methanol-d4, ppm) δ-115.644.

[0694] Preparation of Example 105

[0695]

[0696] To an 8-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 6-fluoro-3-methyl-1H-indazole-5-carboxylic acid (70.0 mg, 0.36 mmol, 1.0 equiv), pyridine (3.00 mL), 2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-6-amine (83.0 mg, 0.361 mmol, 1.00 equiv), EDCI (103.67 mg, 0.541 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O, extracted with 3×10 mL of ethyl acetate, the organic layers were combined, and the resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 100 mg (51.68%) of 6-fluoro-3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-b]pyridin-6-yl)-1H-indazole-5-carboxamide as an orange solid. LCMS: [M+H]+=537.

[0697]

[0698] To a 50-mL round-bottom flask, 6-fluoro-3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-b]pyridin-6-yl)-1H-indazole-5-carboxamide (100.0 mg, 0.186 mmol, 1.00 equiv), DCM (3.00 mL), CF3COOH (3.00 mL) were added. The resulting solution was stirred at room temperature for 16 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 4 mL of DMF, and the pH of the solution was adjusted to 8 with NH3 / H2O. The crude product (70 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Shield RP18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 26% to 39% in 7 minutes); detector, UV 254nm. 16.6 mg (21.92%) of solid 6-fluoro-3-methyl-N-(2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-indazole-5-carboxamide was obtained. LCMS: [M+H] + =407. 1H-NMR: (300 MHz, methanol-d4, ppm) δ8.48–8.40 (m, 2H), 8.25 (d, J = 6.7 Hz, 1H), 7.32 (d, J = 11.1 Hz, 1H), 6.53 (s, 1H), 4.19 (d, J = 14.0 Hz, 1H), 3.59 (d, J = 14.0 Hz, 1H), 3.07 (s, 1H), 2.62–2.51 (m, 4H), 2.40 (m, 1H), 2.12–1.97 (m, 1H), 1.76 (m, 2H), 1.61–1.42 (m, 1H), 1.24 (d, J = 6.1 Hz, 3H). F-NMR: (300 MHz, methanol-d4, ppm) δ-118.207.

[0699] The following Examples in Table N were prepared in a similar manner to Example 105 above using amine E and appropriate reagents and conditions.

[0700] Table N

[0701]

[0702] Preparation of Example 18

[0703]

[0704] A mixture of 2-fluoro-4-pyrazin-2-yl-benzoic acid (46.56 mg, 213.41 umol, 1.5 eq.), HATU (81.14 mg, 213.41 umol, 1.5 eq.) and TEA (43.19 mg, 426.81 umol, 59.41 uL, 3 eq.) in DMF (3 mL) was degassed and purged 3 times with N2, and after 30 minutes, 5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazin-3-amine (50 mg, 142.27 umol, 1 eq.) was added to the mixture and stirred at 15° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (TFA conditions) to give 2-fluoro-N-[5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazin-3-yl]-4-pyrazin-2-yl-benzamide (15 mg, 20.28 umol, 14.26% yield, 90% purity, TFA) as a yellow solid.

[0705]

[0706] To 2-fluoro-N-[5-[(4-methoxyphenyl)methyl]-6-[[(2S)-2-methylpyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridazin-3-yl]-4-pyrazin-2-yl-benzamide (10 mg, 18.13 umol, 1 eq) in TFA (0.5 mL) was added anisole (196.04 ug, 1.81 umol, 1.97 uL, 0.1 eq) and then the mixture was stirred at 130 ° C. under microwave for 6 hours. The reaction mixture was concentrated under reduced pressure (combined with ET16082-1478) to remove the solvent. The residue was purified by preparative HPLC to give a white solid compound (S)-2-fluoro-N-(6-((2-methylpyrrolidin-1-yl)methyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)-4-(pyrazin-2-yl)benzamide (1.4 mg, 100% purity, HCl). LCMS: [M+H] + =432. 1 H-NMR: (400MHz, DMSO-d6, ppm) δ9.28(s,1H),8.78(s,1H),8.68-8.60(m,2H),8.20- 8.13(m,2H),8.08(t,J=7.83Hz,1H),7.40(s,1H),4.99(d,J=14.33Hz,1H),4.64(br d,J=14.33Hz,1H),3.79-3.63(m,2H),3.42(br d,J=10.58Hz,1H),2.44(br d,J=7.06Hz,1H),2.24-2.13(m,1H),2.11(br s,1H),1.94-1.78(m,1H),1.59(d,J=6.62Hz,3H).

[0707] The following Examples in Table O were prepared in a manner similar to Example 18 above using amine F and appropriate reagents and conditions.

[0708] Table O

[0709]

[0710] Preparation of Example 45

[0711]

[0712] 1-Methylindazole-5-carboxamide (45-2)

[0713] In a 100-mL 3-necked round-bottom flask, 1-methylindazole-5-carboxylic acid (1.80 g, 10.22 mmol, 1.00 equiv), DMF (36.0 mL, 465.183 mmol, 45.53 equiv), HATU (5.83 g, 15.326 mmol, 1.50 equiv), DIEA (3.96 g, 30.65 mmol, 3.00 equiv) were added. The resulting solution was stirred at room temperature for 0.5 h, then NH4Cl (1.09 g, 20.434 mmol, 2.00 equiv) was added to the flask, and the resulting solution was allowed to react at room temperature for another 12 h under stirring. The resulting solution was diluted with 50 mL of H2O, extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 4×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.6 g (89.4%) of 1-methylindazole-5-carboxamide (45-2) as a yellow solid. LCMS: [M+H]+=176.

[0714] 6-Chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde(45-4)

[0715] To a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (45-3, 2.60 g, 14.397 mmol, 1.00 equiv), DMF (78.00 mL), Cs2CO3 (14.07 g, 43.191 mmol, 3.00 equiv) were added. The resulting solution was stirred at 0°C in an ice / salt bath. SEMCl (3.12 g, 18.714 mmol, 1.30 equiv) was added to the flask and the resulting solution was allowed to react for another 4 hours at room temperature with stirring. The resulting solution was diluted with 70 mL of ethyl acetate. The solid was filtered off. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 4×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 2.5 g (55.9%) of 6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde (45-2) as a light brown solid. LCMS: [M+H]+=311.

[0716] N-(2-Formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1-methylindazole-5-carboxamide (45-5)

[0717] To a 100-mL 3-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere were added 6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde (45-4, 2.40 g, 7.721 mmol, 1.00 equiv), dioxane (36.00 mL), 1-methylindazole-5-carboxamide (45-2, 1487.87 mg, 0.000 mmol, 1.10 equiv), cesium carbonate (7570.06 mg, 23.163 mmol, 3.00 equiv), Pd2(dba)3 (707.01 mg, 0.772 mmol, 0.10 equiv), and Xantphos (893.48 mg, 1.544 mmol, 0.20 equiv). The resulting solution was stirred at 110° C. in an oil bath for 5 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 50 mL of H2O, extracted with 3×30 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give 1.8 g of a pale yellow solid N-(2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1-methylindazole-5-carboxamide (45-5). LCMS: [M+H]+=450.

[0718] 1-Methyl-N-(2-[[(2R)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide (45-6)

[0719] To an 8-mL glass bottle, N-(2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1-methylindazole-5-carboxamide (45-5, 150 mg, 0.334 mmol, 1.00 equiv), DCM (3.00 mL, 47.190 mmol, 141.44 equiv), (2R)-2-methylazetidine hydrochloride (43.07 mg, 0.401 mmol, 1.20 equiv), acetic acid (2.00 mg, 0.033 mmol, 0.10 equiv) were added. The resulting solution was stirred at room temperature for 1 hour. NaBH(OAc)3 (106.07 mg, 0.501 mmol, 1.50 equiv) was added to the glass bottle, and the resulting solution was stirred at room temperature for 11 hours. The resulting solution was diluted with 15 mL of H2O, extracted with 3×10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 160 mg (68.05%) of yellow solid 1-methyl-N-(2-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide (45-6). LCMS: [M+H]+=505.

[0720] 1-Methyl-N-(2-[[(2R)-2-methylazetidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide (Example 45)

[0721] To an 8-mL glass bottle, 1-methyl-N-(2-[[(2R)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide (160.00 mg, 0.317 mmol, 1.00 equiv), DCM (1.60 mL), CF3COOH (1.60 mL) were added. The resulting solution was stirred at room temperature for 12 hours, the resulting mixture was concentrated in vacuo, and the pH of the solution was adjusted to 8 with Et2NH. The crude product (100 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 27% to 45% in 7 minutes); detector, UV 254nm, to obtain 39.7 mg (33.44%) of white solid 1-methyl-N-(2-[[(2R)-2-methylazetidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)indazole-5-carboxamide (Example 45). LCMS: [M+H] + =375. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.59–8.47(m,2H),8.25–8.17(m,2H),8.08(dd,J=8.9,1.7Hz,1H),7.71(m,1H),6.51(d,J=1.0Hz,1H),4.15(s,3H ),3.84(d,J=13.6Hz,1H),3.72(d,J=13.7Hz,1H),3.50–3.33(m,2H),3. 12–2.98(m,1H),2.23–2.08(m,1H),1.85(m,1H),1.13(d,J=6.2Hz,3H).

[0722] Preparation of Example 46

[0723]

[0724] Prepared in the same manner as Example 45, but with the above modifications. LCMS: [M+H] + =403. 1H-NMR: (300MHz, methanol-d4, ppm) δ8.53 (dd, J=13.7, 1.3Hz, 2H), 8.24–8.17 (m, 2H), 8.08 (dd, J=8.9, 1. 7Hz, 1H), 7.71 (d, J = 8.9Hz, 1H), 6.48 (s, 1H), 4.80 (s, 4H), 4.15 (s, 3H), 3.75 (s, 2H), 3.53 (s, 4H).

[0725] Preparation of Example 104

[0726]

[0727] Prepared from N-(2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-1-methyl-1H-indazole-6-carboxamide (prepared according to Example 45 from 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde and the corresponding carboxamide) and 7-oxa-2-azaspiro[3.5]nonane. LCMS: [M+H] + =431. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.57 (s, 1H), 8.26 (d, J = 10.3Hz, 2H), 8.12 (s, 1H), 7.92 (d, J = 8.5Hz, 1H), 7.78 (d, J=8.5Hz,1H),6.52(s,1H),4.19(s,3H),3.86(s,2H),3.62(t,J=4.8Hz,4H),3.26(s,4H),1.79(t,J=5.2Hz,4H).

[0728] Preparation of Example 73

[0729]

[0730] Step 1: To a 20-mL glass bottle purged and maintained with a nitrogen inert atmosphere, 6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde (350.00 mg, 1.126 mmol, 1.00 equiv), DCM (7.00 mL), (2S)-2-methylazetidine hydrochloride (145.35 mg, 1.351 mmol, 1.20 equiv), AcOH (6.76 mg, 0.113 mmol, 0.10 equiv) were added. The resulting solution was stirred at room temperature for 1 hour, and then NaBH(OAc)3 (357.95 mg, 1.689 mmol, 1.50 equiv) was added to the glass bottle. The resulting solution was stirred at room temperature for 12 hours. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:5) to give 270 mg (65.52%) of (2S)-1-[(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)methyl]-2-methylazetidine as a brown oil. LCMS: [M+H]+=366.

[0731]

[0732] Step 2: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen was added (2S)-1-[(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-2-yl)methyl]-2-methylazetidine (270.00 mg, 0.738 mmol, 1.00 equiv), toluene (15.00 mL), benzylamine-phenyl (267.41 mg, 1.475 mmol, 2.00 equiv), Pd2(dba)3 (67.56 mg, 0.074 mmol, 0.10 equiv), Cs2CO3 (721.12 mg, 2.213 mmol, 3.00 equiv). The resulting solution was stirred in an oil bath at 110° C. for 5 hours, and the resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1) to obtain 180 mg (47.77%) of brown oily N-(2-[[(2S)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2)-c]pyridin-6-yl)-1,1-benzophenone imine. LCMS: [M+H]+=511.

[0733]

[0734] Step 3: In a 100-mL round-bottom flask, N-(2-[[(2S)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy)]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1,1-benzophenone imine (180.00 mg, 0.352 mmol, 1.00 equiv), THF (4.00 mL), H2O (2.00 mL), HCl (0.5 M) (2.00 mL) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 10 mL of H2O, extracted with 2×10 mL of ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to 8 with NaHCO3. The solid was collected by filtration to give 100 mg (54.81%) of 2-[[(2S)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy)]methyl]pyrrolo[3,2-c]pyridin-6-amine as a yellow solid. LCMS: [M+H]+=347.

[0735]

[0736] Step 4: To an 8-mL glass bottle, 2-[[(2S)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy)]methyl]pyrrolo[3,2-c]pyridin-6-amine (100.00 mg, 0.289 mmol, 1.00 equiv), pyridine (2.50 mL), 3-cyclopropyl-1-(oxa-2-yl)indazole-5-carboxylic acid (82.62 mg, 0.289 mmol, 1.00 equiv), EDCI (82.98 mg, 0.434 mmol, 1.50 equiv) were added. The resulting solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated in vacuo, the resulting solution was diluted with 10 mL of H2O, extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 150 mg (62.35%) of 3-cyclopropyl-N-(2-[[(2S)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy)]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1-(oxa-2-yl)indazole-5-carboxamide as a brown oil. LCMS: [M+H]+=615.

[0737]

[0738] Step 5: In a 100-mL round-bottom flask, 3-cyclopropyl-N-(2-[[(2S)-2-methylazetidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-1-(oxa-2-yl)indazole-5-carboxamide (150.00 mg, 0.244 mmol, 1.00 equiv), DCM (3.00 mL), and CF3COOH (3.00 mL) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 3 mL of DMF. The pH of the solution was adjusted to 8 with NH3﹒H2O. The crude product (100 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Prep C18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 18% to 39% in 7 minutes); detector, UV 254nm. 23.3 mg (23.85%) of white solid 3-cyclopropyl-N-(2-[[(2S)-2-methylazetidin-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-1H-indazole-5-carboxamide was obtained. LCMS: [M+H] + =401. 1 H-NMR: (300MHz, methanol-d4, ppm) δ8.55 (t, J = 1.2 Hz, 2H), 8.23 ​​(d, J = 1.0 Hz, 1H), 8. 03(dd,J=8.8,1.7Hz,1H),7.58(dd,J=8.8,0.8Hz,1H),6.51(d,J=0.9Hz,1H), 3.85(d,J=13.6Hz,1H),3.72(d,J=13.7Hz,1H),3.53–3.33(m,2H),3.13–2.98 (m,1H),2.45–2.30(m,1H),2.23–2.08(m,1H),1.85(m,1H),1.17–1.08(m,7H).

[0739] Preparation of Example 107

[0740]

[0741] Step 1: 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (1.0 g, 5.54 mmol, 1.00 equiv), DMF (50.00 mL) and Selectfluor (3.00 g, 8.468 mmol, 1.53 equiv) were added to a 250 mL glass bottle at room temperature. The resulting mixture was stirred at room temperature overnight, and the resulting mixture was diluted with EtOAc (250 mL). Then 250 mL of NaHCO3 (saturated aqueous solution) was added, the resulting mixture was separated and the aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to give 6-chloro-3-fluoro-1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (100 mg, 9.0%) as a yellow solid. LCMS: [M+1]+=199.

[0742]

[0743] Step 2: 6-Chloro-3-fluoro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (100.0 mg, 0.504 mmol, 1.00 equiv), DMF (10.00 mL), Cs2CO3 (328.15 mg, 1.00 mmol, 2.00 equiv) and [2-(chloromethoxy)ethyl]trimethylsilane (125.93 mg, 0.756 mmol, 1.50 equiv) were added to a 20 mL glass bottle at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, and the reaction was quenched with NaHCO3 (saturated) at room temperature. The resulting mixture was extracted with EtOAc (3×40 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, A: water (0.5% TFA); B: acetonitrile, 40% to 85% B gradient in 30 minutes; detector, UV 254nm. 6-chloro-3-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde (90 mg, 54.35%) was obtained as a yellow oil. LCMS: [M+1]+=329.

[0744]

[0745] Step 3: 3-methyl-1-(oxa-2-yl)indazole-5-carboxylic acid (100.0 mg, 0.384 mmol, 1.00 equiv), NH4Cl (61.7 mg, 1.15 mmol, 3.00 equiv), DMF (2.00 mL), DIEA (248.26 mg, 1.92 mmol, 5 equiv) and HATU (219.12 mg, 0.58 mmol, 1.5 equiv) were added to an 8 mL glass bottle at room temperature. The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (30 mL), washed with 2×10 mL of brine, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1:2) to give 3-methyl-1-(oxa-2-yl)indazole-5-carboxamide (80 mg, 80.3%) as a light brown solid. LCMS: [M+1]+=260.

[0746]

[0747] Step 4: 6-Chloro-3-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde (90.0 mg, 0.274 mmol, 1.00 equiv), 3-methyl-1-(oxa-2-yl)indazole-5-carboxamide (80.00 mg, 0.309 mmol, 1.13 equiv), dioxane (3.00 mL), Pd2(dba)3 (25.06 mg, 0.027 mmol, 0.10 equiv), XantPhos (31.67 mg, 0.055 mmol, 0.20 equiv) and Cs2CO3 (267.52 mg, 0.822 mmol, 3.00 equiv) were added to an 8 mL glass bottle at room temperature. Nitrogen was bubbled slowly into the solution and the resulting mixture was stirred at 100° C. under nitrogen atmosphere for 6 hours. The resulting mixture was diluted with EtOAc (50 mL), the resulting mixture was filtered, and the filter cake was washed with EtOAc (1×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give a yellow solid N-(3-fluoro-2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-(oxa-2-yl)indazole-5-carboxamide (75 mg, 38.7%). LCMS: [M+1]+=552.

[0748]

[0749] Step 5: Into an 8 mL glass vial, N-(3-fluoro-2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-(oxa-2-yl)indazole-5-carboxamide (75.0 mg, 0.106 mmol, 1.00 equiv, 78%), DCE (4.00 mL), AcOH (6.37 mg, 0.106 mmol, 1.00 equiv) and (2S)-2-methylpyrrolidine (18.06 mg, 0.212 mmol, 2.00 equiv) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. NaBH(OAc)3 (67.42 mg, 0.318 mmol, 3.00 equiv) was added to the above mixture. The resulting mixture was stirred at room temperature for 16 hours and the reaction was quenched with NaHCO3 (saturated) at room temperature. The resulting mixture was extracted with DCM (3×20 mL), and the combined organic layers were washed with brine (1×130 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a yellow oily N-(3-fluoro-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-(oxa-2-yl)indazole-5-carboxamide (60 mg, 64%). The crude product was used directly in the next step without further purification. LCMS: [M+1] + =621.

[0750]

[0751] Step 6: To an 8 mL glass vial was added N-(3-fluoro-2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-(oxa-2-yl)indazole-5-carboxamide (60.00 mg, 0.068 mmol, 1.00 equiv, 70%), DCM (2.00 mL) and TFA (2.00 mL) at room temperature. The resulting mixture was stirred at room temperature overnight and the resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (5 mL) and the mixture was basified to pH 10 with ammonium hydroxide. The crude product was purified by preparative HPLC under the following conditions (chromatographic column: X-BridgeShield RP18 OBD column, 5um, 19×150mm; mobile phase A: water (0.05% NH3H2O), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: from 33% B to 50% B, 50% B in 7 minutes; wavelength: 220nm) to obtain a white solid N-(3-fluoro-2-[[(2S)-2-methylpyrrolidin-1)-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1H-indazole-5-carboxamide (17.2mg, 62.55%). LCMS: [M+1] + =407. 1 H-NMR: (400MHz, DMSO-d6, ppm) δ12.87(s,1H),11.25(s,1H),10.53(s,1H),8.65(s,1H ),8.60(s,1H),8.25(s,1H),8.01(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),3.96(d,J=14 Hz,1H),3.50(d,J=14Hz,1H),2.87(s,1H),2.57(s,3H),2.43(d,J=6.8Hz,1H),2.24(q ,J=8.8Hz,1H),2.00–1.86(m,1H),1.64-1.62(m,2H),1.36(s,1H),1.12(d,J=6Hz,3H). 19 F-NMR (PH-PUK): (376MHz, DMSO-d6, ppm) δ-176.66.ANAL_SFC: 100%ee.

[0752] Preparation of Example 108

[0753]

[0754] Step 1: To a 100-mL 3-neck round bottom flask purged and maintained with a nitrogen inert atmosphere, 5-bromo-3-methyl-1H-indazole (1.20 g, 5.68 mmol, 1.00 equiv), DMF (15.0 mL), Cs2CO3 (4.63 g, 0.015 mmol, 2.50 equiv) and SEMCl (1.23 g, 7.38 mmol, 1.30 equiv) were added. The resulting solution was stirred at room temperature for 10 hours, and the resulting solution was diluted with 50 mL of ice / water. The resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / hexane (1:5) to obtain 1 g (51.53%) of 5-bromo-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole as a light yellow oil. LCMS: [M+H] + =341.

[0755]

[0756] Step 2: In a 50-mL pressure reactor, 5-bromo-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (1.00 g, 2.930 mmol, 1.00 equiv), CH3CN (20.00 mL), PdCl2 (51.95 mg, 0.293 mmol, 0.10 equiv), XantPhos (339.04 mg, 0.586 mmol, 0.20 equiv), NH4HCO3 (2.32 g, 29.3 mmol, 10.0 equiv), CO (10 atm) were added. The resulting solution was stirred in an oil bath at 120°C for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×20 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1 / 1) to obtain 270 mg (30%) of yellow semi-solid 3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide. LCMS: [M+H] + =30.6.

[0757]

[0758] Step 3: To a 40-mL glass bottle purged and maintained with an inert atmosphere of nitrogen was added 3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide (270.0 mg, 0.884 mmol, 1.00 equiv), dioxane (10.0 mL), 6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine-2-carbaldehyde (274.77 mg, 0.884 mmol, 1.00 equiv), Xantphos (102.29 mg, 0.177 mmol, 0.20 equiv), Pd2(dba)3 (80.94 mg, 0.088 mmol, 0.10 equiv) and Cs2CO3 (864.0 mg, 2.65 mmol, 3.00 equiv). The resulting solution was stirred at 100 ° C. in an oil bath for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×20 mL of brine, and the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1 / 1) to give 300 mg of yellow oily N-(2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide. LCMS: [M+H] + =580.

[0759]

[0760] Step 4: To an 8-mL glass vial purged and maintained with an inert atmosphere of nitrogen was added N-(2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide (150.0 mg, 0.259 mmol, 1.00 equiv), DCE (3.00 mL), 7,7-difluoro-2-azaspiro[3.5]nonane; trifluoroacetaldehyde (134.11 mg, 0.518 mmol, 2.00 equiv) and AcOH (1.55 mg, 0.026 mmol, 0.10 equiv). The resulting solution was stirred at room temperature for 30 minutes, and then NaBH(OAc)3 (109.7 mg, 0.517 mmol, 2.00 equiv) was added to the glass vial. The resulting solution was allowed to react for another 16 hours at room temperature with stirring, and the resulting solution was diluted with 20 mL of NaHCO3 (5%). The resulting solution was extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2×mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 120 mg (63.98%) of yellow oily N-[2-([7,7-difluoro-2-azaspiro[3.5]non-2-yl]methyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl]-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide. LCMS: [M+H] + =725.

[0761]

[0762] Procedure: To a 50-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (320.0 mg, 1.337 mmol, 1.00 equiv), DCM (25.0 mL), DAST (1.08 g, 6.700 mmol, 5.01 equiv) were added. The resulting solution was stirred at room temperature for 20 hours in a water / ice bath, the resulting solution was diluted with 20 mL NaHCO3, extracted with 3×20 mL dichloromethane, and the organic layers were combined. The resulting mixture was washed with 2×20 mL brine, the mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 320 mg (91.6%) of solid tert-butyl 7,7-difluoro-2-azaspiro [3.5] nonane-2-carboxylate. 1H-NMR: (400MHz, DMSO-d6, ppm) δ3.54–3.42(m,1H),3.33–3.23(m,3H),2.23(d,J=4.6Hz,1H),1.87(m,3H),1.75(m,2H),1.38(m,11H). 19 F-NMR: (400MHz, DMSO-d6, ppm) δ-101.481.

[0763]

[0764] Step 7: To a 50-mL round-bottom flask, tert-butyl 7,7-difluoro-2-azaspiro[3.5]nonane-2-carboxylate (320.0 mg, 1 eq.), DCM (5.0 mL), CF3COOH (5.0 mL) were added. The resulting solution was stirred at room temperature for 10 hours. The resulting mixture was concentrated in vacuo. The crude product was purified by slurry from Et2O to give 150 mg (47%) of white solid 7,7-difluoro-2-azaspiro[3.5]nonane; trifluoroacetaldehyde. 1 H-NMR: (300MHz, DMSO-d6, ppm) δ8.76 (s, 2H), 3.73-3.65 (m, 4H), 2.25 (d, J = 18.0Hz, 1H), 1.94–1.84 (m, 7H).

[0765]

[0766] Step 5: In a 50-mL round-bottom flask, N-[2-([7,7-difluoro-2-azaspiro[3.5]non-2-yl]methyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl]-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide (120.00 mg), DCM (3.00 mL), CF3COOH (3.00 mL) were added. The resulting solution was stirred at room temperature for 12 hours, and the resulting mixture was concentrated in vacuo. The resulting solution was diluted with 4 mL of DMF, and the pH value of the solution was adjusted to 8 with NH3H2O. The crude product (80 mg) was purified by preparative HPLC under the following conditions: chromatographic column, XBridge Shield RP18 OBD column, 5um, 19×150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (Phase B from 20% to 45% in 7 minutes); detector, UV 254nm, to obtain 16.7 mg white solid N-[2-([7,7-difluoro-2-azaspiro[3.5]non-2-yl]methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-3-methyl-1H-indazole-5-carboxamide. LCMS: [M+H] + =465. 1 H-NMR: (300 MHz, methanol-d4, ppm) δ8.54 (m, 1H), 8.48 (m, 1H), 8.20 (s, 1H), 8.04–8.00 (m, 1H), 7.60 (d, J=8.7 Hz, 1H), 6.48 (s, 1H), 3.83 (s, 2H), 3.22 (s, 4H), 2.67 (s, 3H), 1.89-1.82 (m, 8H). 19 F-NMR: (300 MHz, methanol-d4, ppm) δ-99.161.

[0767] Preparation of Example 109

[0768]

[0769] Prepared according to Example 108 using N-(2-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)-3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole-5-carboxamide and 6,6-difluoro-2-azaspiro[3.3]heptane. LCMS: [M+H] + =437. 1H-NMR: (300MHz, methanol-d4, ppm) δ8.53 (m, 1H), 8.48 (m, 1H), 8.19 (s, 1H), 8.05 (dd, J=8.8, 1.8Hz, 1H), 7.60 (d, J= 8.9Hz,1H),6.47(s,1H),3.78(d,J=2.2Hz,2H),3.42(d,J=2.3Hz,4H),2.74-2.70(m,4H),2.66–2.64(m,3H). 19 F-NMR: (300 MHz, methanol-d4, ppm) δ-93.610.

[0770] FRET assay

[0771] The compounds of the present application were tested in the TR-FRET ENL screening assay. TR-FRET (time-resolved fluorescence energy transfer) can be used to quantify the binding of the ENL YEATS domain to crotonylated histone peptides (H3K9cr, aa1-20). Streptavidin-Europium (Eu) chelate binds to the biotinylated peptide, while Anti-6xHIS ULight TMTM Binding to 6xHIS-ENL. When the Eu chelate is excited at 320nm, fluorescence resonance energy transfer (FRET) occurs if Eu and ULight are brought into proximity via ENL binding to the acyl peptide. ULight emission (FRET) is measured at 665nm and normalized to Eu emission at 615nm to reduce well-to-well variability.

[0772] FRET Assay - Protocol 1

[0773] The compounds of the present application were dissolved in DMSO at a concentration of 3 mM and then diluted in assay buffer (50 mM HEPESPH7.0, 150 mM sodium chloride, 0.05% bovine serum albumin (BSA), 0.2% Pluronic F-127) so that the assay contained 1% DMSO. In a white 384 shallow well microplate (Proxiplate-384 Plus, PerkinElmer, 6008280), 150 nL of compound or vehicle (1% DMSO in assay buffer) and 5 uL 30 nM ENL protein (6xHIS ENL YEATS domain, EpiCypher, 15-0069) for high control (HC) wells were combined and incubated at room temperature for 15 minutes. Low control (LC) wells received 5 uL assay buffer instead of ENL protein. Then add 5 μ L 15nM H3K9cr peptide (H3aa1-20, biotinylated; EpiCypher, 12-0099) in the assay buffer and incubate at room temperature for 30 minutes. Finally, add 5 μ L mixture of 45nM Anti-6HIS ULight (PerkinElmer, TRF0105) and 1.5nM streptavidin-europium chelate (PerkinElmer, AD0060), and incubate at room temperature for another 30 minutes. Use PerkinElmer 2104 EnVision (xenon flash lamp excitation, 320nm ± 37.5nm excitation filter, 407nm cut-off dichroic mirror, 615nm ± 4.25 (europium) nm and 665nm ± 3.75nM (ULight) emission filter) to measure TR-FRET signal. Draw compound concentration response curves in duplicate in the concentration range of 0.15nM-30uM. The response minus the LC value at each compound concentration was converted to percent inhibition of the vehicle control response (HC-LC). The relationship between % inhibition and compound concentration was analyzed using a four-parameter logistic equation to estimate the slope of the lower and upper asymptotes, the compound concentration that produced 50% inhibition (IC50 value), and the midpoint position.

[0774] FRET Assay - Protocol 2

[0775] The compounds of the present application were dissolved in DMSO and diluted to 500 μM in assay buffer (50 mM Tris-HCl pH 8.0, 150 mM NaCl, 0.5% casein, and 0.1% NP-40). Compound dilutions were prepared in assay buffer supplemented with 5% DMSO. In a white 384-well Optiplate (PerkinElmer, 6007299), 4 μL of compound and 4 uL 625 nM human ENL YEATS (accession number Q03111; aa1-150; EpiCypher, 15-0069) were mixed and incubated at 23° C. for 15 minutes. Then 4 μL of 25 nM H3K9cr peptide (H3aa1-20, biotinylated; EpiCypher, 12-0099) in assay buffer was added and incubated at 23° C. for 30 minutes. In previous studies (not shown), the optimal concentration for assay development was determined by titration of each binding partner from 1000-1 nM (1:2 dilution). 8 μL of a mixture of 37.5 nM Anti-6HIS ULight (PerkinElmer, TRF0105) and 1.25 nM Streptavidin-Europium Chelate (PerkinElmer, AD0060) was added and incubated at 23°C for 60 min. TR-FRET signals (665 nm signal / 615 nm signal × 10,000) were measured using a PerkinElmer 2104 EnVision (Xenon flash lamp excitation, 320 nm ± 37.5 nm excitation filter, 407 nm cut-off dichroic mirror, 615 nm ± 4.25 (Europium) nm and 665 nm ± 3.75 nM (ULight) emission filters). Each IC50 apparent value was determined by 10-point data curves (in duplicate) to determine upper and lower limits, and the value of the compound that inhibited ≥50% of the signal was calculated. When necessary (to avoid calculation errors in GraphPad Prism), a bottom signal constraint equal to the mean of the lowest signal was applied (maximum inhibition). The results show that these compounds can block the interaction of a group of epigenetic proteins with acylated histones and can be used as inhibitors of these proteins in a wide range of biological contexts.

[0776] Table P

[0777]

[0778]

[0779] Example of analysis by FRET assay - Protocol 2

[0780] Cell assay

[0781] The cell-based assay was used to evaluate the ability of test compounds to reduce cell viability in MV4:11 (MLL-AF4MLL) and K562 cells cultured in IMDM (Iscove's Modified Dulbecco's medium) cell culture medium (Gibco, 12440061) containing 10% FBS. The assay was performed for 12 days, with cells split on days 4 and 8. Compound concentration response curves were plotted repeatedly over a concentration range of 0.15nM-30uM. On day 0, 300nL of compound or vehicle was plated directly into a 96-well cell culture plate (Corning, 3599) with 5000 cells per well in a volume of 100uL. Blank wells received cell culture medium. The plates were incubated at 37°C and 5% CO2 for 4 days. On days 4 and 8, the cells were split and cultured for an additional 4 days, with aliquots of cells removed for CTG readings. For cell splitting, 270 nL of compound or DMSO was added to a new 96-well cell culture plate, to which 90 uL of culture medium and 10 uL of cells from the original assay plate (after mixing) or 100 uL of culture medium (blank well) were added. The above steps were repeated on day 8.

[0782] CellTiter- Homogeneous luminescence assay kit (Promega, G9243) was used to assess cell viability. This quantified ATP, indicating the presence of metabolically active cells. On days 4, 8, and 12, 20ul of the remaining cell suspension was aspirated into a 384-well plate (Corning 3570) containing an equal volume of CellTiter-Glo reagent. The plate was incubated at room temperature for 10 minutes before recording the luminescence signal using an EnVision plate reader (PE, 2104). The resulting data were analyzed as follows:

[0783] Inhibition rate (%) = 100% × (Lum 载体 -Lum 样本 ) / (Lum 载体 -Lum 空白 )

[0784] The vehicle is cells treated with 0.3% DMSO, and the blank is culture medium. IC50 values ​​were calculated by fitting the curve using XLfit (v5.3.1.3): Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*slope)).

[0785] Table Q

[0786]

Claims

1. A compound, which is a compound shown in the following formula I: I in: R 1 Selected from: H, (C 1-6 ) alkyl, aryl (C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkyl, heterocyclic group, heterocyclic group (C 1-6 ) alkyl, (C 1-6 ) alkylamino (C 1-6 ) alkyl, heterocyclic amino (C 1-6 ) alkyl, heterocyclic group (C 1-6 ) alkylamino (C 1-6 ) alkyl, (C 3-12 )cycloalkylamino(C 1-6 ) alkyl, (C 3-12 )cycloalkyl(C 1-6 ) alkylamino (C 1-6 ) alkyl, arylamino (C 1-6 ) alkyl, and aryl (C 1-6 ) alkylamino (C 1-6 )alkyl; R 4 is selected from the group consisting of H, CH3, F and Cl; R 5 selected from 5-membered or 6-membered carbocyclic or heterocyclic rings; bicyclic 5-6 carbocyclic or heterocyclic rings and bicyclic 6-6 carbocyclic or heterocyclic rings, wherein the carbocyclic or heterocyclic rings may be optionally selected from (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halogen, (C 1-6 ) haloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 0-3 H 1-7 )、-CONH(C 0-3 H 1-7 ), -CN, -NH2, -CH2OH, benzyloxy, and one or more groups of a heterocyclic group, wherein the heterocyclic group is optionally substituted by (C 1-6 ) alkyl, (C 1-6 ) substituted by alkoxy, hydroxy, =0 or halogen; R 6 Selected from H, Me, F and Cl.

2. The compound according to claim 1, wherein R 5 is a carbocyclic or heterocyclic ring selected from phenyl, indazole, pyridine, imidazopyridine, pyrazolopyrimidine, imidazopyrazine, triazolopyridine and benzoxazine, or a reduced form thereof, wherein the carbocyclic or heterocyclic ring may be optionally substituted.

3. The compound according to any one of claims 1 to 2, wherein R 1 It's hydrogen.

4. The compound according to claim 1, wherein R 4 It's hydrogen.

5. The compound according to claim 1, wherein R 6 is hydrogen or methyl.

6. The compound according to claim 1, wherein R 5 Selected from optionally substituted pyridine, indazole, pyrazine, pyrazole, thiazole and pyrimidine, substituted by optionally substituted heterocycle, -CN or -SO2NHCH3.

7. The compound according to claim 1, wherein R 5 is selected from (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halogen, (C 1-6 ) haloalkyl, -SO2(C 1-6 ) alkyl, SO2NH(C 0-3 H 1-7 ), -CN, -NH2, -CH2OH, benzyloxy, and one or more groups of a heterocyclic group, wherein the heterocyclic group is optionally substituted by (C 1-6 ) alkyl, (C 1-6 ) is substituted with alkoxy, hydroxy, =0 or halogen.

8. The compound according to claim 7, wherein R 5 is phenyl substituted by fluorine and optionally substituted heterocycle.

9. The compound according to claim 2, wherein R 5 It is an indazole substituted with a methyl group.

10. Use of the compound according to claim 1 in an effective dose in the preparation of a medicament for treating leukemia patients. The use according to claim 10 , wherein the medicament further comprises a BET inhibitor.

12. A compound, which is a compound represented by the following formula: 。 13. A compound, which is a compound represented by the following formula: 。 14. A compound, which is a compound represented by the following formula: 。 15. A compound, which is a compound represented by the following formula: 。 16. A compound, which is a compound represented by the following formula: 。 17. A compound, which is a compound represented by the following formula: 。 18. A compound, which is a compound represented by the following formula: 。 19. A compound, which is a compound represented by the following formula: 。 20. A compound, which is a compound represented by the following formula: 。 21. A compound, which is a compound represented by the following formula: 。

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