阅读说明：本技术 1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚衍生物化合物及其用途 (1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole derivative compound and application thereof ) 是由 张靖 汪翔 杰西卡·D·波多尔 于 2019-08-15 设计创作，主要内容包括：本发明涉及1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚衍生物化合物及其用途。特别地,本发明的化合物具有抗菌活性和/或能够使耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素或β-内酰胺类抗生素和β-内酰胺酶抑制剂的组合物再敏感。本发明还涉及一种生产和使用所述化合物的方法。()

1. A compound having the formula:

wherein

n is an integer of1 to 4;

z, a1, a2, a3, a4, and a5 are each independently 0 or 1, provided that at least one of a 1-a 5 is 1;

Ar¹is phenyl or 6-membered heteroaryl containing a nitrogen atom;

Cyc¹is a 5-, 6-or 7-membered heterocyclic group containing a nitrogen atom, except R^2aAnd R^2bIn addition, the heterocyclic group optionally further contains 1 to 3 additional substituents;

X¹is-C (═ O) -, -C (═ O) -NR⁶-or-SO₂–NH–；

R^1aAnd R^1cEach independently is C₁-C₆An alkylene group;

R^1bis optionally substituted C₁-C₆An alkylene group;

X²is O or NR⁶；

R¹Each independently of the others being halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group;

R^2aand R^2bEach independently hydrogen, halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, - (C)_1-6Alkylene) -heterocyclyl-OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group, or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a cycloalkyl group; and

q is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₃-C₈Cycloalkyl, or optionally substituted heterocycloalkyl.

2. The compound of claim 1, wherein Q is optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted cyclopropyl.

3. The compound of claim 2, wherein Q is selected from:

(a) phenyl optionally having one, two or three substituents, wherein each substituent is independently selected from chloro, trifluoromethoxy, trifluoromethyl, methyl, ethyl, nitro, -NH-C (═ O) -CH₃、–NH–C(＝O)–(CH₂)₂–CO₂H、–NH–C(＝O)–CH₂-CN, bromomethyl, -PO₄(R^x)₂and-CH₂PO₄(R^x)₂Wherein R is^xEach independently is hydrogen or a metal ion;

(b) heteroaryl selected from isoxazolyl, thienyl, thiazolyl, furyl and 1H-pyrazolyl, each of which is optionally substituted with one or two substituents, wherein each substituent is independently selected from halide, C₁-C₆Alkyl and optionally substituted phenyl.

4. The compound of claim 1, wherein n is 0, 1, or 2.

5. The compound of claim 4, wherein n is 1 or 2.

6. The compound of claim 1, wherein R¹Each independently of the others is halogen, hydroxy, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

7. The compound of claim 6, wherein R¹Each independently is chloro, fluoro, methoxy or hydroxy.

8. The compound of claim 1, wherein R^2aIs hydrogen, methyl, hydroxymethyl (HOCH)₂-), (1, 3-dioxaindolin-2-yl) methyl, aminomethyl or a salt thereof, ((3- (trifluoromethyl) benzoyl) oxy) methyl, ((4- (trifluoromethyl) benzoyl) oxy) -methyl, - (CH)₂)_a-NH-C(＝NH)-NH₂Or a salt thereof, 2-hydroxyethyl, 3-hydroxyethyl, 1-hydroxyethyl, (2-hydroxyethyloxy) methyl, (1-pyridinium) methyl, 2- (1-pyridinium) ethyl, 2-aminoethyl, 2-hydroxyethyl, -C (═ O) NHCH₃、–C(＝O)NHCH₂CH₂OH、–CH₂NHC(＝O)CH₂NH₂Or a salt thereof, -CH₂NHCH₂CH₂OH or a salt thereof, -CH₂NHCH₂CH₂NH₂Or a salt thereof, or a (dimethylamino) methyl group, wherein a is 1 or 2.

9. The compound of claim 8, wherein R^2bIs H, and R^2aIs ethyl, isopropyl, trifluoromethyl, cyclopropyl or fluoromethyl; or R^2aAnd R^2bIs methyl; or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a cyclopropyl group.

10. The compound of claim 1, wherein R³Is hydrogen, aminomethyl (H)₂NCH₂-) or a salt thereof, a carboxylic acid methyl ester group (-CO)₂Me), carboxyl group (-CO)₂H) Hydroxymethyl, -CH₂–NH–C(＝NH)–NH₂Or a salt thereof, or an aminomethyl group or a salt thereof.

11. The compound of claim 1, wherein the compound is selected from the group consisting of:

wherein

x is an integer of 0 to 3;

R⁶is C₁-C₆Alkyl, optionally substituted cycloalkyl, heterocyclyl, -OR^aand-NR^bR^c；

n、R¹、R²、R³、R⁴、R^a、R^b、R^cAnd Q is as defined in claim 1; and

a is O or NH.

12. The compound of claim 1, wherein a1, a2, and a4 are 0; and a3 is 1.

13. The compound of claim 13, wherein R^1bis-CH₂CH (OH) -; or a moiety of the formula:

14. the compound of claim 1, wherein formula- (R)^1a)_a1–(X¹)_a2–(R^1b)_a3–(R^1c)_a4–(X²)_a5The parts of (a) and (b) comprise: -CH₂The (R) -or (S) -isomer of CH (OH) -; -C (═ O) -NH-; -C (═ O) -NH-CH₂–；–CH₂C (═ O) -NH-; -C (═ O) -; a methylene group; -C (═ O) CH (NH)₂) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH [ NH (C (═ O) CH₃)]–；–C(＝O)CH(NH₂)CH₂-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (N (C (═ O) CH)₃)₂)CH₂–；–C(＝O)C(＝O)–；–C(＝O)CH(NHC(＝O)CH₃)CH₂-the (R) -or (S) -isomer of (a); -C (═ O) CH (NHC (═ O) CH₃) -the (R) -or (S) -isomer of (a); -C (═ O) CH₂–；–C(＝O)CH(NH₂)CH₂-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (NHC (═ O) CH₃)CH₂-the (R) -or (S) -isomer of (a); the (R) -or (S) -isomer of-C (═ O) ch (oh) -; -C (═ O) C (═ NOH) -; -S (O)₂–NHC(＝O)–；–C(＝O)C(＝NOCH₂CH₂N(CH₃)₂) -or a salt thereof; -C (═ O) CH (NH)₂) -or the (R) -or (S) -isomer of a salt thereof; -S (O)₂NHC(＝O)CH₂–；–CH₂C(＝O)NH–；–CH₂C(＝O)NHS(O)₂–；–C(＝O)CH(CH₂CH₂(R) -or (S) -isomer of OH-; -C (═ O) NHCH (CH)₂(R) -or (S) -isomer of OH-; -CH₂C(＝O)NHCH₂–；–C(＝O)NH–；–C(＝O)NHCH₂–；–S(O)₂NH–；–S(O)₂NHCH₂–；–CH(CH₂(R) -or (S) -isomer of OH-; -CH₂CH(OH)CH₂(R) -or (S) -isomers of (A-I)A body; -CH₂The (R) -or (S) -isomer of ch (oh) C (═ O) NH-; -CH (CH)₂OH) C (═ O) NH — (R) -or (S) -isomer; -CH (CH)₂OH)CH₂(R) -or (S) -isomer of NH-; -CH (CH)₂OPO₃H₂) (R) -or (S) -isomer of C (═ O) NH-or a salt thereof; -CH (CH)₂OPO₃H₂)CH₂(R) -or (S) -isomer of NH-or a salt thereof; -CH₂C(＝O)NHS(O)₂–；–CH(CH(OH)CH₃) (R) -or (S) -isomer of C (═ O) NH-; -CH₂CH₂NH–；–CH(CH₂NH₂) C (═ O) NH —, or a salt thereof; -CH (CH)₂CH₂OH) C (═ O) NH — (R) -or (S) -isomer; -CH₂CH₂O–；–CH₂CH₂C(＝O)NH–；–CH₂The (R) -or (S) -isomer of ch (oh) C (═ O) NH-; -CH₂CH(NH₂) -or the (R) -or (S) -isomer of a salt thereof; -CH₂CH(OH)CH(OH)–；–CH₂C(＝O)NH–；–CH₂CH₂CH(OH)–；–CH₂CH₂CH(NH₂) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (NH)₂)CH₂-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (NHC (═ O) CH₃)CH₂-or a salt thereof; -C (═ O) CH (NHCH)₂CH₂OH) -or a salt thereof; -C (═ O) CH (NHCH)₂CH₃) -or a salt thereof; -C (═ O) CH (NHCH)₂CH₂CH₃) -or a salt thereof; -C (═ O) CH (NHCH)₂CH₂NH₂) -or a salt thereof; -C (═ O) CH (NHCH)₃) -or a salt thereof; -C (═ NH) NH-, or salts thereof; -C (═ O) CH₂CH₂–；–C(＝NH)NHCH₂-or a salt thereof; -C (═ O) CH₂NH–；–C(＝O)CH₂CH(NH₂) -or a salt thereof; -the (R) -or (S) -isomer of-C (═ O) ch (oh) -or a salt thereof; -C (═ O) CH (CH)₂OH) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) C [ (OH) (CH)₂OH)]-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (oh)) (CH₃) Or a (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (CH)₂CH₂OH) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) NHCH (CH)₂NH₂) -or a salt thereof; -C (═ O) C (═ NOCH)₂CH₂N⁺(CH₃)₃)–；–C(＝O)C(＝NOCH₂CO₂H)–；–C(＝O)C(＝NOC(CH₃)(CH₃)CO₂H) -; isomers or mixtures of-C (═ O) ch (oh) -; -C (═ NH) NHCH₂-or a salt thereof; -C (═ O) CH (NH)₂) -or isomers or mixtures of salts thereof; -C (═ O) NHCH₂–；–C(＝O)CH(CH₂NH₂) -or isomers or mixtures of salts thereof; -isomers or mixtures of-C (═ O) ch (oh) -; -CH₂CH(OPO₃H₂) -or a salt thereof; or-CH₂CH(O(CH₂OPO₃H₂) -or a salt thereof.

15. The compound of claim 1, wherein the compound is selected from the compounds in table a.

16. The compound of claim 1, having the formula:

wherein

n、a1、a2、a3、a4、a5、Ar¹、Cyc¹、R¹、R^2a、R^2b、R^1a、X¹、R^1b、R^1c、X²、R⁵And Q is as defined in claim 1; and

R³、R⁴and R⁷Each independently hydrogen, halogen, optionally substituted C₁-C₆Alkyl radicalOptionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group.

17. The compound of claim 16, wherein R⁴Is hydrogen, methyl, hydroxymethyl (HOCH)₂-), (1, 3-dioxaindolin-2-yl) methyl, aminomethyl or a salt thereof, ((3- (trifluoromethyl) benzoyl) oxy) methyl, ((4- (trifluoromethyl) benzoyl) oxy) -methyl, - (CH)₂)_a–NH–C(＝NH)–NH₂Or a salt thereof, 2-hydroxyethyl, 3-hydroxyethyl, 1-hydroxyethyl, (2-hydroxyethyloxy) methyl, (1-pyridinium) methyl, 2- (1-pyridinium) ethyl, 2-aminoethyl, 2-hydroxyethyl, -C (═ O) NHCH₃、–C(＝O)NHCH₂CH₂OH、–CH₂NHC(＝O)CH₂NH₂Or a salt thereof, -CH₂NHCH₂CH₂OH or a salt thereof, -CH₂NHCH₂CH₂NH₂Or a salt thereof, or a (dimethylamino) methyl group, wherein a is 1 or 2.

18. An antibiotic composition comprising a compound of any one of claims 1 to 17.

19. The antibiotic composition of claim 18 further comprising a beta-lactam antibiotic.

20. The antibiotic composition of claim 18, further comprising penicillin, cephalosporin, penem, monobactam, amoxicillin/clavulanic acid, imipenem/cilastatin, ampicillin/flucloxacillin, piperacillin/tazobactam, piperacillin/sulbactam, amoxicillin/sulbactam, ampicillin/sulbactam (sultam), amoxicillin/sulbactam pivoxil, cefaloin/tazobactam, cefoperazone/sulbactam, cefoperazone/tazobactam, ceftriaxone/tazobactam, meropenem/valbactam, and ceftazidime/avibactam, or a combination thereof.

21. The antibiotic composition of claim 20 wherein the cephalosporin comprises cefathiamidine, cefamandole, cephaloacetonitrile (cephaloacetonitrile), cefadroxil (cephalohydroxamic; Duricef), cefadroxil/trimethoprim, cephalexin (cephalexin; Kerifli), cephalexin/trimethoprim, cefalexin (ceferacin), cefalonium (cephalonine), ceftiofur (cephaloridine), cephalothin (cephalothin), cefapirin (cefapirin, Cefadril), ceftriazine, cefazepril, cefuroxime, cefazolin (cefazolin; Ancefef, Kafiozhen), cephradine (cephradine; dexrazine), cefixodil, ceftriaxone, cefaclor (Cefadrox, Neodarone, Colorale, Raniclor), cefonicid (Monocid), cefprozil (cefprozil, sprixate), cefuroxime (Zefu, Zinnat, Celifloxin, Ceftin, Biofuroksym, [19] Xorimax), ceftizona, cefmetazole, cefotetan, chlorocephem (Lorabid), cefbuperazone, cefmetazole (Zefazone), cefminox, cefotetan (Cefotan), cefoxitin (mefosan), cefotiam (Pansporin), cefcapene (cefcaperin), cefcapene, cefdaxime, cefdini (Sefdin, Zinir, Kefnir), cefditoren, cefetamet, cefixime (Fixx, Zifi, Superx), cefmenoxime, cefodizime, cefotaxime (Kalfuron), cefravinine (Celcaritin), cefpodoxime (Vantin, PECEF, Silicef), cefteram, Ceamex, Encelin (Exceptin), ceftiofur (ceftiofur), cefteram, ceftiofur (ceftiofur), ceftiofur (cefteram), cefteram (cefteram), cefteram (cefteram), cefteram, ceft, Fortum, Fortaz), latamoxef (hydroxycarboxamidome), cefixdine, cefepime (maspin), cefotaxime, cefoselis, cefozopran, cefpirome (Cefrom), cefquinome, flomoxef, cefepime, ceftaroline, cefalogen or mixtures thereof.

22. The antibiotic composition of any one of claims 18 to 21 further comprising a beta-lactamase inhibitor or other resistance modulator, or a combination thereof.

23. The antibiotic composition of claim 22, wherein the beta-lactamase inhibitor comprises clavulanic acid, sulbactam, tazobactam, avibactam, releptian (MK-7655), tipipenem, 6-methylenepenem 2, and a boron-based transition state inhibitor (BATSI).

24. A method of treating a bacterial infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 17 or an antibiotic composition of any one of claims 18 to 23.

25. A method of treating a methicillin-resistant staphylococcus aureus infection in a subject, comprising administering to a subject having a methicillin-resistant staphylococcus aureus infection a therapeutically effective amount of the compound of any one of claims 1 to 17 or the antibiotic composition of any one of claims 18 to 23.

26. The method of claim 24 or 25, wherein the beta-lactam antibiotic comprises penicillin, cephalosporin, penem, monobactam, amoxicillin/clavulanic acid, imipenem/cilastatin, ampicillin/flucloxacillin, piperacillin/tazobactam, piperacillin/sulbactam, amoxicillin/sulbactam, ampicillin/sulbactam (sultamicin), amoxicillin/sulbactam pivoxil, cefalo/tazobactam, cefoperazone/sulbactam, cefoperazone/tazobactam, ceftriaxone/tazobactam, meropenem/vabactam, and ceftazidime/avibactam or a combination thereof.

27. The method according to claims 24 to 26, wherein the beta-lactamase inhibitor or other resistance modulator comprises clavulanic acid, sulbactam, tazobactam, avibactam, releptian (MK-7655), tipipenem, 6-methylenepenem 2, and a boron-based transition state inhibitor (BATSI).

Technical Field

The invention relates to a1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole derivative compound and application thereof. In particular, the compounds of the present invention have antibacterial activity and/or are capable of re-sensitizing methicillin-resistant Staphylococcus aureus (methicillin-resistant Staphylococcus aureus) to β -lactam antibiotics or a combination of β -lactam antibiotics and β -lactamase inhibitors. The invention also relates to a method for producing and using said compounds.

Background

Antibiotics are among the most important and most widely used drugs. Their widespread use has led to the development of resistance in their pathogenic bacterial subjects. The emergence of multi-drug resistant bacteria has become a global public health threat. Severe infections with multiple resistant microorganisms often lead to considerable patient mortality and morbidity (morbidity). For example, more people die from methicillin-resistant staphylococcus aureus (MRSA) infections than from hiv/aids, parkinson's disease, and murder. Until 20 years ago, the development of structural analogues of existing antibiotics was accompanied by the emergence of new resistances. Currently, there are not enough analogs in antibiotic channels to resist the emergence of impending and future resistance. Furthermore, since 1960, the study of classes of antibiotics with new structures has resulted in only two new classes of antibacterials. In recent years, the pharmaceutical industry has invested a lot of resources and has performed high-throughput screening of large-size compound libraries for targets determined by genetic methods. However, these efforts have had limited progress.

Resistance-modifying agent (RMA) is a very advantageous alternative. These target non-essential resistance-conferring genes and can further extend the life span (life span) of antibiotics currently in clinical use, which have been optimized for toxicity and large-scale production. For example, clavulanic acid (clavulanic acid) is a beta-lactamase inhibitor. The use of clavulanic acid in combination with amoxycillin (amoxycillin) restores the efficacy of amoxycillin on a variety of β -lactamase producing bacteria.

Despite the current efforts in identifying and synthesizing RMAs, there is a continuing and urgent need for RMAs that can expand the effectiveness of antibiotics in the treatment of drug-resistant bacteria.

Disclosure of Invention

Some aspects of the invention provide a compound having the formula:

wherein n is an integer of 0 to 4; z, a1, a2, a3, a4, and a5 are each independently 0 or 1, provided that at least one of a1 to a5 is 1; ar (Ar)¹Is phenyl or 6-membered heteroaryl containing a nitrogen atom; cyc¹Is a 5-, 6-or 7-membered heterocyclic group containing a nitrogen atom, except R^2aAnd R^2bIn addition, the heterocyclic group optionally further contains 1 to 3 additional substituents; x¹is-C (═ O) -, -C (═ O) -NR⁶-or-SO₂–NH–；R^1aAnd R^1cEach independently is C₁-C₆Alkylene (alkylene); r^1bIs optionally substituted C₁-C₆An alkylene group; x²Is O or NR⁶；R¹Each independently of the others being halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group; r^2aAnd R^2bEach independently hydrogen, halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group, or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a cycloalkyl group; and Q is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted C₃-C₈A cycloalkyl group.

Some compounds of formula I are resistance modulators ("RMAs"). Without being bound by any theory, it is believed that RMAs target non-essential, resistance-conferring genes and restore antibiotic sensitivity of bacteria. One significant advantage of RMAs is that they can extend the market life of known antibiotics that have been optimized for large-scale production and have well-studied toxicity profiles. In a particular aspect of the invention, some compounds of formula I selectively re-sensitize methicillin-resistant Staphylococcus aureus to β -lactam antibiotics or to combinations of β -lactam antibiotics and β -lactamase inhibitors, such as penicillin (penillimin), cephalosporin (cephalosporin), penem (penem), monobactam (monobactam), Amoxicillin (Amoxicillin)/clavulanic acid, Imipenem (Imipenem)/cilastatin (cilastatin), Ampicillin (Amcilllin)/flucloxacillin (flucloxacillin), Piperacillin (Piperacillin)/tazobactam (tazobactam), piperalin/sulbactam (sulbactam), Amoxicillin/sulbactam, Ampicillin/sulbactam (sultam)), Amoxicillin/sulbactam (sulbactam), sulbactam (sulbactam), and/cefazolidone (Ceolactim/sulbactam), Cefoperazone (Cefoperazone)/sulbactam, Cefoperazone/tazobactam, Ceftriaxone (Ceftriaxone)/tazobactam, Meropenem (Meroperem)/valbactam (vaboractam), and Ceftazidime (Ceftazidime)/avibactam (avibactam) or combinations thereof.

In other embodiments, the compounds of the present invention have antibiotic activity without the need for additional antibiotic compounds, such as β -lactam antibiotic compounds. Thus, some of the compounds of the present invention may be used alone or in combination with β -lactam antibiotics to treat bacterial infections. Some of the compounds of formula I are themselves effective antibiotics such as methicillin-susceptible and methicillin-resistant staphylococcus aureus, Enterococcus faecium (e.faecalis), escherichia coli (e.coli), klebsiella pneumoniae (k.pneumoniae), acinetobacter baumannii (a.baumann), Enterococcus (Enterococcus), salmonella enterica (s.enterica), and the like.

In another aspect of the invention, there is provided an antibiotic composition comprising a compound of formula I. In some embodiments, the antibiotic composition further comprises a beta-lactam antibiotic. In other embodiments, the antibiotic composition further comprises a beta-lactamase inhibitor, or other resistance modulator, or a combination thereof. Exemplary beta-lactamase inhibitors useful in the compositions of the present invention include, but are not limited to, clavulanic acid, sulbactam, tazobactam, avibactam, relebactam (MK-7655), tebipenem (tebipenem), 6-methylenepenem 2 (6-methylideneepenem 2), and boron-based transition state inhibitors (BATSI).

Another aspect of the invention provides a method of treating a bacterial infection in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I or a composition comprising a compound of formula I as disclosed herein.

Other aspects of the invention also provide a method of producing the various compounds and/or intermediate compounds disclosed herein.

Although some specific substituents at different positions of the compounds of formula I are disclosed in the specific compounds disclosed herein, it should be noted that combinations of different substituents at different positions may be combined to form other embodiments. In this way, the present invention encompasses a variety of compounds.

Detailed Description

As used herein, the terms "halide", "halogen" and "halogen" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a saturated straight-chain monovalent hydrocarbon moiety of1 to 20, typically 1 to 15, and typically 1 to 10 carbon atoms, or a saturated branched-chain monovalent hydrocarbon moiety of 3 to 20, typically 3 to 15, and typically 3 to 10 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl (2-propyl), t-butyl, pentyl, isopentyl, hexyl, and the like. Each alkyl group may also be optionally substituted with one or more substituents, such as halogen, heteroatoms (e.g., alkoxy, hydroxy, amino, alkylamino, thiol, alkylthio, carbonyl, etc.). Heteroatom-substituted alkyl groups may sometimes be referred to as heteroalkyl groups.

"alkylene" means a saturated linear divalent hydrocarbon moiety of1 to 20, typically 1 to 15, and typically 1 to 10 carbon atoms, or a branched saturated divalent hydrocarbon moiety of 3 to 20, typically 3 to 15, and typically 3 to 10 carbon atoms. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, and the like.

"alkoxide" OR "alkoxy" means a compound of the formula-OR^xWherein R is^xIs an alkyl group as defined herein. "alkoxycarbonyl" refers to the formula-C (═ O) OR^zWherein R is^zIs alkyl, aralkyl, aryl, haloalkyl, and the like as defined herein.

"haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogen atoms are replaced by the same or different halogen atoms. The term "haloalkyl" also includes perhaloalkyl groups in which all of the alkyl hydrogen atoms are replaced with halogen atoms. Exemplary haloalkyl groups include, but are not limited to, -CH₂Cl、–CF₃、–CH₂CF₃、–CH₂Cl₃And the like.

"cycloalkyl" refers to a non-aromatic, usually saturated, monovalent monocyclic or bicyclic hydrocarbon moiety having from 3 to 10 ring carbons. Cycloalkyl groups may be optionally substituted in the ring structure with one or more (typically one, two or three) substituents. When two or more substituents are present in a cycloalkyl group, each substituent is independently selected.

The terms "(cycloalkyl) alkyl" and "cycloalkylalkyl" are used interchangeably herein and refer to the formula-R^dR^eWherein as defined herein, R^dIs alkylene, R^eIs a cycloalkyl group. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.

"aryl" refers to a monovalent mono-, bi-, or tricyclic aromatic moiety having 6 to 15 ring atoms, such as phenyl, naphthyl, and the like. "optionally substituted aryl" refers to aryl groups optionally substituted with one or more (typically one, two or three) substituents in the aryl ring structure. When two or more substituents are present in an aryl group, each substituent is independently selected.

The terms "aralkyl" and "(aryl) alkyl" are used interchangeably herein and refer to the formula-R^dR^eWherein R is as defined herein^dIs alkylene, R^eIs an aryl group. Exemplary aralkyl or arylalkyl groups include, but are not limited to, benzyl (i.e., benzyl), naphthylmethyl, phenylethyl, phenylpropyl, and the like. "aralkyloxy" means a compound of the formula-OR^bAr^bWherein R is as defined herein^bIs alkylene, Ar^bIs an optionally substituted aryl group.

"alkenyl" means a straight chain monovalent hydrocarbon moiety of 2 to 10 carbon atoms or a branched monovalent hydrocarbon moiety of 3 to 10 carbon atoms that contains at least one carbon-carbon double bond, such as ethenyl, propenyl, and the like.

"alkynyl" refers to a straight chain monovalent hydrocarbon moiety of 2 to 10 carbon atoms or a branched monovalent hydrocarbon moiety of 3 to 10 carbon atoms containing at least one carbon-carbon triple bond, such as ethenyl, propenyl, and the like.

"acyl" refers to a moiety of the formula-C (O) R ', wherein R' is alkyl, haloalkyl, aryl, or aralkyl.

The terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably herein and refer to a non-aromatic monocyclic or bicyclic moiety having 3 to 8 ring atoms, wherein one or two ring atoms is selected from N, O or S (O)_nWherein n is an integer from 0 to 2, the remaining ring atoms are C, wherein one or two C atoms may optionally be carbonyl groups. The heterocyclyl ring may be optionally independently substituted with one or more (preferably one, two or three) substituents. When two or more substituents are present in a heterocyclyl, each substituent is independently selected. Exemplary substituents for heterocyclyl groups include, but are not limited to, alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano (cyanoo), optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted phenylalkyl (phenylalkyl), optionally substituted heteroarylalkyl (heteroarylalkyl), acyl, - (alkylene)_n-COOR (n is 0 or 1, R is hydrogen, alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or optionally substituted heteroarylalkyl) or- (alkylene)_n–CONR^aR^b(wherein n is 0 or 1, and R^aAnd R^bIndependently of one another, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or R and R', together with the nitrogen atom to which they are attached, form a heterocyclyl ring. More specifically, the term heterocyclyl includes, but is not limited to, oxetane (oxetane), azetidine (azetidine), aziridine (aziridine), tetrahydropyranyl (tetrahydropyranyl), piperidinyl (piperidino), piperazinyl (piperzino), diazepine (diazepin), morpholinyl (morpholino) and thiomorpholinyl (thiomorpholino), thiomorpholinyl-1-oxide (thiomorpholino-1-oxide), thiomorpholinyl-1, 1-dioxide (thiomorpholino-1,1-dioxide), and derivatives thereof.

"Sulfonyl" refers to the formula-S (O)₂R^yWherein R is^yIs alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl or (cycloalkyl) alkyl.

"enantiomeric excess (enantiomeric excess)" refers to the difference between the amounts of enantiomers. The percent enantiomeric excess (% ee) can be calculated by subtracting the percent of one enantiomer from the percent of the other. For example, if the percentage of the (R) -enantiomer is 99% and the percentage of the (S) -enantiomer is 1%, the% ee of the (R) -enantiomer is 99% -1% or 98%.

"leaving group" has the meaning commonly associated therewith in synthetic organic chemistry, i.e., an atom or group capable of being substituted with a nucleophile, including halogen (e.g., chlorine, bromine, and iodine), alkylsulfonyloxy (alkanesulfonyloxy), arylsulfonyloxy (arenesulfonyloxy), alkylcarbonyloxy (alkylcarbonyloxy) (e.g., acetoxy), arylcarbonyloxy (arylcarbonyloxy), methanesulfonyloxy, toluenesulfonyloxy (tosyloxy), trifluoromethane-sulfonyloxy (trifluoromethane-sulfonyloxy), aryloxy (e.g., 2, 4-dinitrophenoxy), methoxy, N, O-dimethylhydroxyamino (N, O-dimethylhydroxyamino), and the like.

"pharmaceutically acceptable excipient" refers to an excipient that can be used in the preparation of pharmaceutical compositions that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients that can be used for veterinary as well as human pharmaceutical use.

By "pharmaceutically acceptable salt" of a compound is meant a pharmaceutically acceptable salt that possesses the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; or from a mixture of compounds such as acetic acid, propionic acid, hexanoic acid, cyclopentane-propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a salt formed by complexing with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like.

The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to a pharmacologically essentially inactive derivative of the parent drug molecule that requires spontaneous or enzymatic bioconversion in an organism to release the active drug. Prodrugs are variants or derivatives of the compounds of the present invention which have a group that is cleavable under metabolic conditions. Prodrugs are compounds of the present invention which are pharmaceutically active in vivo when they are subjected to solvolysis or enzymatic degradation under physiological conditions. The prodrug compounds of the present invention may be referred to as mono-, di-, tri-, etc., depending on the number of biotransformation steps required to release the active drug in the organism and indicate the number of functional groups present in the precursor type. Prodrug forms generally offer The advantage of solubility, histocompatibility or delayed release in The mammalian body (see Bundgard, Design of produgs, pp.7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp.352-401, Academic Press, San Diego, calif., 1992). Prodrugs well known in the art include acid derivatives well known to those skilled in the art, such as, but not limited to, esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with an amine, or basic groups which react to form an acylated base derivative. In addition, the prodrug derivatives of the present invention may be combined with other features taught herein to enhance bioavailability. For example, compounds of the present invention having a free amino, amido, hydroxyl or carboxyl group can be converted into prodrugs. Prodrugs include compounds comprising a polypeptide chain of an amino acid residue or two or more (e.g., two, three, or four) amino acid residues covalently linked by peptide bonds to a free amino, hydroxyl, or carboxylic acid group of a compound of the invention. The amino acid residues include 20 naturally occurring amino acids, typically represented by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine (demosine), isodesmosine (isodemosine), 3-methylhistidine, norvaline (norvaline), β -alanine, γ -aminobutyric acid, citrulline homocysteine (citrulline homocysteine), homoserine, ornithine and methionine sulfone (methionine sulfone). Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of the compounds of the present invention through the carbonyl carbon prodrug side chain.

"protecting group" refers to a moiety other than an alkyl group that shields, reduces, or prevents a reactive group in a molecule when the moiety is attached to the reactive group. Examples of protecting groups can be found in the following documents: T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis,3^rd edition,John Wiley&Sons, New York,1999 and Harrison et al, Compendium of Synthetic Organic Methods, Vols.1-8(John Wiley and Sons,1971-1996), the entire contents of which are incorporated herein by reference. Representative hydroxyl protecting groups include acyl, benzyl and trityl ethers (trityl ethers), tetrahydropyranyl ethers (tetrahydropyranyl ethers), trialkylsilyl ethers (trialkylsilyl ethers) and allyl ethers (allyl ethers). Representative amino or amine protecting groups include formyl (formamyl), acyl (e.g., acetyl, trifluoroacetyl, and benzoyl (benzoyl)), benzyl, alkoxycarbonyl (e.g., benzyloxycarbonyl (CBZ) and tert-butoxycarbonyl (Boc)), Trimethylsilyl (TMS), 2-trimethylsilanyl-ethanesulfonyl (2-trimethylsilanyl-ethanesulfonyl) (SES), trityl and substituted trityl, allyloxycarbonyl (allyloxycarbonyl), 9-fluorenylmethoxycarbonyl (9-Fluoromethoxycarbonyl) (FMOC), nitro-veratryloxycarbonyl (NVOC), sulfonyl, and the like.

"corresponding protecting group" means the appropriate protecting group corresponding to the heteroatom to which it is attached (i.e., N, O, P or S).

"therapeutically effective amount" refers to an amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effectively treat the disease. Generally, a therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

A "treatment" and "treatment" of a disease comprising: (1) prevention of disease, i.e., the avoidance of clinical symptoms of disease in a mammal that may be exposed to or predisposed to disease but does not experience or exhibit symptoms of disease; (2) inhibiting a disease, i.e., arresting or reducing the development of a disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

When describing a chemical reaction, the terms "treating", "contacting", and "reacting" are used interchangeably herein and refer to adding or mixing two or more reagents under suitable conditions to produce an indicated and/or desired product. It will be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of the two reagents initially charged, i.e. there may be one or more intermediates which are produced in a mixture which ultimately results in the formation of the indicated and/or the desired product.

As used herein, the terms "those defined above" and "those defined herein" when referring to variables are intended to encompass the broad definition of the variables as well as any narrow definition, if any, by reference.

In one particular aspect of the invention, there is provided a compound having the formula:

wherein n is an integer of 0 to 4; z, a1, a2, a3, a4 and a5 are each independently 0 or 1, provided that a1 to a5 is 1; ar (Ar)¹Is phenyl or 6-membered heteroaryl containing a nitrogen atom; cyc¹Is a 5-, 6-or 7-membered heterocyclic group containing a nitrogen atom, except R^2aAnd R^2bIn addition, the heterocyclic group optionally further contains 1 to 3 additional substituents; x¹is-C (═ O) -, -C (═ O) -NR⁶-or-SO₂–NH–；R^1aAnd R^1cEach independently is C₁-C₆An alkylene group; r^1bIs optionally substituted C₁-C₆An alkylene group; x²Is O or NR⁶；R¹Each independently of the others being halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group; r^2aAnd R^2bEach independently hydrogen, halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or nitrogen protecting group, or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, each of which is optionally substituted; and Q is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted C₃-C₈A cycloalkyl group.

Some compounds of formula I are resistance modulators ("RMAs"). Without being bound by any theory, it is believed that RMAs target non-essential, resistance-conferring genes and restore antibiotic sensitivity of bacteria. One significant advantage of RMAs is that they can extend the market life of known antibiotics that have been optimized for large-scale production and have well-studied toxicity profiles. In a particular aspect of the invention, some compounds of formula I selectively re-sensitize methicillin-resistant staphylococcus aureus to β -lactam antibiotics, such as penicillins, cephalosporins, penems, monobactans, amoxicillins/clavulanic acid, imipenem/cilastatin, ampicillin/flucloxacillin, piperacillin/tazobactam, piperacillin/sulbactam, amoxicillins/sulbactam, ampicillin/sulbactam (sultam), amoxicillins/sulbactam pivoxil, cefaloin/tazobactam, cefoperazone/sulbactam, cefoperazone/tazobactam, ceftriaxone/tazobactam, meropenem/vabactam, and ceftazidime/avibactam or combinations thereof.

In some embodiments, the compounds of formula I are capable of re-sensitizing methicillin-resistant staphylococcus aureus to (I) a beta-lactam antibiotic and/or (ii) a combination of a beta-lactam antibiotic and a beta-lactamase inhibitor.

In other embodiments, the compounds of formula I have antibiotic activity without the need for additional antibiotic compounds, such as β -lactam antibiotic compounds. Thus, some of the compounds of the present invention may be used alone or in combination with beta-lactam antibiotics and/or beta-lactamase inhibitors to treat bacterial infections. In other embodiments, some of the compounds of the invention are themselves effective antibiotics against methicillin-susceptible and methicillin-resistant staphylococcus aureus, enterococcus faecium, escherichia coli, klebsiella pneumoniae (k.11ydorxyl11), acinetobacter baumannii, enterococcus, salmonella enterica, and the like.

In some embodiments, the compound of formula I is selected from compounds of the formula:

wherein n, a1, a2, a3, a4, a5, Ar¹、Cyc¹、R¹、R^2a、R^2b、R^1a、X¹、R^1b、R^1c、X²、R⁵And Q is as defined herein; and R is³、R⁴And R⁷Each independently hydrogen, halogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR^aor-NR^bR^cWherein R is^aIs hydrogen, C₁-C₆Alkyl radical, C₁-C₆A haloalkyl or hydroxy protecting group, and wherein R^bAnd R^cEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In some embodiments, the compounds of the present invention are compounds of formula I-A. In other embodiments, the compounds of the invention are of formula I-B. In other embodiments, the compounds of the invention are of formula I-C. In other embodiments, the compounds of the invention are of formula I-D. In other embodiments, the compounds of the invention are of formulae I-E. In other embodiments, the compounds of the invention are of formula I-F. In other embodiments, the compounds of the invention are of the formula I-G.

In other embodiments, the compound of formula I is selected from compounds of the formula:

wherein x is an integer from 0 to 3; r⁶Is C₁-C₆Alkyl, optionally substituted cycloalkyl, heterocyclyl, -OR^aand-NR^bR^c；n、R¹、R²、R³、R⁴、R^a、R^b、R^cAnd Q is as defined herein; and A is O or NH. In a particular embodiment, the compounds of the invention are of the formula I-H. In another embodiment, the compounds of the invention are of formula I-J. In another embodiment, the compounds of the invention are of formula I-K. In another embodiment, the compounds of the invention are of formula I-L. In another embodiment, the compounds of the invention are of formula I-M. In another embodiment, the compounds of the invention are of formula I-N. In some embodiments, the compounds of the present invention are of formula I-O.

In other embodiments, Q is optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted cyclopropyl. In some embodiments, Q is selected from: (a) phenyl optionally having one, two or three substituents, wherein each substituent is independently selected from: chloro, trifluoromethoxy, trifluoromethyl, methyl, ethyl, nitro, -NH-C (═ O) - (CH)₂)₂–CO₂H、–NH–C(＝O)–CH₃、–NH–C(＝O)–CH₂-CN, bromomethyl, -PO₄(R^x)₂、–OCH₂PO₄(R^x)₂and-CH₂PO₄(R^x)₂Wherein each R^xIndependently hydrogen or a metal ion; and (b) heteroaryl selected from isoxazolyl (isoxazoyl), thienyl (thiophenyl), thiazolyl (thiazoyl), furyl (furanyl), and 1H-pyrazolyl (1H-pyrazoyl), pyridyl (pyridyl), pyrimidyl (pyrimidyl), isothiazolyl (isothiazolyl), and the like, each of which is optionally substituted with one or two substituents, wherein each substituent is independently selected from halogen, amino, hydroxy, C₁-C₆Alkyl, alkoxy, -CONR^bR^c、–NHCOR^d、–NHR^dAnd optionally substituted phenyl, and wherein R^b、R^cAnd R^dEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In other embodiments, Q is piperazine (piperazine), pyrrolidine (pyrolidine), imidazolidine (imidazolidine), homopiperazine (diazepane) (each of which is optionally substituted, e.g., optionally substituted phenyl, optionally substituted heteroaryl (e.g., pyridine)), and the like. Exemplary substituents for phenyl and heteroaryl (e.g., pyridyl) groups are those disclosed herein.

In some embodiments, n is 0, 1, or 2. In other embodiments, n is 1 or 2.

In other embodiments, R¹Each independently of the others is halogen, hydroxy, C₁-C₆Alkyl or C₁-C₆Alkoxy, -CONR^bR^c、–NHCOR^d、–NHR^dAnd wherein R is^b、R^cAnd R^dEach independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In some cases, R¹Each independently is chloro, fluoro, methoxy or hydroxy.

In other embodiments, R^2aComprises the following steps:

the presence of hydrogen in the presence of hydrogen,

the methyl group is a group selected from the group consisting of,

(1, 3-dioxaindolin-2-yl) methyl,

an aminomethyl group or a salt thereof,

((3- (trifluoromethyl) benzoyl) oxy) -methyl,

((4- (trifluoromethyl) -benzoyl) oxy) -methyl,

–(CH₂)_a–NH–C(＝NH)–NH₂or a salt thereof, wherein a is 1 or 2,

2-hydroxyethyl group, and a process for producing the same,

3-hydroxyethyl group, and the like in the amino group,

1-hydroxyethyl group, and a pharmaceutically acceptable salt thereof,

(2-hydroxyethoxy) methyl group, and (2-hydroxyethoxy) methyl group,

(1-pyridinium) -methyl ((1-pyridinium) -methyl),

2- (1-pyridinium) ethyl group,

2-amino-ethyl group (2-amino-ethyl group),

–C(＝O)NR^a1R^a2(wherein R is^a1And R^a2Each independently is hydrogen or C_1-6Alkyl groups such as methyl, ethyl, propyl, t-butyl, etc.),

–C(＝O)NHCH₂CH₂X^a(wherein X^ais-OH, -SH or-NH₂)，

–CH₂NHC(＝O)–CH₂NR^a1R^a2(wherein R is^a1And R^a2Each independently is hydrogen or C_1-6Alkyl groups such as methyl, ethyl, propyl, t-butyl, etc.) or salts thereof,

–CH₂NHCH₂CH₂X^a(wherein X^ais-OR¹、–SR¹or-NR^a1R^a2Wherein R is^a1And R^a2Each independently is hydrogen or C_1-6Alkyl groups such as methyl, ethyl, propyl, t-butyl, etc.) or salts thereof,

–CH₂NHCH₂CH₂X^a(wherein X^ais-OH, -SH or-NH₂) Or a salt thereof, or

–R^x1–X^aWherein R is^x1Is C_1-6Alkylene, e.g. methylene, ethylene, etc., X^ais-OR^a1、–S^a1or-NR^a1R^a2(wherein R is^a1And R^a2Each independently is hydrogen, C_1-6Alkyl (e.g., methyl, ethyl, propyl, t-butyl, etc.) or heterocycloalkyl (e.g., aziridinyl, azetidinyl, etc.). -R^x1–X^aSpecific examples of (d) include, but are not limited to, (dimethylamino) methyl, hydroxymethyl (HOCH)₂-, (azetidinyl) methyl, and the like.

In other embodimentsIn the scheme, R^2bIs H, and R^2aIs ethyl, isopropyl, trifluoromethyl, cyclopropyl or fluoromethyl; or R^2aAnd R^2bIs methyl; or R^2aAnd R^2bTogether with the carbon atom to which they are attached form a cyclopropyl group.

In other embodiments, R³Is hydrogen, aminomethyl (H)₂NCH₂-) or a salt thereof, a carboxylic acid methyl ester group (-CO)₂Me), carboxyl group (-CO)₂H) Hydroxymethyl, -CH₂–NH–C(＝NH)–NH₂Or a salt thereof, or an aminomethyl group or a salt thereof.

In other embodiments, a1, a2, and a4 are 0; and a3 is 1. In some cases, R^1bis-CH₂CH (OH) -; or a heteroaryl of the formula:

in other embodiments, a moiety of the formula:

–(R^1a)_a1–(X¹)_a2–(R^1b)_a3–(R^1c)_a4–(X²)_a5–

the method comprises the following steps: -CH₂The (R) -or (S) -isomer of CH (OH) -; -C (═ O) -NH-; -C (═ O) -NH-CH₂–；–CH₂C (═ O) -NH-; -C (═ O) -; a methylene group; -C (═ O) CH (NH)₂) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH [ NH (C (═ O) CH₃)]–；–C(＝O)CH(NH₂)CH₂-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (N (C (═ O) CH)₃)₂)CH₂–；–C(＝O)C(＝O)–；–C(＝O)CH(NHC(＝O)CH₃)CH₂-the (R) -or (S) -isomer of (a); -C (═ O) CH (NHC (═ O) CH₃) -the (R) -or (S) -isomer of (a); -C (═ O) CH₂–；–C(＝O)CH(NH₂)CH₂-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (NHC (═ O) CH₃)CH₂Of (R) -or (S) -isoA structure body; the (R) -or (S) -isomer of-C (═ O) ch (oh) -; -C (═ O) C (═ NOH) -; -S (O)₂–NHC(＝O)–；–C(＝O)C(＝NOCH₂CH₂N(CH₃)₂) -or a salt thereof; -C (═ O) CH (NH)₂) -or the (R) -or (S) -isomer of a salt thereof; -S (O)₂NHC(＝O)CH₂–；–CH₂C(＝O)NH–；–CH₂C(＝O)NHS(O)₂–；–C(＝O)CH(CH₂CH₂(R) -or (S) -isomer of OH-; -C (═ O) NHCH (CH)₂(R) -or (S) -isomer of OH-; -CH₂C(＝O)NHCH₂–；–C(＝O)NH–；–C(＝O)NHCH₂–；–S(O)₂NH–；–S(O)₂NHCH₂–；–CH(CH₂(R) -or (S) -isomer of OH-; -CH₂CH(OH)CH₂-the (R) -or (S) -isomer of (a); -CH₂The (R) -or (S) -isomer of ch (oh) C (═ O) NH-; -CH (CH)₂OH) C (═ O) NH — (R) -or (S) -isomer; -CH (CH)₂OH)CH₂(R) -or (S) -isomer of NH-; -CH (CH)₂OPO₃H₂) (R) -or (S) -isomer of C (═ O) NH-or a salt thereof; -CH (CH)₂OPO₃H₂)CH₂(R) -or (S) -isomer of NH-or a salt thereof; -CH₂C(＝O)NHS(O)₂–；–CH(CH(OH)CH₃) (R) -or (S) -isomer of C (═ O) NH-; -CH₂CH₂NH–；–CH(CH₂NH₂) C (═ O) NH —, or a salt thereof; -CH (CH)₂CH₂OH) C (═ O) NH — (R) -or (S) -isomer; -CH₂CH₂O–；–CH₂CH₂C(＝O)NH–；–CH₂The (R) -or (S) -isomer of ch (oh) C (═ O) NH-; -CH₂CH(NH₂) -or the (R) -or (S) -isomer of a salt thereof; -CH₂CH(OH)CH(OH)–；–CH₂C(＝O)NH–；–CH₂CH₂CH(OH)–；–CH₂CH₂CH(NH₂) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (NH)₂)CH₂-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (NHC (═ O) CH₃)CH₂-or a salt thereof；–C(＝O)CH(NHCH₂CH₂OH) -or a salt thereof; -C (═ O) CH (NHCH)₂CH₃) -or a salt thereof; -C (═ O) CH (NHCH)₂CH₂CH₃) -or a salt thereof; -C (═ O) CH (NHCH)₂CH₂NH₂) -or a salt thereof; -C (═ O) CH (NHCH)₃) -or a salt thereof; -C (═ NH) NH-, or salts thereof; -C (═ O) CH₂CH₂–；–C(＝NH)NHCH₂-or a salt thereof; -C (═ O) CH₂NH–；–C(＝O)CH₂CH(NH₂) -or a salt thereof; -the (R) -or (S) -isomer of-C (═ O) ch (oh) -or a salt thereof; -C (═ O) CH (CH)₂OH) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) C [ (OH) (CH)₂OH)]-or the (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (oh)) (CH₃) Or a (R) -or (S) -isomer of a salt thereof; -C (═ O) CH (CH)₂CH₂OH) -or the (R) -or (S) -isomer of a salt thereof; -C (═ O) NHCH (CH)₂NH₂) -or a salt thereof; -C (═ O) C (═ NOCH)₂CH₂N⁺(CH₃)₃)–；–C(＝O)C(＝NOCH₂CO₂H)–；–C(＝O)C(＝NOC(CH₃)(CH₃)CO₂H) -; isomers or mixtures of-C (═ O) ch (oh) -; -C (═ NH) NHCH₂-or a salt thereof; -C (═ O) CH (NH)₂) -or isomers or mixtures of salts thereof; -C (═ O) NHCH₂–；–C(＝O)CH(CH₂NH₂) -or isomers or mixtures of salts thereof; -isomers or mixtures of-C (═ O) ch (oh) -; -CH₂CH(OPO₃H₂) -or a salt thereof; or-CH₂CH(O(CH₂OPO₃H₂) -or a salt thereof. Unless the context clearly requires otherwise, the terms "(R) -or (S) -isomer" and "isomer or mixture" are used interchangeably to indicate that the compound may be one particular isomer or an enantiomeric excess of a particular isomer or a racemic mixture of isomers. In fact, unless expressly stated to the contrary, all optically active compounds are considered to include the pure isomer, enantiomeric excess or racemic mixture of one or more isomers of such a compound。

In other embodiments, R⁴Is hydrogen, methyl, hydroxymethyl (i.e. HOCH)₂-), (1, 3-dioxoindolin-2-yl) methyl, aminomethyl or a salt thereof, ((3- (trifluoromethyl) benzoyl) -oxy) methyl, ((4- (trifluoromethyl) benzoyl) oxy) -methyl, - (CH)₂)_a–NH–C(＝NH)–NH₂Or a salt thereof (wherein a is 1 or 2), 2-hydroxyethyl, 3-hydroxyethyl, 1-hydroxyethyl, (2-hydroxyethoxy) methyl, (1-pyridinium) methyl, 2- (1-pyridinium) ethyl, 2-aminoethyl, 2-hydroxyethyl, -C (═ O) NHCH₃、–C(＝O)NHCH₂CH₂OH、–CH₂NHC(＝O)CH₂NH₂Or a salt thereof, -CH₂NHCH₂CH₂OH or a salt thereof, -CH₂NHCH₂CH₂NH₂Or a salt thereof, or a (dimethylamino) methyl group.

Some specific representative compounds of the invention include those shown in the examples section as well as the following specific compounds in table a:

table a: representative compounds of the invention (including the compounds shown below and disclosed in the examples section as belonging to the general structure of formula I)

Another aspect of the invention provides an antibiotic composition comprising any one of the compounds disclosed herein. In some embodiments, the antibiotic composition further comprises a beta-lactam antibiotic. Exemplary beta-lactam antibiotics include, but are not limited to, penicillin, cephalosporin, penem, monobactam, amoxicillin/clavulanic acid, imipenem/cilastatin, ampicillin/flucloxacillin, piperacillin/tazobactam, piperacillin/sulbactam, amoxicillin/sulbactam, ampicillin/sulbactam (sultam), amoxicillin/sulbactam pivoxil, cefalon/tazobactam, cefoperazone/sulbactam, cefoperazone/tazobactam, ceftriaxone/tazobactam, meropenem/valbactam, and tacrolidine/avibactam, or combinations thereof. In general, all known beta-lactam antibiotics are included within the scope of the present invention. A list of beta-lactam antibiotics (see also the website pdr. net) and Merck Index (see also the rs.org/Merck-Index online version) can be found, for example, in the physics's Desk Reference, 72 th edition, all of which are incorporated herein by Reference in their entirety.

A group of specific beta-lactam antibiotics, i.e. cephalosporins, including but not limited to Cefathiamidine (Cefathiamidine), Cefamandole (Cefamandole), cefetanide (cefetamide), Cefadroxil (Cefadroxil) (cefhydroxyoxime (cefadroxyl), duricf, Cefadroxil/Trimethoprim (Trimethoprim), cephalexin (Cefalexin) (cephalexin), Keflax (Keflex)), cephalexin/Trimethoprim, cefaloxin (cefaloxin), cefalonine (Cefalonium), ceftiofur (cefaloxime), cefaloxime (Cefazolin), Cefazolin (Cefazolin), kephalin (Cefapirin), Cefapirin (Cefapirin), cefapizone (Cefazolin) (Cefazolin (Cefapirin), Cefapirin (Cefapirin), Cefapirin (Cefapirin) (cefapizone (Cefapirin), cefapizone (Cefazolin), cefapizone (cef, Kiflavone (Kefzol), cephradine (Cefradine) (cephradine; Velosef), Cefradine (Cefroxadine), Ceftezole (Ceftezole), Cefaclor (Cefaclor) (Cetylo (Ceclor), Neodaro (Distacor), Kofule (Keflor), Raniclor (Cefonicid) (Monocid), Cefprozil (Cefprozil) (Cefprozil (Cefproxil); Serpentine (Cefzil)), Cefuroxime (Cefzin), Cefuroxime (Cefurazoxime) (Zefu, Zinnat, Welifloxacin (Cenacif), Ceftin, Biofurosym, [19] Xorimax), Cefazolam (Cefzonam), Cefmetazole (Cefmetazole) (Ceftazone), cefmetazone (Cefazine), Cefmetazole (Cefazine (Ceftazone) (Ceftazone), Cefazine (Cefazone), Cefazine (Cefazone (Ceftazone), Cefazine) (Cefazone (Ceftazone), Cefazone (Cefazone), Cefazone (Cefmazine) (Cefazone), Cefmazine) (Cefazone (Cefmazine) (Ceftazone) (Ceftazone), Cefazone (Cefax (Cefaxme) (Cefax), Cefax (Cefa, Cefdinir (Cefdinir) (Sefdin, Zinir, omnief, Kefnir), Cefditoren (Cefditoren), Cefetamet (Cefetamet), Cefixime (Cefixime) (Fixx, Zifi, Superx), Cefmenoxime (Cefmenoxime), cefdizime (cefdizime), Cefotaxime (Cefixime) (kevlar (Claforan)), cefuroxime) (compactin (Convenia)), cefimidazole (ceffimizole), Cefpodoxime (Cefpodoxime) (Vantin, PECEF, Silifef), Cefteram (cefaclor), cefameter (cefuroxime) (Cedasatin), Cefixime (Cefixime) (Ceftibuten) (Cedazox), cefixuroxime (Nafiorior) (Forxel, Exnexel), Cefixime (Cefaxim), Cefepime (Cexilime) (Cexazine (Cevaxeme), Cefepime (Cefazime (Cefazine), Cefepime) (Ceftivafloxacin (Ceftime (Cezime), Cefepime (Ceftime (Ceftivafloxacin (Cezime), Cefepime) (Cexil)), Cefepime) (Cexil), Cefepime) (Cexil)), Cefepime) (Cexil (Cefax), Cefepime) (Cexil) (Cefax (Cexil (Cefax)), Cefepime) (Cexil) (Cefax (Cexil) (Cefax)), Cefepime) (, Cefotaxime (ceftuprenam), Cefoselis (Cefoselis), Cefozopran (Cefozopran), Cefpirome (cefirome) (ceffrom), Cefquinome (Cefquinome), Flomoxef (Flomoxef), cefpiramide (Ceftobiprole), cefaclor (Ceftaroline), and cefprozil.

Exemplary penicillins that may be used in the compositions of the present invention include, but are not limited to, piperacillin, amoxicillin, Mezlocillin (Mezlocillin), azlocillin, ampicillin (pivalicillin), pitocillin (Hetacilin), Bacampicillin (bacampicilin), maytansillin (Metampicillin), phthalazinil (Talampicilin), Epicillin (Epicilin), Mezlocillin, mezlillin (Mecillinim) (pivicilin (Pivimillinm)), Sulbenicillin (Sulbenicillin), Cloxacillin (Cloxacillin) (Dicloxacillin), flucloxacillin (Fluocillin), sultamicilin (Sultacillin), lunicilin (Lenampiicilin), penicillin G (Penicilin G), fururicillin (furbenicilin), Oxacillin (penicillin), Oxacillin (Oxalicillin), Methicillin (Metillin), penicillin (Benziclinicilin), penicillin (Benziclinicilin (Benziclinin), penicillin (Benziclinicilin), penicillin (Benziclinin), penicillin (Benziclinicilin), penicillin (Benziclinin (Benzilin), penicillin (Benziclinicilin), penicillin (Benzi, Nafcillin (Nafcillin), epicillin, Ticarcillin (Ticarcillin), Carbenicillin (Carbenicillin) (cairinin), Temocillin (Temocillin) and penicillin v (penicillin v) (Phenoxymethylpenicillin).

Exemplary penems useful in the present invention include, but are not limited to, meropenem, imipenem, Biapenem (Biapenem), Faropenem (Faropenem), Ritipenem (Ritipenem), Panipenem (Panipenem), and Ertapenem (Ertapenem).

Exemplary monobactams useful in the present invention include, but are not limited to, Aztreonam (Aztreonam), Tigemonam (Tigemonam), Carumonam (Carumonam), and nocardicin a (nocardicin a).

In some embodiments, the antibiotic composition may further comprise a beta-lactamase inhibitor or other resistance modulator, or a combination thereof. Exemplary beta-lactamase inhibitors include, but are not limited to, clavulanic acid, sulbactam, tazobactam, avibactam, releptian (MK-7655), tebipenem, 6-methylene penem2, and boron-based transition state inhibitors (BATSI), among others. Other beta-lactamase inhibitors are well known to those skilled in the art.

Another aspect of the invention provides a method of treating a bacterial infection in a subject. Such methods generally comprise administering to a subject in need of such treatment a therapeutically effective amount of any one of the compounds disclosed herein or any one of the antibiotic compositions disclosed herein. In a particular embodiment, the method is for treating a methicillin-resistant staphylococcus aureus infection in a subject.

Combinations of the various embodiments may be combined with other embodiments. In this way, a wide variety of compounds are included within the scope of the present invention. Appendix a shows some exemplary compounds of the invention incorporating various embodiments. Accordingly, a particular embodiment of the invention includes the compounds shown in appendix a. It is also to be understood that the scope of the present invention also includes the more general structure of the particular variable groups represented in the compounds of appendix A. For example, when a methyl group is present as a substituent (e.g., in a heteroaryl group), the generic term "alkyl" may be used to include such compounds, and when chlorine is present, the generic term "halide" may be used. Thus, many general substituents are included within the scope of the present invention.

The compounds of the present invention may be administered to a patient or subject to achieve a desired physiological effect. Typically, the patient is an animal, typically a mammal, and usually a human. The compounds may be administered in a variety of forms suitable for the chosen route of administration, i.e. orally or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenously; intramuscular administration; subcutaneous injection; in the eye; in the embryo layer; transepithelial (including transdermal, ocular (opthalmic), sublingual, and buccal); topical (including ocular, dermal, ocular, rectal and nasal inhalation by insufflation (insufflation) and aerosol inhalation (aerosol); intraperitoneal administration; and the rectal system.

The active compounds may be administered orally, for example, with an inert diluent or an ingestible carrier, or may be enclosed in hard or soft shell gelatin capsules, or may be compressed into tablets, or may be incorporated directly into the food. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of digestible tablets (tablets), buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations may contain at least 0.1% of the active compound. The percentage of the composition and formulation may of course vary and may conveniently be between about 1% to about 10% of the weight of the unit. In such therapeutically useful compositions, the amount of active compound is such that a suitable dosage will be obtained. Typical compositions or formulations according to the invention are prepared such that an oral dosage unit form contains from about 1 to about 1000mg of the active compound.

Tablets, troches, pills, capsules and the like may also contain the following: binders, such as gum tragacanth, acacia (acacia), corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; and sweetening agents such as sucrose, lactose or saccharin may be added, or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules can be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained release formulations and preparations. In addition to the usual dosage forms described above, the compounds of the invention may also be administered by controlled release means and/or delivery devices (delivery devices) capable of releasing the active ingredient (prenylation inhibitor) at the desired rate, to maintain a constant pharmacological activity over the desired period of time. Such dosage forms provide a drug supply to the body for a predetermined period of time, thereby maintaining drug levels within a therapeutic range for a longer period of time than conventional uncontrolled agents. Examples of controlled release pharmaceutical compositions and delivery devices suitable for administration of the active ingredients of the present invention are described in U.S. patent nos.: 3,847,770, 3,916,899, 3,536,809, 3,598,123, 3,630,200, 4,008,719, 4,687,610, 4,769,027, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,566, and 5,733,566, the disclosures of which are incorporated herein by reference.

The pharmaceutical compositions used in the methods of the present invention may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. Generally, compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The active compounds can also be administered parenterally. Solutions of the active compound as a free base or a pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under common conditions of storage and use, these formulations contain preservatives to prevent microbial growth.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability is achieved. It is stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent for the dispersion medium and includes, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like). In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption delaying agents for injectable compositions, such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle (vehicle) which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional ingredient desired from a previously sterile-filtered solution thereof.

As noted above, the compounds of the present invention can be administered to mammals alone or in combination with a pharmaceutically acceptable carrier, in proportions determined by the solubility and chemical nature of the compounds, the chosen route of administration and standard pharmaceutical practice.

The dosage of the therapeutic agents of the present invention that is most suitable for prophylaxis or therapy can be readily determined by the physician and will vary with the form of administration and the particular compound selected and also with the particular patient being treated. The physician will often wish to start the treatment with small doses, in small increments, until the optimum effect is achieved in this case. The therapeutic dose is generally from about 0.1 to about 1000 mg/day, preferably from about 10 to about 500 mg/day, or from about 0.1 to about 250mg/kg body weight per day, preferably from about 0.1 to about 500mg/kg body weight per day, and can be administered in several different dosage units. Oral administration may require higher doses, about 2-fold to 10-fold.

Although the compounds of formula I can be readily synthesized by one of skill in the art reading this disclosure, one general synthetic method for generating the various substituents is shown in the synthetic scheme below. It will be appreciated that some of the reactions shown in the synthetic schemes below may be combined to produce other combinations of substituents for compounds of formula I. For example, synthesis 1 may be combined with any of syntheses 6-12 to yield different compounds of formula I. In a similar manner, synthesis 2 can be combined with any of syntheses 6-12 to yield further compounds of formula I. It will be appreciated that in some cases it may be desirable to use one or more protecting groups to prevent unwanted substitution. These methods will be apparent to those skilled in the art upon reading this disclosure.

General synthetic route for compounds of formula I for different substituents:

synthesis 1:

synthesis 2:

synthesis 3:

synthesis 4:

synthesis 5:

synthesis 6:

synthesis 7:

synthesis 8:

synthesis 9:

synthesis 10:

synthesis 11:

synthesis 12:

other objects, advantages and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. In the examples, the process constructively simplified to practice is described in the present time, and the process performed in the laboratory is illustrated in the past time.

Examples

General scheme 1

(2, 2-Dimethoxyethyl) carbamic acid benzyl ester: to 2, 2-Dimethoxyethan-1-amine (8g, 76.2mmol) and Et at 0 deg.C₃To a mixture of N (23.1g, 228.6mmol) in DCM (80mL) was added benzyl chloroformate (14.3g, 83.8mmol) dropwise. The mixture was stirred at room temperature for 4 h. TLC showed the reaction was complete. The reaction was quenched with water (100mL) and extracted with DCM (3X 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: EtOAc ═ 4:1 to 2:1) to give benzyl (2, 2-dimethoxyethyl) carbamate (11g, yield: 60.4%) as a colorless oil.

((6-chloro-2- (3-chlorobenzoyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl group Carbamic acid benzyl ester trifluoroacetic acid: to a mixture of benzyl (2, 2-dimethoxyethyl) -carbamate (1.71g, 7.15mmol) in 2-butanol (30mL) was added 2- (5-chloro-1H-indol-3-yl) ethane-1-amine (1.53g, 7.86mmol), TFA (0.74g), and water (1 mL). The mixture was stirred at 100 ℃ for 16 h. The reaction was then cooled to room temperature. The precipitate was collected by filtration to give ((6-chloro-2- (3-chlorobenzoyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indol-1-yl) methyl) carbamic acid benzyl ester trifluoroacetic acid (3.5g, yield: 98.9%). LCMS: [ M + H]⁺＝370.1。

General scheme 2

6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-1-carboxylic acidAcid(s): 2- (5-chloro-1H-indol-3-yl) ethylamine hydrochloride (23.1g, 0.1mol) was dissolved in water (300mL) with heating. Glyoxylic acid (50% by weight in water, 13.35mL, 0.12mol, 1.2 equiv) was added to the reaction mixture, followed by dropwise addition of sodium hydroxide solution (4.68g, 0.117mol, 1.17 equiv in 100mL of water). The pH of the reaction solution was adjusted to 4.0 with acetic acid (about 11mL) and the mixture could be stirred at room temperature until LCMS showed disappearance of all starting material (about 16 h). The solution was then cooled and filtered to yield an impure solid. The solid was dried under vacuum and suspended in methanol at 0 ℃ and then rapidly filtered by suction to give 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-1-carboxylic acid (20g, 80% yield).

6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole hydrochloride: reacting 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-1-carboxylic acid (10g, 40mmol) was dissolved in 10mL concentrated HCl and 75mL H₂And heating to 125 ℃ in O, and keeping the temperature for 30 min. Then 1mL of concentrated hydrochloric acid was added to the reaction mixture every 30min until all starting material disappeared as detected by LCMS. During heating, bubble formation and precipitation of a green solid were observed. Cooling the solution to room temperature, cooling to 0 deg.C, maintaining the temperature for another 30min, collecting solid precipitate, and adding H₂O (3X 30 mL). Then the solid is dried in a drying oven by an oil pump to obtain 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole hydrochloride (8.0g, 82% yield).¹H NMR(500MHz,DMSO-d₆)δ11.35(s,1H),9.61(s,2H),7.53(d,J＝2.0Hz,1H),7.39(d,J＝8.5Hz,1H),7.10(dd,J＝8.6,2.1Hz,1H),4.33(s,2H),3.40(t,J＝6.0Hz,2H),2.92(t,J＝6.0Hz,2H)。

General scheme 3

(6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methanol: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] at 0 ℃ under argon]Indole-1-carboxylic acid (2.5g, 10mmol) in anhydrous THFAdding LiAlH in three batches₄Powder (1.14g, 30 mmol). After stirring at room temperature for 30min, the reaction mixture was heated to reflux for 16h, then cooled to room temperature and quenched with water and sodium hydroxide solution. The resulting suspension was filtered and washed with diethyl ether (3X 20 mL). The filtrate was concentrated and purified by silica gel chromatography (DCM/MeOH ═ 10: 1-5: 1) to give (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methanol (1.89g, 80% yield). LC-MS: [ M + H ]]⁺:237.1。

General scheme 4

2-hydroxy-3-nitropropionic acid: in a round bottom flask, cold 3N sodium hydroxide (105mL) and nitromethane (32mL, 595mmol) were added sequentially to glyoxylic acid monohydrate 1(27.6g, 300 mmol). The reaction mixture was stirred at room temperature for 14h and then heated at 70 ℃ for 1 h. After cooling the resulting solution in an ice-water bath, cold 6N H was added to the reaction mixture at 0 deg.C₂SO₄(100 mL). The mixture was extracted with ethyl acetate (1X 100mL, then 9X 50 mL). The combined organic phases were washed with MgSO₄Dried and concentrated under reduced pressure at 40 ℃ to give a brown oil. Dichloromethane was added to the crude residue to give a brown solid. The precipitate was filtered and dried in air to give 2-hydroxy-3-nitropropionic acid (35g, 86%).¹H NMR(300MHz,DMSO-d₆)δ4.86(dd,J＝13.3,3.9Hz,1H),4.72(dd,J＝13.3,7.0Hz,1H),4.59(dd,J＝7.0,3.9Hz,1H),4.01–3.61(m,1H)。

2-hydroxy-3-nitropropionic acid methyl ester: to a solution of 2-hydroxy-3-nitropropionic acid (2.7g, 20mmol) in 20mL of anhydrous methanol at 0 deg.C was slowly added SOCl₂(2.9ml, 40mmol) and then stirred at room temperature for 14 h. And concentrating the reaction mixture under reduced pressure, and drying by an oil pump to obtain the 2-hydroxy-3-nitro methyl propionate. The crude product was purified by flash column chromatography on silica gel (hexane/ethyl acetate 3: 1-1: 1) to give methyl 2-hydroxy-3-nitropropionate (2.86g, 95% yield).¹H NMR(300MHz,CDCl₃)δ4.81–4.76(m,2H),4.68(q,J＝4.4Hz,1H),3.90(s,3H),3.44(dd,J＝4.5,1.2Hz,1H)。

(E) Methyl 3-nitroacrylate (tetrahedron, 60 (2); 397-: methyl 2-hydroxy-3-nitropropionate (1.49g, 10mmol) was dissolved in anhydrous dichloromethane (10mL) and cooled to-20 ℃. Triethylamine (4.2mL, 30mmol) and methanesulfonyl chloride (2.32mL, 15mmol) were then added. The reaction mixture was stirred at-20 ℃ for 1h, then diluted with DCM and quenched with sodium bicarbonate solution and extracted with DCM (3 × 10 mL). The combined organic phases were washed with brine and then with Na₂SO₄Drying, concentration and purification by silica gel chromatography (hexane/EA 10: 1-5: 1) gave methyl (E) -3-nitroacrylate (1.10g, 85% yield) as a pale yellow oil.¹H NMR(500MHz,CDCl₃)δ7.70(d,J＝13.5Hz,0H),7.11(d,J＝13.5Hz,0H),3.89(s,H)。

Methyl 2- (5-chloro-1H-indol-3-yl) -3-nitropropionate (Journal of Organic Chemistry, 70) (5)，1941-1944；2005): silica gel (5.0g) was added to CeCl₃·7H₂O (11.2g, 3mmol) and NaI (0.134g, 3mmol) in acetonitrile (100mL) and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed by rotary evaporation. To a mixture of 5-chloroindole (303mg, 2mmol) and silica gel mixture (1.15 g prepared above) was added methyl (E) -3-nitroacrylate (262mg, 2mmol) and the mixture was stirred for 2 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (3 × 10 mL). The combined organic phases were concentrated and purified by silica gel chromatography (hexane/EA 8: 1-5: 1) to give methyl 2- (5-chloro-1H-indol-3-yl) -3-nitropropionate (424mg, 75% yield).¹H NMR(500MHz,CDCl₃)δ8.37(s,1H),7.65–7.60(m,1H),7.32(dd,J＝8.7,1.0Hz,1H),7.21(dt,J＝8.7,1.5Hz,1H),7.19–7.15(m,1H),5.20(ddd,J＝14.2,9.3,1.1Hz,1H),4.75–4.63(m,2H),3.77(d,J＝1.2Hz,3H)。

3-amino-2- (5-chloro-1H-indol-3-yl) propionic acid methyl ester: to a solution of methyl 2- (5-chloro-1H-indol-3-yl) -3-nitropropionate (60mg, 0.212mmol) and zinc (278mg, 4.245mmol) was addedAcetic acid (1.2mL, 21.2mmol) was added and the reaction mixture was stirred at room temperature for 16 h. LC-MS showed that all starting material disappeared. The reaction mixture was filtered off over celite and washed with ethyl acetate (3X 3 mL). The filtrate was concentrated under reduced pressure, basified with 1N sodium hydroxide solution, and extracted with ethyl acetate (3X 5 mL). The combined organic phases were washed with brine and Na₂SO₄Drying, concentration and purification by silica gel chromatography (DCM/MeOH 20: 1-3: 1) gave methyl 3-amino-2- (5-chloro-1H-indol-3-yl) propionate (46mg, 85% yield).¹H NMR (500MHz, methanol-d)₄)δ7.61(d,J＝2.1Hz,1H),7.33(d,J＝8.6Hz,1H),7.25(s,1H),7.09(dd,J＝8.6,2.0Hz,1H),4.01(dd,J＝8.3,6.4Hz,1H),3.69(s,3H),3.32(q,J＝1.6Hz,1H),3.07(dd,J＝12.9,6.4Hz,1H)。

6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-4-carboxylic acid methyl ester: formalin (35% solution, 0.194mL, 2.612mmol) was added to a solution of methyl 3-amino-2- (5-chloro-1H-indol-3-yl) propionate (550mg, 2.176mmol) and concentrated HCl (0.181mL, 2.176mmol) in methanol (5 mL). The mixture was stirred at room temperature for 16 h. Collecting precipitate formed in the reaction process, washing twice with methanol, and vacuum drying to obtain 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-4-carboxylic acid methyl ester hydrochloride (374mg, 65% yield).¹H NMR (500MHz, methanol-d)₄)δ11.11(s,1H),7.67(d,J＝2.0Hz,1H),7.36(d,J＝8.7Hz,1H),7.16(dd,J＝8.7,2.1Hz,1H),4.55–4.41(m,2H),4.29(t,J＝3.8Hz,1H),4.03(dd,J＝12.9,2.6Hz,1H),3.80(s,3H),3.57(dd,J＝12.9,4.9Hz,1H)。

(6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-4-yl) methanol: LiAlH is added under argon at 0 DEG.C₄The powder (182mg, 4.8mmol) was added to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] in three portions]Indole-4-carboxylic acid methyl ester (240mg, 0.8mmol) in anhydrous THF (6 mL). After stirring at room temperature for 30min, the reaction mixture was heated to reflux for 16 h. The mixture was then cooled to room temperature and quenched with water and sodium hydroxide solution. The suspension was then filtered and the filtrate was washed with diethyl ether (3X 10 mL). The combined organic solutions were concentrated and purified by flash chromatography on silica gel (DCM/MeO)H ═ 10: 1-5: 1) to give (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-4-yl) methanol (161mg, yield 85%).¹H NMR (500MHz, chloroform-d) δ 8.37(s,1H),7.47(d, J ═ 2.0Hz,1H),7.13(d, J ═ 8.6Hz,1H),7.06(dd, J ═ 8.6,2.0Hz,1H),4.07(dd, J ═ 10.5,3.2Hz,1H),4.01(d, J ═ 4.5Hz,1H),3.91(d, J ═ 15.4Hz,1H),3.81(d, J ═ 15.4Hz,1H),3.40(dd, J ═ 12.4,2.2Hz,1H),3.12(dd, J ═ 12.4,4.3Hz,1H),3.00(d, J ═ 3.5, 1H).

General scheme 5

N- ((5-chloro-1H-indol-3-yl) methyl) -N-ethylethylamine: to a mixture of 30% formaldehyde (6.0mL) and dimethylamine (5.8g, 79.2mmol, 1.2 equiv.) in 60% acetic acid (18mL) was added 5-chloro-1H-indole (10.0g, 66.0mmol, 1.0 equiv.). The mixture was stirred at room temperature for 4 h. The mixture was poured into 15% aqueous NaOH (500mL) at 0 ℃. The obtained mixture is substituted by CH₂Cl₂(3X 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel column Chromatography (CH)₂Cl₂/CH₃OH 10: 1-5: 1) to yield N- ((5-chloro-1H-indol-3-yl) methyl) -N-ethyl-amine as a white solid (3.3g, yield: 21%).

N- ((5-chloro-1H-indol-3-yl) methyl) -N-ethylethylamine: to a mixture of N- ((5-chloro-1H-indol-3-yl) methyl) -N-ethylethylamine (3.30g, 13.94mmol, 1.0 eq) and formylaminomalonic acid diethyl ester (5.67g, 27.88mmol, 2.0 eq) in toluene (50mL) was added sodium hydroxide (195mg, 4.88mmol, 0.35 eq). The mixture was stirred at 125 ℃ for 24 h. The reaction suspension was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether: EtOAc ═ 5: 1-0: 1) to give N- ((5-chloro-1H-indol-3-yl) methyl) -N-ethyl ethylamine (3.5g, yield: 68%) as an off-white solid.

2-amino-3- (5-chloro-1H-indol-3-yl) propionic acid: to N- ((5-chloro-1H-indole-3-)Yl) methyl) -N-ethylethylamine (700mg, 1.9mmol, 1.0 eq) in H₂To the mixture in O (10mL) was added NaOH (304mg, 7.6mmol, 4.0 equiv). The mixture was stirred at 100 ℃ for 7 h. Acetic acid (1.5mL) was added and the mixture was stirred at 130 ℃ for 5 h. After cooling the solution to room temperature, the precipitate was collected by filtration to give the crude product 2-amino-3- (5-chloro-1H-indol-3-yl) propionic acid or 5-chlorotryptophan (5-chlorotryptohan) as a white solid (550mg, crude).

6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxylic acid (Chemical)&Pharmaceutical Bulletin,35(8),3284-91；1987): 5-Chlorotritryptophan (239mg, 1.0mmol), 35% formalin (0.1mL, 1.17mmol) and 0.1M H were added at room temperature₂SO₄(1.56mL) in 0.55mL H₂O and 0.78mL EtOH were stirred for 18 h. The resulting precipitate was collected, washed with water (3X 1mL), and dried under high vacuum to give 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-3-carboxylic acid (200mL, 80% yield). The crude product was taken to the next step without further purification. LC-MS: [ M + H]⁺:251.0。

(6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-3-yl) methanol: LiAlH is added under argon at 0 DEG.C₄The powder (182mg, 4.788mmol) was added to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] in three portions]Indole-3-carboxylic acid (200mg, 0.798mmol) in anhydrous THF (5 mL). After stirring at room temperature for 30min, the reaction mixture was heated to reflux for 16h, then cooled to room temperature and quenched with water and sodium hydroxide solution. The suspension was filtered and washed with diethyl ether (3X 10 mL). The filtrate was dried over sodium sulfate, concentrated and purified by silica gel flash chromatography (DCM/MeOH ═ 10: 1-3: 1) to give (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-3-yl) methanol (150mg, yield 80%).¹H NMR (500MHz, methanol-d)₄)δ7.42(d,J＝2.0Hz,1H),7.30(d,J＝8.6Hz,1H),7.07(dd,J＝8.6,2.1Hz,1H),4.37–4.22(m,2H),3.93(dd,J＝11.7,4.1Hz,1H),3.75(dd,J＝11.7,7.0Hz,1H),3.50–3.42(m,1H),2.92(ddd,J＝15.7,4.8,1.1Hz,1H),2.82–2.72(m,1H)。

General scheme 6

To a solution of amine (1.0 eq) and N, N-diisopropylethylamine (3.0 eq) in absolute ethanol was added a solution of epoxide (1.2 eq) in ethanol. The reaction mixture was heated at reflux for 12h, then concentrated and purified by silica gel flash chromatography to give the desired product (yield, 30-60%).

2- (6-chloro-8-methoxy-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (3-chlorophenyl) Ethane-1-ol (Journal of Medicinal Chemistry,51 (6); 1925-：

To 6-chloro-8-methoxy-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]To a solution of indole hydrochloride (41mg, 0.15mmol) and DIPEA (0.078mL, 0.45mmol) in anhydrous ethanol (2mL) was added 2- (3-chlorophenyl) oxirane (28mg, 0.18 mmol). The reaction mixture was then heated to reflux overnight. The mixture was concentrated and purified by silica gel column chromatography to give 2- (6-chloro-8-methoxy-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ]]Indol-2-yl) -1- (3-chlorophenyl) ethan-1-ol (17mg, 60%).¹H NMR (500MHz, chloroform-d) δ 8.08(s,1H),7.44(d, J ═ 2.1Hz,1H),7.28(d, J ═ 3.5Hz,3H),7.10(d, J ═ 1.6Hz,1H),6.62(s,1H),4.83(dd, J ═ 10.5,3.3Hz,1H),3.94(s,3H), 3.94-3.87 (m,1H),3.75(d, J ═ 14.6Hz,1H), 3.18-3.04 (m,1H),2.90(ddd, J ═ 11.8,6.8,4.9Hz,1H),2.85(dd, J ═ 12.6,3.4, 1H), 2.82-2.77 (m, 2.64H), 2.5H, 12.5 (ddd, 1H).

2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl-1- (3, 4-dichlorobenzene) Yl) Ethan-1-ol formate salt：

¹H NMR(400MHz,DMSO-d₆)δ10.89(d,J＝10.0Hz,1H),8.16(s,1H),7.62(t,J＝2.2Hz,1H),7.56(dd,J＝8.3,3.4Hz,1H),7.43–7.32(m,2H),7.26(dd,J＝8.5,3.5Hz,1H),6.99(dt,J＝8.6,1.6Hz,1H),4.74(t,J＝6.3Hz,1H),3.81(dq,J＝12.9,6.7Hz,1H),3.17–2.90(m,2H),2.72(dddt,J＝38.0,18.9,13.0,6.3Hz,4H),2.46(s,1H),1.26(dd,J＝53.0,6.6Hz,3H)。LCMS:[M+H]⁺＝409.1。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (4-chloro-3- (trifluoromethyl) Phenyl) ethane-1-ol formate salt：

¹H NMR(400MHz,DMSO-d₆)δ10.92(s,1H),8.15(s,1H),7.87(d,J＝1.9Hz,1H),7.76–7.64(m,2H),7.38(d,J＝2.1Hz,1H),7.27(d,J＝8.5Hz,1H),6.99(dd,J＝8.5,2.1Hz,1H),5.51(s,1H),4.93(t,J＝6.3Hz,1H),3.80–3.63(m,2H),2.95–2.66(m,4H),2.64(d,J＝5.7Hz,2H)。LCMS:[M+H]⁺＝429.1,431.1。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (3-chloro-5- (trifluoromethyl) Phenyl) ethane-1-ol formate salt：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),8.16(s,1H),7.82–7.69(m,3H),7.38(d,J＝1.7Hz,1H),7.27(d,J＝8.5Hz,1H),6.99(m,J＝8.5Hz,1H),5.57(s,1H),4.95(t,J＝6.1Hz,1H),3.86–3.65(m,2H),2.89(m,J＝5.6Hz,1H),2.84–2.71(m,3H),2.63(t,J＝4.8Hz,2H)。LCMS:[M+H]⁺＝429.1,431.1。

3- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (3-chlorophenyl) propane-1- Alcohol(s)：

¹H NMR(400MHz,DMSO-d₆):δ10.91(s,1H),7.39(d,J＝8.3Hz,2H),7.35(d,J＝7.6Hz,1H),7.33–7.25(m,3H),7.00(m,1H),5.58(s,1H),4.69(t,J＝6.1Hz,1H),3.61(s,2H),2.76(s,2H),2.71–2.58(m,4H),1.97–1.70(m,2H)。LCMS:[M+H]⁺＝375.0,377.0。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (4-chlorophenyl) ethanol hydrochloride Salt (salt)：

¹H NMR(400MHz,DMSO-d₆):δ11.36(d,J＝8.4Hz,1H),10.65～10.58(m,1H),7.56～7.52(m,2H),7.45～7.38(m,4H),7.13(d,J＝8.8Hz,1H),6.51～6.43(m,1H),5.32～5.25(m,1H),4.77～4.54(m,2H),3.92～3.63(m,1H),3.55～3.41(m,2H),3.13～2.96(m,2H)。LCMS:[M+H]⁺＝361.0。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (4- (trifluoromethyl) phenyl) Ethanol：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),7.69～7.61(m,4H),7.38(d,J＝1.6Hz,1H),7.28(d,J＝8.4Hz,1H),7.00(dd,J＝8.4,2.0Hz,1H),5.4(d,J＝2.8Hz,1H),4.92(s,1H),3.78～3.70(m,2H),2.89～2.63(m,6H)。LCMS:[M+H]⁺＝395.1。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3- (trifluoromethyl) phenyl) Ethanol：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),7.75(s,1H),7.71(d,J＝7.2Hz,1H),7.59～7.56(m,2H),7.38(d,J＝2.0Hz,1H),7.28(d,J＝8.4Hz,1H),7.00(dd,J＝8.4,2.0Hz,1H),5.41(s,1H),4.93(t,J＝5.2Hz,1H),3.78～3.70(m,2H),2.89～2.64(m,6H)。LCMS:[M+H]⁺＝395.0。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3, 4-dichlorophenyl) ethanol Formate salt：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),8.18(s,1H),7.64(d,J＝1.6Hz,1H),7.59(d,J＝8.4Hz,1H),7.40～7.37(m,2H),7.28(d,J＝8.4Hz,1H),7.00(dd,J＝8.4,2.0Hz,2H),4.84(t,J＝5.6Hz,2H),3.76～3.68(m,2H),2.91～2.62(m,6H)。LCMS:[M+H]⁺＝395.0。

3-chloro-5- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -1-hydroxyethyl) benzenes Phenol and its salts：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),9.84(s,1H),7.38(d,J＝1.6Hz,1H),7.28(d,J＝8.8Hz,1H),6.99(dd,J＝1.6,8.4Hz,1H),6.85(s,1H),6.76(s,1H),6.66～6.65(m,1H),5.24(s,1H),4.73(s,1H),2.73(s,2H),2.88～2.81(m,2H),2.73～2.63(m,4H)。LCMS:[M+H]⁺＝377.2。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3-chlorophenyl) -ethylamine carboxylic acid Salt (salt)：

¹H NMR(400MHz,CD₃OD):δ7.46～7.42(m,3H),7.34～7.31(m,2H),7.21(d,J＝8.4Hz,1H),6.99(dd,J＝8.4,2.0Hz,1H),4.14～4.1(m,1H),3.82～3.72(m,2H),3.62(d,J＝14.0Hz 1H),3.22(dd,J＝13.6,5.2Hz,1H),3.08～3.05(m,1H),2.79～2.78(m,2H),2.64～2.61(m,1H)。LCMS:[M+H]⁺＝360.2。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3-chloro-4-fluorophenyl) ethanol Formate salt：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),8.39(s,H),7.59(dd,J＝7.2,1.6Hz,1H),7.42～7.33(m,3H),7.28(d,J＝8.4Hz,1H),7.00(dd,J＝8.8,2.4Hz,1H),4.84～4.81(m,1H),3.76～3.58(m,2H),2.89～2.62(m,6H)。LCMS:[M+H]⁺＝379.2。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (2, 3-dichlorophenyl) ethanol：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),7.62～7.60(m,1H),7.55～7.53(m,1H),7.41～7.37(m,2H),7.28(d,J＝8.4Hz,1H),7.00～6.97(m,1H),5.57(s,1H),5.22～5.21(m,1H),3.78～3.77(m,2H),2.90(t,2H),2.71～2.65(m,4H)。LCMS:[M+H]⁺＝395.0。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (4- (trifluoromethyl) phenyl) Ethanol：

¹H NMR(400MHz,DMSO-d₆):δ10.87(s,1H),7.47～7.45(m,3H),7.41(s,1H),7.30(d,J＝8.8Hz,1H),7.0(d,J＝8.4Hz,1H),5.49(s,1H),4.80(d,J＝4.0Hz,2H),3.79～3.77(m,1H),3.68(s,2H),3.07～3.04(m,1H),2.91～2.87(m,1H),2.83～2.73(m,2H),2.69～2.64(m,1H),2.45～2.42(m,1H)。LCMS:[M+H]⁺＝427.2。

2- (6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -1- (3-chloro-4- Tolyl) Ethanolate：

¹H NMR(400MHz,DMSO-d₆):δ10.88～10.84(m,1H),8.23(s,1H),7.42～7.39(m,2H),7.31～7.20(m,3H),7.02～6.99(m,1H),5.25(brs,1H),4.75～4.68(m,2H),3.86～3.77(m,1H),3.68～3.59(m,2H),3.20～3.05(m,2H),2.92～2.86(m,1H),2.80～2.72(m,1H),2.68～2.58(m,1H),2.46～2.41(m,1H),2.95～2.89(m,3H)。LCMS:[M+H]⁺＝405.0。

2- (6-chloro-1- (morpholinomethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (3,4- Dichlorophenyl) ethane-1-ol dihydrochloride：

¹H NMR (400MHz, methanol-d)₄):δ7.69-7.64(m,1H),7.53-7.49(m,2H),7.42-7.36(m,2H),7.18-7.15(m,1H),5.30(br,1H),4.40-2.80(m,18H)。LCMS:[M+H]⁺＝494.5。

2- (6-chloro-1- ((4-methylpiperazin-1-yl) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole- 2-yl) -1- (3, 4-dichlorophenyl) ethane-1-ol trihydrochloride：

¹H NMR (400MHz, methanol-d)₄)δ7.70(s,1H),7.53-7.50(m,2H),7.45-7.34(m,2H),7.17-7.13(m,1H),5.57-5.45(m,1H),5.32-5.23(m,1H),3.95-3.72(m,2H),3.59-3.39(m,7H),3.30-3.10(m,5H),2.95(d,J＝6.4Hz,3H),2.91-2.58(m,2H)。LCMS:[M+H]⁺＝509.2。

2- (6-chloro-4-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (2, 3-dichlorobenzene Yl) ethane-1-alkoxide：

¹H NMR (400MHz, methanol-d)₄)δ10.91-10.85(m,0.49H),7.75-7.72(m,1H),7.63-7.56(m,2H),7.44-7.33(m,2H),7.13(d,J＝8.4Hz,1H),5.73-5.21(m,1H),4.85-4.51(m,2H),4.10-3.90(m,1H),3.86-3.54(m,2H),3.48-3.40(m,1H),3.29-3.11(m,1H),1.58–1.47(m,3H)。LCMS:[M+H]⁺＝409.2。

General scheme 7

The compound 2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- Representative Synthesis of (3, 4-dichlorophenyl) ethane-1-ol：

To a mixture of DMSO (40mL) was added 95% NaH (704mg, 27.88 mmol). The mixture was stirred at room temperature for 15 min. To this calcium iodomethane sulfonate (6.04g, 27.43mmol) was added portionwise at room temperature. The mixture was stirred at 40 ℃ for 3 h. 3, 4-Dichlorobenzaldehyde (4g, 22.86mmol) was then added dropwise. The mixture was stirred at room temperature for 3h, then quenched with aqueous ammonium chloride and extracted with EtOAc (3X 40 mL).The organic layer was washed with Na₂SO₄Dried and filtered. The filtrate was concentrated to give 2- (3, 4-dichlorophenyl) oxirane (1.3g, yield: 30.1%).

To a mixture of 2- (3, 4-dichlorophenyl) oxirane (89.08mg, 0.471mmol) in EtOH (10mL) was added ((6-chloro-2- (2,2, 2-trifluoroacetyl) -2,3,4, 9-tetrahydro-1H-2 l 4-pyrido [3, 4-b)]Indol-1-yl) methyl) carbamic acid benzyl ester (200mg, 0.428mmol) and Et₃N (130.05mg, 1.29 mmol). The mixture was stirred at 80 ℃ for 16 h. The mixture was then concentrated and the residue was purified by silica gel column chromatography (PE: EtOAc ═ 3:1) to give ((6-chloro-2- (2- (3, 4-dichlorophenyl) -2-hydroxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a colorless oil]Indol-1-yl) methyl) carbamic acid benzyl ester (110mg, yield: 45.9%). This material was used directly in the next step. LCMS: [ M + H]⁺＝559.8。

To ((6-chloro-2- (2- (3, 4-dichlorophenyl) -2-hydroxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) carbamic acid benzyl ester (110mg, 0.197mmol) in DCM (10mL) was added TMSI (0.22mL, 1.35 mmol). The mixture was stirred at 0 ℃ to room temperature for 4 h. LCMS indicated the reaction was complete. The mixture was added dropwise to ice water and then extracted with DCM (3 × 10 mL). The combined organic layers were concentrated to give the crude product, which was purified by preparative high performance liquid chromatography (mobile phase: 0.1% HCOOH/CH)₃CN/H₂O) further purification to give 2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b) as a white solid]Indol-2-yl) -1- (3, 4-dichlorophenyl) ethane-1-ol (17mg, yield: 20.3%).¹H NMR(400MHz,DMSO-d₆)δ11.07(s,1H),8.35(s,1H),7.60(ddd,J＝18.8,12.7,5.0Hz,2H),7.47–7.25(m,3H),7.08–6.98(m,1H),4.84(d,J＝9.2Hz,1H),3.90(s,2H),3.18–2.55(m,10H),2.40(s,1H)。LCMS:[M+1]⁺＝424.0,426.0。

General scheme 8

3, 5-dichloro-N-(2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) aniline Representative Synthesis of (A)

2- ((3, 5-dichlorophenyl) amino) acetic acid ethyl ester: a mixture of 3, 5-dichloroaniline (500mg, 3.51mmol), ethyl 2-bromoacetate (585.6mg, 3.51mmol) and DIEA (1.36g, 10.52mmol) in MeCN (5mL) was heated to 80 ℃ and stirred for 16 h. The reaction solution was concentrated to give ethyl (3, 5-dichlorophenyl) glycinate (800mg, yield: 100%) as a yellow solid. LCMS: [ M + H]⁺＝248.1。

2- ((3, 5-dichlorophenyl) amino) ethanol: to a solution of ethyl (3, 5-dichlorophenyl) glycinate (800mg, 3.23mmol) in THF (10mL) was added LiBH dropwise₄(2M in THF, 2.4mL, 4.84 mmol). The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The resulting solution was concentrated in vacuo to give a crude product, which was purified by silica gel chromatography eluting with petroleum ether and ethyl acetate 5:1 to give the product 2- ((3, 5-dichlorophenyl) amino) ethane-1-ol as a yellow oil (424mg, yield: 67%). LCMS: [ M + H]⁺＝206.1。

2- ((3, 5-dichlorophenyl) amino) methanesulfonic acid ethyl ester: to 2- ((3, 5-dichlorophenyl) amino) ethan-1-ol (424mg, 206mmol) and Et₃N (624.8mg, 6.17mmol) in CH₂Cl₂To the solution in (10mL) was added MsCl (282.9mg, 2.47mmol) dropwise. The reaction was stirred at room temperature for 2h, then quenched with water and with CH₂Cl₂And (4) extracting. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give ethyl 2- ((3, 5-dichlorophenyl) amino) methanesulfonate as a brown oil (640mg, yield: 100%). LCMS: [ M + H]⁺＝283.9。

3, 5-dichloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) aniline: 2- ((3, 5-dichlorophenyl) amino) methylsulfonylEthyl acid ester (116.8mg, 0.41mmol), 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]A mixture of indole hydrochloride (100mg, 0.41mmol) and DIEA (159.2mg, 1.23mmol) in DMF (2mL) was heated to 70 ℃ and stirred for 16 h. The reaction solution was concentrated, and the residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₄HCO₃/CH₃CN/H₂O) purification to give 3, 5-dichloro-N- (2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b) as a yellow solid]Indol-2-yl) ethyl) aniline (25mg, yield: 15%).¹H NMR(400MHz,DMSO-d₆):δ10.93(s,1H),7.39(d,J＝2.0Hz,1H),7.29(d,J＝8.4Hz,1H),7.01(dd,J＝8.4,2.0Hz,1H),6.62(d,J＝2.0Hz,2H),6.58(t,J＝2.0Hz,1H),6.21(t,J＝5.2Hz,1H),3.67(s,2H),3.26～3.21(m,2H),2.82(t,J＝6.0Hz,2H),2.74(t,J＝8.4Hz,2H),2.69～2.67(m,2H)。LCMS:[M+H]⁺＝394.2。

3-chloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) carbamic acid Salt (salt)：

¹H NMR(400MHz,DMSO-d₆):δ10.93(s,1H),8.17(s,1H),7.39(d,J＝2.0,Hz,1H),7.29(d,J＝8.8Hz,1H),7.06(t,J＝8.0Hz,1H),7.01(dd,J＝8.4,2.0Hz,1H),6.62(t,J＝2.0Hz,1H),6.57～6.51(m,2H),5.84(s,1H),3.68(s,2H),3.23(d,J＝4.4Hz,2H),2.84～2.67(m,6H)。LCMS:[M+H]⁺＝360.0。

4-chloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) carbamic acid Salt (salt)：

¹H NMR(400MHz,DMSO-d₆):δ10.94(s,1H),8.22(s,1H),7.39(d,J＝2.0Hz,1H),7.28(d,J＝8.4Hz,1H),7.08(d,J＝11.6Hz,2H),6.99(dd,J＝2.0,8.8Hz,1H),6.61(d,J＝8.8Hz,2H),5.69(br,1H),3.68(s,2H),3.22～3.19(m,2H),2.84～2.81(m,2H),2.77～2.74(m,2H),2.69～2.68(m,2H)。LCMS:[M+H]⁺＝360.2。

(6-chloro-2- (2- ((3-chlorophenyl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-1- Based) methanol：

¹H NMR(400MHz,DMSO-d₆):δ10.85(s,1H),7.41(s,1H),7.40～7.24(m,1H),7.01～6.79(m,2H),6.61～6.58(m,3H),5.83(s,1H),4.76(s,1H),3.71～3.62(m,3H),3.17～3.10(m,3H),2.90～2.71(m,4H),2.47(s,1H)。LCMS:[M+H]⁺＝390.3。

(6-chloro-2- (2- ((3, 4-dichlorophenyl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole Indole-1-yl) methanol：

¹H NMR(400MHz,DMSO-d₆):δ10.85(s,1H),7.41(s,1H),7.40～7.24(m,2H),7.01～6.99(m,1H),6.80～6.79(d,J＝2.4Hz,1H),6.61～6.58(m,1H),6.05(t,1H),4.76(s,1H),3.71～3.62(m,3H),3.17～3.10(m,3H),2.90～2.71(m,4H),2.44(s,1H)。LCMS:[M+H]⁺＝426.3。

N- (2- (1- (aminomethyl) -6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) -3, 4-dichloroaniline：

¹H NMR(400MHz,DMSO-d₆):δ11.31(s,1H),8.20(s,2H),7.46(s,1H),7.34～7.32(d,J＝8.8Hz,1H),7.26～7.24(d,J＝8.4Hz,1H),7.07～7.04(m,1H),6.88～6.87(d,J＝2.4Hz,1H),6.69～6.66(m,1H),6.52～6.22(m,1H),4.04～4.02(m,2H),3.20～3.16(m,3H),3.09～3.03(m,2H),2.96～2.93(m,1H),2.86～2.71(m,3H),2.54～2.52(m,2H)。LCMS:[M+H]⁺＝423.0。

General scheme 9

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorobenzene Yl) representative Synthesis of acetamide：

2-Bromoacetic acid: to a solution of 2-amino-2- (4-chlorophenyl) acetic acid (1g, 5.90mmol, 1.0 eq) in THF (10mL) was added LiOH. H₂O (494mg, 11.8mmol, 2.0 equiv.). The reaction was stirred at 25 ℃ for 20 min. Subjecting the reaction mixture to hydrogenation with H₂O (5mL) was diluted, acidified to pH 3-4 with 1N hydrochloric acid, and extracted with ethyl acetate (20mL × 3). The organic solution is treated with Na₂SO₄Drying and concentration gave 2-bromoacetic acid as a colorless oil (1g, 32.9% yield). [ M-H ]]^-＝137.0,139.0。

2-bromo-N- (3-chlorophenyl) acetamide: to a solution of 2-bromoacetic acid (1g, 7.20mmol, 1.0 equiv.), 3-chloroaniline (1.1g, 7.90mmol, 1.1 equiv.), and HATU (4g, 10.80mmol, 1.5 equiv.) in DCM (20mL) under argon was added Et₃N (1.45g, 14.40mmol, 2.0 equiv.). The reaction mixture was stirred at 25 ℃ for 3H and then with H₂O (20mL) was quenched and extracted with EtOAc (20 mL. times.3). The organic solution is treated with Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography (DCM: MeOH ═ 20:1) to give 2-bromo-N- (3-chlorophenyl) acetamide as a colourless oil (340mg, 68.5% yield). LCMS (liquid Crystal display Module) [ M-H ]]^-＝246.0,248.0。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorobenzene Yl) acetamide: to a solution of 2-bromo-N- (3-chlorophenyl) acetamide (48mg, 0.19mmol, 1.0 eq) in DMF (2mL) was added (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methanol (60mg, 0.25mmol, 1.3 eq) and K₂CO₃(186mg, 1.35mmol, 7.0 equiv.). The reaction was stirred at 25 ℃ for 3H and then with H₂Quenched with O (20mL) and extracted with ethyl acetate (20 mL. times.3). The organic solution is treated with Na₂SO₄Drying and concentrating, purifying the residue by preparative high performance liquid chromatography to obtain 2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] as a white solid]Indol-2-yl) -N- (3-chlorophenyl) acetamide (9.29mg, 11.88%).¹H NMR(400MHz,CDCl₃):δ9.71(s,1H),8.15(s,1H),7.72(s,1H),7.54–7.45(m,2H),7.24–7.20(m,2H),7.11(m,J＝8.3Hz,2H),4.03–3.94(m,1H),3.93–3.79(m,2H),3.42(q,J＝17.2Hz,2H),3.26(d,J＝8.9Hz,1H),3.07(d,J＝13.2Hz,1H),2.85(d,J＝5.4Hz,1H),2.68(d,J＝15.8Hz,1H)。LCMS:[M+H]⁺＝404.0,406.0。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]indol-2-yl-N- (3-chlorophenyl) -2-methylpropane Amides of carboxylic acids：

¹H NMR(400MHz,DMSO-d₆)δ10.98(s,1H),9.96(s,1H),7.88(t,J＝2.0Hz,1H),7.62-7.58(m,1H),7.41(d,J＝2.0Hz,1H),7.33-7.27(m,2H),7.11-7.07(m,1H),7.24-7.18(m,2H),7.03-6.98(dd,J＝2,8.4Hz,1H),3.81(s,2H),2.72-2.63(m,4H),1.32(s,6H)。LCMS:[M+H]⁺＝402.1,404.1。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N1- (3-chlorophenyl) -N3-methyl Malonamide：

¹H NMR(400MHz,CD₃OD)δ7.82(t,J＝2.1Hz,1H),7.49(dd,J＝8.0,2.0Hz,2H),7.35(d,J＝8.1Hz,1H),7.33–7.28(m,1H),7.19(ddd,J＝8.1,2.1,1.0Hz,1H),7.10(dd,J＝8.6,2.1Hz,1H),4.72(s,1H),4.50(s,2H),3.62(s,2H),3.08(s,2H),2.87(s,3H)。LCMS:[M+H]⁺＝431.0,433.0。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorobenzene Yl) acetamide：

¹H NMR(400MHz,CDCl₃):δ9.71(s,1H),8.15(s,1H),7.72(s,1H),7.54–7.45(m,2H),7.24–7.20(m,2H),7.11(m,J＝8.3Hz,2H),4.03–3.94(m,1H),3.93–3.79(m,2H),3.42(q,J＝17.2Hz,2H),3.26(d,J＝8.9Hz,1H),3.07(d,J＝13.2Hz,1H),2.85(d,J＝5.4Hz,1H),2.68(d,J＝15.8Hz,1H)。LCMS:[M+H]⁺＝404.0,406.0。

2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorobenzene Yl) acetamide diformate：

¹H NMR(400MHz,CD₃OD):δ8.52(s,1H),7.84(t,J＝1.9Hz,1H),7.45(d,J＝1.9Hz,1H),7.41(d,J＝8.1Hz,1H),7.32–7.25(m,2H),7.14–7.05(m,2H),4.01(d,J＝10.1Hz,1H),3.71–3.58(m,2H),3.40–3.33(m,1H),3.27–3.17(m,2H),3.13(m,J＝2.9Hz,1H),2.92(m,J＝5.8Hz,1H),2.64(d,J＝14.3Hz,1H)。LCMS:[M+H]⁺＝403.1,405.1。

2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorobenzene Yl) acetamide：

¹H NMR(400MHz,CD₃OD):δ8.52(s,1H),7.84(t,J＝1.9Hz,1H),7.45(d,J＝1.9Hz,1H),7.41(d,J＝8.1Hz,1H),7.32–7.25(m,2H),7.14–7.05(m,2H),4.01(d,J＝10.1Hz,1H),3.71–3.58(m,2H),3.40–3.33(m,1H),3.27–3.17(m,2H),3.13(m,J＝2.9Hz,1H),2.92(m,J＝5.8Hz,1H),2.64(d,J＝14.3Hz,1H)。LCMS:[M+H]⁺＝403.1,405.1。

2- (7-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-N- (4-chlorophenyl) acetamidomethyl Acid salts：

¹H NMR(400MHz,DMSO-d₆)δ10.95(s,1H),9.98(s,1H),7.70(d,J＝8.8Hz,2H),7.41(s,1H),7.37-7.34(m,2H),7.30-7.28(m,1H),7.01-6.99(m,1H),3.79(s,2H),3.40(s,2H),2.91-2.81(m,2H),2.74-2.73(m,2H)。LCMS:[M+H]⁺＝374.2。

2- (7-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-N- (4-chlorophenyl) acetamidomethyl Acid salts：

¹H NMR(400MHz,DMSO-d₆)δ10.95(s,1H),10.03(s,1H),8.26(s,1H),7.88(s,1H),7.56(d,J＝8.0Hz,1H),7.41(s,1H),7.35-7.28(m,3H),7.11(d,J＝8.0Hz,1H),7.02-6.99(m,1H),3.79(s,2H),3.41(s,2H),2.91-2.89(m,2H),2.74-2.73(m,2H)。LCMS:[M+H]⁺＝374.2。

2- (6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-N- (4)-chloro-2- Hydroxyphenyl) acetamide formate salt：

¹H NMR(400MHz,DMSO-d₆):δ10.95(s,1H),10.50(s,1H),8.03(s,1H),7.59～7.65(m,1H),7.45(d,J＝2.0Hz,1H),7.29(d,J＝8.8Hz,1H),7.02(dd,J＝10.8Hz,1H),5.63(s,1H),3.68～3.75(m,3H),3.51(d,J＝17.2Hz,1H),3.17～3.30(m,3H),3.03～3.04(m,1H),2.67～2.76(m,1H)。LCMS:[M+H]⁺＝436.0。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]indol-2-yl-N- (5-chloro-6-methylpyridine-2- Yl) acetamide：

¹H NMR(400MHz,DMSO-d₆):δ10.99(s,1H),10.15(s,1H),8.0(d,J＝8.8Hz,1H),7.86(d,J＝8.4Hz,1H),7.43(s,1H),7.31(d,J＝8.8Hz,1H),7.02(dd,J＝2.0Hz,8.4Hz,1H),3.83(s,2H),3.46(s,2H),2.93(t,J＝5.2Hz,2H),2.72(brs,2H),2.45(s,3H)。LCMS:[M+H]⁺＝389.2。

2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]indol-2-yl-N- (5-chloro-6- (hydroxy) Methyl) pyridin-2-yl) acetamide：

¹H NMR(400MHz,DMSO-d₆):δ11.02(brs,1H),10.11(brs,1H),8.09(d,J＝8.8Hz,1H),7.91(d,J＝8.4Hz,1H),7.44(d,J＝1.6Hz,1H),7.30(d,J＝8.4Hz,1H),7.03(dd,J＝2.0Hz,8.8Hz,1H),5.22(t,1H),4.54(d,J＝6.0Hz,2H),3.99-3.96(m,1H),3.50-3.40(m,2H),3.15-3.12(m,1H),2.93-2.89(m,1H),2.72-2.68(m,2H),1.43(d,J＝6.8Hz,3H)。LCMS:[M+H]⁺＝419.1。

2- (6-chloro-1- (2-hydroxyethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]indol-2-yl-N- (5-chloro-) 6-methylpyridin-2-yl) acetamide

¹H NMR(400MHz,DMSO-d₆):δ10.92(brs,1H),10.24(brs,1H),7.98(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.43(d,J＝1.6Hz,1H),7.30(d,J＝8.8Hz,1H),7.03(dd,J＝2.0Hz,8.4Hz,1H),4.75(t,J＝5.2Hz,1H),3.89(t,J＝6.0Hz,1H),3.70-3.58(m,4H),3.19-3.11(m,1H),2.97-2.92(m,1H),2.70～2.72(m,1H),2.55～2.54(m,1H),2.47(s,3H),1.98-1.94(m,2H)。LCMS:[M+H]⁺＝433.2。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (5-chloro-6- (trifluoromethyl) Pyridin-2-yl) acetamide formate salt

¹H NMR(400MHz,DMSO-d6):δ11.01(brs,1H),10.66(brs,1H),8.40(d,J＝9.2Hz,1H),3.96(br,1H),8.24(d,J＝9.2Hz,1H),7.42(s,1H),7.29(d,J＝8.4Hz,1H),7.01(dd,J＝1.2,8.4Hz,1H),3.83(s,2H),3.52(s,2H),2.95～2.92(m,2H),2.71(br,2H)。¹⁹F NMR(376.5MHz,DMSO-d6):δ-64.69。LCMS:[M+H]⁺＝443.1。

2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (1-methyl-1H- Imidazol-4-yl) acetamide formate salt

¹H NMR(400MHz,DMSO-d₆):δ11.02(brs,1H),9.73(brs,1H),8.32(br,1H),7.42-7.38(m,2H),7.29(d,J＝8.8Hz,1H),7.23(s,1H),7.03(dd,J＝2.4Hz,8.8Hz,1H),3.94～3.90(m,1H),3.62(s,3H),3.37(d,J＝2.4Hz,1H),3.12-3.06(m,1H),2.90-2.84(m,1H),2.71-2.60(m,2H),1.40(d,J＝5.6Hz,3H)。LCMS:[M+H]⁺＝358.2。

2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (5-chloro-6- (2-) Hydroxyethyl) pyridin-2-yl) acetamide

¹H NMR(400MHz,DMSO-d₆):δ11.02(brs,1H),10.07(brs,1H),7.99(d,J＝8.4Hz,1H),7.87(d,J＝8.8Hz,1H),7.44(d,J＝1.6Hz,1H),7.30(d,J＝8.4Hz,1H),7.03(dd,J＝8.8Hz,2.0Hz,1H),4.70(t,J＝5.6Hz,1H),3.99-3.95(m,1H),3.75-3.69(m,2H),3.51-3.39(m,2H),3.15-3.11(m,1H),2.97-2.90(m,3H),2.71-2.64(m,2H),1.42(d,J＝6.8Hz,3H)。LCMS:[M+H]⁺＝433.1。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (5-chloro-2- Methylpyridin-3-yl) acetamide

¹H NMR(400MHz,DMSO-d₆):δ11.01(brs,1H),10.14(brs,1H),8.32-8.29(m,2H),7.46(d,J＝1.6Hz,1H),7.31(d,J＝8.4Hz,1H),7.04(dd,J＝8.4Hz,2.0Hz,1H),5.32-5.29(m,1H),3.81-3.70(m,3H),3.55-3.51(m,1H),3.39-3.37(m,1H),3.29-3.19(m,1H),3.05-3.02(m,1H),2.82-2.78(m,1H),2.77-2.58(m,1H),2.48-2.45(m,3H)。LCMS:(M+H)⁺＝419.1。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3, 5-di Chloro-6-methylpyridine-2-Yl) acetamide

¹H NMR(400MHz,DMSO-d₆):δ10.99(brs,1H),10.43(brs,1H),8.23(s,1H),7.45(d,J＝2.0Hz,1H),7.32(d,J＝8.8Hz,1H),7.05(dd,J＝8.4Hz,2.0Hz,1H),5.18(t,J＝5.2Hz,1H),3.84～3.81(m,1H),3.73～3.70(m,2H),3.51～3.39(m,2H),3.22～3.18(m,1H),3.02～2.99(m,1H),2.83～2.76(m,1H),2.57～2.51(m,1H),2.51(s,3H)。LCMS:[M+H]⁺＝455.1。

2- (6-chloro-1- (tetrahydrofuran-2-yl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (5-chloro-6-methylpyridin-2-yl) acetamide

¹H NMR(400MHz,MeOD):δ8.01(d,J＝8.0Hz,1H),7.74(t,J＝8.8Hz,1H),7.51(s,1H),7.34(d,J＝8.8Hz,1H),7.12(dd,J＝8.8Hz,1.6Hz,1H),4.48(br,2H),4.00(br,2H),3.80-3.31(m,4H),3.16-2.93(m,2H),2.49(s,3H),2.41-2.07(m,2H),1.94-1.87(m,2H)。LCMS:[M+H]⁺＝459.2。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (5-chloro-6- Cyclopropyl pyridin-2-yl) acetamide formate salt

¹H NMR(400MHz,DMSO-d₆)δ10.94(s,1H),10.45(s,1H),7.92(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.45(d,J＝4.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.03(dd,J＝8.0,2.0Hz,1H),5.27(br,1H),3.75-3.65(m,3H),3.54(d,J＝20.0Hz,1H),3.26-3.16(m,2H),3.04-3.00(m,1H),2.79-2.72(m,1H),2.55-2.54(m,1H),2.42-2.37(m,1H),1.08-1.04(m,1H),1.04-0.96(m,3H)。LCMS:[M+H]⁺＝445.1。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (5-chloro-6- Propylpyridin-2-yl) acetamide

¹H NMR(400MHz,DMSO-d₆)δ10.94(s,1H),10.49(s,1H),8.01(d,J＝8.0Hz,1H),7.85(d,J＝8.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.03(dd,J＝8.0Hz,2.0Hz,1H),5.20(t,J＝4.0Hz,1H),3.76-3.67(m,3H),3.55(d,J＝16.0Hz,1H),3.36-3.32(m,1H),3.22-3.16(m,1H),3.02-2.98(m,1H),2.78-2.74(m,3H),2.56-2.51(m,1H),1.72-1.66(m,2H),0.94(t,J＝8.0Hz,3H)。LCMS:[M+H]⁺＝447.0。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (6-chloro-5- Methylpyridazin-3-yl) acetamide formate

¹H NMR(400MHz,DMSO-d₆)δ11.10(brs,1H),10.99(brs,1H),8.41(s,1H),7.45(d,J＝1.2Hz,1H),7.31(d,J＝8.4Hz,1H),7.03(dd,J＝8.4Hz,2.0Hz,1H),3.80-3.56(m,5H),3.04-3.01(m,2H),2.78-2.74(m,2H),2.40(s,3H)。LCMS:[M+H]⁺＝420.1。

2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]indol-2-yl-N- (6-methoxy) Yl-5- (trifluoromethyl) pyridin-2-yl) acetamide

¹H NMR(400MHz,DMSO-d₆)δ10.97(s,1H),10.83(s,1H),8.08(d,J＝8.4Hz,1H),7.86(d,J＝8.4Hz,1H),7.46(d,J＝2.0Hz,1H),7.31(d,J＝8.8Hz,1H),7.04(dd,J＝8.4Hz,2.0Hz,1H),5.44-5.42(m,1H),3.96(s,3H),3.80-3.66(m,3H),3.61(d,J＝17.6Hz,1H),3.33-3.29(m,1H),3.25-3.18(m,1H),3.08-3.03(m,1H),2.78-2.74(m,1H),2.56-2.49(m,1H)。LCMS:[M+H]⁺＝469.1。

General scheme 10

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorophenyl) -3-hydroxypropano Synthetic representation of amides：

3- ((3-chlorophenyl) amino) -3-oxopropanoic acid ethyl ester: ethyl 3-chloro-3-oxopropionate (2g, 13.3mmol, 1.0 equiv.) and 3-chloroaniline (1.7g, 13.3mmol, 1.0 equiv.) were dissolved in DCM (10mL), triethylamine (2.1g, 19.95mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo to give the crude product, which was further purified by silica gel chromatography to give ethyl 3- ((3-chlorophenyl) amino) -3-oxopropanoate (2.57g, 80% yield).

2-bromo-3- ((3-chlorophenyl) amino) -3-oxopropanoic acid ethyl ester: to a mixture of ethyl 3- ((3-chlorophenyl) amino) -3-oxopropanoate (1.1g, 4.55mmol, 1.0 equiv.) in acetic acid (AcOH, 5mL) was added Br₂(dibromine) (727.4mg, 4.55mmol, 1.0 equiv.). After stirring at room temperature for 1h, the reaction mixture was poured into water (20mL) and extracted with ethyl acetate (3X 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was further purified by silica gel column chromatography (eluent: PE: EA ═ 5:1) to give 2-bromo-3- ((3-chlorophenyl)) Amino) -3-oxopropanoic acid ethyl ester (1.2g, 82.3% yield).

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -3- ((3-chlorophenyl) amino) -3- Oxopropionic acid ethyl ester: to a mixture of ethyl 2-bromo-3- ((3-chlorophenyl) amino) -3-oxopropanoate (344mg, 1.07mmol, 1.0 equiv.) in MeCN (5mL) was added 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b-)]Indole hydrochloride (260.9mg, 1.07mmol, 1.0 equiv.) and potassium carbonate (444.3mg, 3.22mmol, 3.0 equiv.). The mixture was stirred at 50 ℃ for 2h, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA ═ 5:1) to give 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -3- ((3-chlorophenyl) amino) -3-oxopropanoic acid ethyl ester (532mg, yield 100%).

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorophenyl) -3-hydroxypropano Amides of carboxylic acids: to 0 ℃ 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ]]To a solution of indol-2-yl) -3- ((3-chlorophenyl) amino) -3-oxopropanoic acid ethyl ester (328mg, 0.73mmol, 1.0 eq) in THF (5mL) was slowly added LiBH₄(32.01mg, 1.46mmol, 2.0 equiv.). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was then poured into ice-water (20mL) and extracted with ethyl acetate (3X 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.07% HCOOH/CH)₃CN/H₂O) purification to give 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b) as a white solid]Indol-2-yl) -N- (3-chlorophenyl) -3-hydroxypropionamide (27.78mg, 8.4% yield).¹H NMR:(400MHz,DMSO-d₆)δ10.92(s,1H),10.12(s,1H),7.90(t,J＝2.1Hz,1H),7.52(dt,J＝8.3,1.4Hz,1H),7.40–7.23(m,3H),7.11(ddd,J＝7.9,2.0,1.0Hz,1H),6.99(dd,J＝8.6,2.1Hz,1H),4.88(t,J＝5.2Hz,1H),4.01(d,J＝15.0Hz,1H),3.93(dt,J＝11.8,6.2Hz,1H),3.87–3.75(m,2H),3.49(t,J＝6.1Hz,1H),2.95(dp,J＝22.9,5.8Hz,2H),2.67(t,J＝5.6Hz,2H)。LCMS:[M+H]⁺＝404。

General scheme 11

((6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3, 4-dichlorobenzene Radical) Synthesis of methanones：

((6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3, 4-dichlorobenzene Yl) methanone: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methoxide hydrochloride (45mg, 190.11. mu. mol) in TFH (10mL) was added 3, 4-dichlorobenzoic acid (36.31mg, 190.11. mu. mol), HATU (144.49mg, 380.23. mu. mol) and Et₃N (38.48mg, 380.23. mu. mol). The mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with EtOAc (3X 20 mL). The organic layer was washed with Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo to give a crude product, which was purified by preparative high performance liquid chromatography (mobile phase: 0.1% NH)₄OH/CH₃CN/H₂O) purification to obtain ((6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3, 4-dichlorophenyl) methanone.¹H NMR(400MHz,DMSO-d₆)δ11.21–10.81(m,1H),7.87–7.63(m,2H),7.46(d,J＝6.8Hz,2H),7.33(dd,J＝30.7,8.5Hz,1H),7.06(d,J＝8.6Hz,1H),5.63(s,1H),5.46(s,0H),5.22(s,1H),4.83–4.60(m,1H),3.89(s,1H),3.65(dt,J＝21.8,13.9Hz,2H),2.78(s,1H),2.66(d,J＝4.1Hz,1H)。LCMS:[M+H]⁺＝409.0,411.0。

(6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3, 5-dichlorobenzene Yl) methanone：

¹H NMR(400MHz,DMSO-d₆)δ11.01(d,J＝107.7Hz,1H),7.73(d,J＝18.0Hz,1H),7.56(d,J＝9.7Hz,2H),7.46(d,J＝11.8Hz,1H),7.36(d,J＝8.6Hz,1H),7.29(d,J＝8.5Hz,0H),7.05(d,J＝8.4Hz,1H),5.62(s,0.59H),5.49(s,0.33H),5.22(s,0.57H),4.74(d,J＝22.7Hz,0.7H),3.88(s,1H),3.66(ddd,J＝30.0,22.9,11.6Hz,2H),2.88–2.59(m,2H)。LCMS:[M+H]⁺＝409.0,411.0。

(1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3, 4-dichlorobenzene Yl) methanone：

¹H NMR(400MHz,DMSO-d₆)δ11.08(s,1H),8.73(t,J＝5.5Hz,1H),8.15(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H),7.77(d,J＝8.4Hz,1H),7.41(d,J＝2.0Hz,1H),7.29(s,1H),7.02(dd,J＝8.5,2.1Hz,1H),4.18(d,J＝6.1Hz,1H),3.93–3.80(m,1H),3.43–3.33(m,1H),3.17–3.07(m,1H),2.94–2.80(m,1H),2.59(s,2H)。LCMS:[M+H]⁺＝408.0。

(1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3-chlorophenyl) carbaldehyde Ketone formates：

¹H NMR(400MHz,DMSO-d₆)δ11.10(s,1H),8.67(s,1H),8.21(s,1H),7.95(s,1H),7.85(d,J＝7.7Hz,1H),7.60(s,1H),7.53(d,J＝7.7Hz,1H),7.42(s,1H),7.31(d,J＝8.6Hz,1H),7.02(dd,J＝8.5,2.0Hz,1H),4.21(d,J＝6.6Hz,1H),3.89(d,J＝14.1Hz,1H),3.17–3.12(m,2H),2.95–2.81(m,1H),2.60(s,2H)。LCMS:[M+H]⁺＝374.0,376.0。

(1- (2-aminoethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indoles-2-yl) (3-chlorophenyl) Ketone：

¹H NMR(400MHz,DMSO-d₆)δ10.95(s,1H),8.86(t,J＝5.3Hz,1H),7.87(t,J＝1.9Hz,1H),7.80(dt,J＝7.7,1.4Hz,1H),7.59(ddd,J＝8.0,2.2,1.1Hz,1H),7.50(t,J＝7.9Hz,1H),7.37(d,J＝2.0Hz,1H),7.27(d,J＝8.5Hz,1H),6.98(dd,J＝8.5,2.1Hz,1H),4.03(d,J＝8.5Hz,1H),3.46(q,J＝6.5Hz,2H),3.18–3.08(m,1H),2.88(dt,J＝12.7,6.1Hz,1H),2.59–2.54(m,2H),2.15(dt,J＝10.3,3.3Hz,1H),1.82(dq,J＝13.2,6.5Hz,1H)。LCMS:[M+H]⁺＝388.1,390.1。

1- ((6-chloro-2- (3-chlorobenzoyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl Yl) guanidine hydrochloride：

¹H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),7.85(t,J＝6.4Hz,1H),7.63(s,1H),7.60–7.50(m,3H),7.50–7.39(m,4H),7.32-7.15(m,1H),7.10(dd,J＝8.6,2.1Hz,2H),5.94(d,J＝8.2Hz,1H),3.93-3.83(m,1H),3.73–3.49(m,4H),2.67(d,J＝6.2Hz,2H)。LCMS:[M+H]⁺＝416.1,418.1。

1- (2- (6-chloro-2- (3-chlorobenzoyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) ethyl Yl) guanidine hydrochloride：

¹H NMR(400MHz,DMSO-d₆)δ11.37(s,1H),7.62–7.44(m,7H),7.37(d,J＝8.6Hz,2H),7.22(s,1H),7.08(dd,J＝8.5,2.1Hz,1H),5.77(d,J＝9.8Hz,1H),5.32(t,J＝4.9Hz,1H),3.69(d,J＝13.4Hz,1H),2.67(d,J＝4.6Hz,2H),2.14(d,J＝46.3Hz,2H),1.99(p,J＝7.0,6.5Hz,2H)。LCMS:[M+H]⁺＝430.1,432.1。

(6-chloro-1- (((2-hydroxyethyl) amino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole-2- Yl) (3-chlorophenyl) methanone：

¹H NMR(400MHz,CD₃OD)δ8.48(s,1H),7.64(d,J＝2.2Hz,1H),7.59–7.47(m,4H),7.46(dd,J＝4.9,2.0Hz,1H),7.33(d,J＝8.6Hz,1H),7.10(dt,J＝8.7,2.9Hz,1H),6.05(dd,J＝9.6,3.7Hz,1H),3.92(dd,J＝14.3,5.2Hz,1H),3.85(t,J＝5.3Hz,2H),3.65–3.51(m,3H),3.28(t,J＝5.2Hz,1H),3.15(dt,J＝12.6,5.2Hz,1H),2.94-2.83(m,1H),2.74(dd,J＝15.6,3.9Hz,1H)。LCMS:[M+H]⁺＝418.1,420.1。

(6-chloro-1- ((methylamino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3-chlorobenzene Yl) Methanone formate salt：

¹H NMR(400MHz,CD₃OD)δ7.37(d,J＝2.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.08(d,J＝8.0Hz,1H),7.02(dd,J＝8.6,2.0Hz,1H),6.91(d,J＝7.8Hz,1H),5.01(d,J＝117.8Hz,2H),3.79(s,2H),2.81(s,2H),2.40(s,3H)。LCMS:[M+H]⁺＝388.1,390.1。

2-amino-1- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl-2- (3, 4-dichlorobenzene) Yl) ethane-1-one hydrochloride：

¹H NMR(400MHz,DMSO-d₆)δ11.12(d,J＝52.6Hz,1H),8.77(s,2H),7.93(d,J＝2.1Hz,1H),7.82–7.71(m,1H),7.54(dd,J＝8.4,2.1Hz,1H),7.47–7.40(m,1H),7.31(dd,J＝14.9,8.6Hz,1H),7.03(dd,J＝8.6,2.1Hz,1H),5.84(d,J＝30.9Hz,1H),4.93–4.74(m,2H),4.30–4.15(m,1H),3.81–3.47(m,2H),2.77–2.62(m,1H),2.36–2.09(m,1H)。LCMS:[M+H]⁺＝408.0,410.0。

2-amino-1- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl-2- (4-chloro-3-hydroxybenzene Yl) ethane-1-one formate：

¹H NMR(400MHz,DMSO-d₆)δ11.03(d,J＝30.1Hz,1H),8.19(s,1H),7.46–7.36(m,1H),7.36–7.24(m,2H),7.07–6.93(m,2H),6.90–6.75(m,1H),5.06–4.61(m,3H),3.72(q,J＝6.8,6.3Hz,2H),2.64(d,J＝16.6Hz,1H)。LCMS:[M+H]⁺＝390.0,392.0。

2-amino-1- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -2- (4-chloro-3- (tris) Fluoromethyl) phenyl) ethan-1-one hydrochloride：

¹H NMR(400MHz,DMSO-d₆)δ11.07(d,J＝76.6Hz,1H),8.78(t,J＝7.1Hz,2H),8.09(dd,J＝84.7,2.1Hz,1H),7.93–7.72(m,2H),7.41(d,J＝2.1Hz,1H),7.30(dd,J＝23.4,8.6Hz,1H),7.03(ddd,J＝8.6,4.1,2.1Hz,1H),5.95(dd,J＝30.1,5.4Hz,1H),4.91–4.67(m,2H),4.32–4.11(m,1H),3.88–3.55(m,2H),2.70(dd,J＝13.5,7.7Hz,1H),2.21–2.02(m,1H)。LCMS:[M+H]⁺＝442.0,444.0。

3-amino-N- ((6-chloro-2- (3-chlorobenzoyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-1- Yl) methyl) propionamide：

¹H NMR(400MHz,CD₃OD):δ7.62–7.46(m,3H),7.42(d,J＝7.4Hz,2H),7.31(d,J＝8.6Hz,1H),7.08(m,J＝8.6Hz,1H),6.07(d,J＝6.8Hz,1H),3.99–3.79(m,2H),3.71–3.62(m,1H),3.61–3.52(m,1H),3.21(m,J＝6.6Hz,2H),2.79–2.70(m,2H),2.60(m,J＝11.8,6.0Hz,2H)。LCMS:[M+H]⁺＝445.1,447.1。

(6-chloro-1- ((dimethylamino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3-chloro Phenyl) methanone formate salt：

¹H NMR(400MHz,CD₃OD):δ7.59(s,1H),7.56–7.37(m,4H),7.31(d,J＝8.2Hz,1H),7.06(d,J＝8.2Hz,1H),5.99(s,1H),3.86(m,J＝4.7Hz,1H),3.67–3.54(m,1H),3.16–3.01(m,1H),2.76(m,J＝16.5,14.5Hz,3H),2.54(s,6H)。LCMS:[M+H]⁺＝402.0,404.0。

(6-chloro-1- ((methylamino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3-chlorobenzene Yl) Methanone formate salt：

¹H NMR(400MHz,CD₃OD)δ7.37(d,J＝2.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.08(d,J＝8.0Hz,1H),7.02(dd,J＝8.6,2.0Hz,1H),6.91(d,J＝7.8Hz,1H),5.01(d,J＝117.8Hz,2H),3.79(s,2H),2.81(s,2H),2.40(s,3H)。LCMS:[M+H]⁺＝388.1,390.1。

2-amino-N- ((6-chloro-2- (3-chlorobenzoyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-1- Radical) methyl) acetylAmine formate salt：

¹H NMR(400MHz,DMSO-d₆)δ11.26(d,J＝126.3Hz,1H),8.65(s,1H),8.02(d,J＝100.2Hz,3H),7.61–7.26(m,6H),7.09(dd,J＝8.8,2.0Hz,1H),5.85–5.28(m,1H),4.82–3.84(m,1H),3.68(d,J＝13.6Hz,1H),3.62–3.42(m,4H),2.67(d,J＝4.0Hz,2H)。LC-MS:[M+H]⁺＝431.1,433.1。

(6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (4-chloro-2, 3-dihydroxyphenyl) methanone：

¹H NMR(400MHz,CD₃OD)δ7.37(d,J＝1.6Hz,1H),7.24(d,J＝8.4Hz,1H),7.02(dd,J＝8.4,2.0Hz,1H),6.90(d,J＝8.4Hz,1H),6.73(d,J＝8.4Hz,1H),4.58(s,2H),3.77(s,2H),2.81(s,2H)。LCMS:[M+H]⁺＝377.0,379.0。

(6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (3-chloro-2-hydroxy-4-tolyl) methyl Ketones：

¹H NMR(400MHz,CD₃OD)δ7.37(d,J＝2.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.08(d,J＝8.0Hz,1H),7.02(dd,J＝8.6,2.0Hz,1H),6.91(d,J＝7.8Hz,1H),5.01(d,J＝117.8Hz,2H),3.79(s,2H),2.81(s,2H),2.40(s,3H)。LC-MS:[M+H]⁺＝375.0,377.0。

(3- ((2-aminoethyl) amino) -5-chlorophenyl) (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole- 2-yl) methanone formate salt：

¹H NMR(400MHz,CD₃OD)δ8.54(s,1H),7.38(s,1H),7.28-7.19(m,1H),7.05(m,1H),6.80(br,1H),6.72(br,1H),6.63(m,1H),4.86(br,2H),4.65-4.07(m,1H),3.74(s,1H),3.36(m,2H),3.09(m,2H),2.85(m,2H)。LC-MS:[M+H]⁺＝403.1,405.1。

3-amino-1- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -2- (4-chlorophenyl) propan Alkan-1-one formates：

¹H NMR(400MHz,DMSO-d₆)δ11.12(m,1H),8.32(m,1H),7.43-7.26(m,6H),7.02(m,1H),4.80-4.62(m,2H),4.36(br,2H),3.96-3.70(m,4H),3.17(br,2H),2.81-2.62(m,3H),2.13(m,1H)。LCMS:[M+H]⁺＝388.0,390.0。

1- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl-2- (3, 4-dichlorophenyl) -2-hydroxy Ethyl-1-one：

¹H NMR(400MHz,CD₃OD)δ7.66(d,J＝2.0Hz,1H),7.54(d,J＝8.3Hz,1H),7.44–7.16(m,3H),7.01(dd,J＝8.6,1.9Hz,1H),5.57(d,J＝29.7Hz,1H),4.79–4.45(m,2H),4.09–3.71(m,2H),2.83–2.33(m,2H)。LCMS:[M+H]⁺＝409.0,411.0。

2-amino-1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-3- (4-chlorophenyl) propan-e Alk-1-one hydrochloride：

¹H NMR(400MHz,DMSO-d₆):δ11.20～11.03(m,1H),8.36(br,3H),7.43～7.22(m,6H),7.06(dd,J＝8.8,2.0Hz,1H),4.88～4.71(m,2H),4.55～4.25(m,1H),3.92～3.42(m,2H),3.13～2.97(m,2H),2.73～2.21(m,2H)。LCMS:[M+H]⁺＝388.2。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (4-chlorophenyl) -2- ((2-hydroxy-2) Ethyl) amino) propan-1-one：

¹H NMR(400MHz,DMSO-d₆):δ11.06～10.92(m,1H),7.40～7.39(m,1H),7.32～7.29(m,1H),7.27～7.24(m,3H),7.19～7.13(m,1H),7.03～7.01(m,1H),4.80～4.75(t,1H),4.57～4.41(m,2H),4.01～3.79(m,1H),3.78～3.52(m,2H),3.39～3.34(m,2H),2.79～2.54(m,4H),2.43～2.38(m,2H),2.08(br,1H)。LCMS:[M+H]⁺＝432.1。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-3- (4-chlorophenyl) -2- (ethylamino) Yl) propan-1-one formate：

¹H NMR(400MHz,CDCl₃)δ8.38(s,1H),8.10(d,J＝20.0Hz,1H),7.395(d,J＝2.0Hz,1H),7.24-7.12(m,5H),6.96(d,J＝4.0Hz,1H),4.97(d,J＝8.0Hz,1H),4.57-4.43(m,2H),4.13-4.03(m,1H),3.91–3.54(m,2H),3.25–3.11(m,2H),2.96–2.87(m,2H),2.73–2.61(m,2H),2.33–2.11(m,1H),1.45–1.09(m,3H)。LCMS:[M+H]⁺＝416.1。

2- ((2-aminoethyl) amino) -1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (4-chlorophenyl) propan-1-one formate：

¹H NMR(400MHz,DMSO-d₆):δ11.21(s,1H),8.41(br,1H),7.42～7.39(m,1H),7.33～7.14(m,5H),7.04～7.01(m,1H),4.80～4.74(m,1H),4.57～4.40(m,1H),4.03～3.89(m,1H),3.79～3.48(m,2H),2.82～2.55(m,7H),2.45～2.40(m,1H)。LCMS:[M+H]⁺＝431.1。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (4-chlorophenyl) propane-1-carboxylic acid Ketones：

¹H NMR(400MHz,DMSO-d₆):δ8.28～7.74(m,1H),7.45～7.41(m,1H),7.26～7.09(m,6H),4.81～4.54(m,1H),3.97～3.72(m,2H),3.04～2.97(m,2H),2.78～2.66(m,4H)。LCMS:[M+H]⁺＝373.1。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (6- (trifluoromethyl) pyridine- 3-yl) propan-1-one：

¹H NMR(400MHz,DMSO-d₆):δ8.64～8.61(m,1H),8.09～7.84(br,1H),7.79～7.75(m,2H),7.61～7.53(m,1H),7.45～7.41(m,1H),7.24～7.21(m,1H),7.13～7.10(m,1H),4.80～4.59(m,2H),3.97～3.75(m,2H),3.16～3.11(m,2H),2.85～2.73(m,4H)。LCMS:[M+H]⁺＝408.1。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (6- (trifluoromethyl) pyridine- 3-yl) propan-1-one：

¹H NMR(400MHz,DMSO-d₆):δ11.11～11.04(m,1H),8.83～8.81(m,1H),8.26(br,1H),8.16～8.11(m,1H),7.89～7.82(m,1H),7.43(s,1H),7.35～7.31(m,1H),7.04～7.02(m,1H),4.68(s,2H),4.52(s,1H),3.83～3.74(m,3H),2.99～2.94(m,2H),2.76～2.63(m,2H)。LCMS:[M+H]⁺＝423.2。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -2- ((4-chlorophenyl) amino) ethane Ketone formates：

¹H NMR(400MHz,DMSO-d₆)δ11.08(s,1H),7.46(s,1H),7.35-7.33(m,1H)，7.10-7.02(m,3H),6.70-6.65(m,2H),5.91-5.87(m,1H),4.76-4.71(m,2H),4.07-4.02(m,2H),3.84-3.80(m,2H),2.79-2.67(m,2H)。LCMS:[M+H]⁺＝374.2。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-4- (2-hydroxyethyl) phenyl) Ketone：

¹H NMR(400MHz,DMSO-d₆):δ11.18～10.87(m,1H),7.51～7.46(m,1H),7.38～7.30(m,2H),7.05(d,J＝7.2Hz,1H),4.82～4.63(m,3H),3.96～3.65(m,4H),2.93～2.90(m,2H),2.75(s,2H)。LCMS:[M+H]⁺＝389.2。

(4-Butylphenyl) (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) methanones：

¹H NMR(400MHz,DMSO-d₆)δ11.16-10.86(m,1H),7.45(s,1H),7.38-7.28(m,5H),7.04(d,J＝8.0Hz,1H),4.80-4.59(m,2H),3.96-3.62(m,2H),2.75(br s,1H),2.64(t,J＝7.6Hz,2H),1.62-1.54(m,2H),1.37-1.28(m,2H),0.91(t,J＝7.2Hz,3H)。LCMS:[M+H]⁺＝367.2。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-4- (3-hydroxypropyl) phenyl) Ketone：

¹H NMR(400MHz,DMSO-d₆)δ11.16-10.84(m,1H),7.54-7.26(m,5H),7.04(d,J＝8.0Hz,1H),4.81-4.56(m,3H),3.96(s,1H),3.62(br s,1H),3.49-3.42(m,2H),2.80-2.75(m,4H),1.78-1.70(m,2H)。LCMS:[M+H]⁺＝403.2。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3- (trifluoromethyl) phenyl) methanone：

¹H NMR(400MHz,DMSO-d₆)δ11.17-10.83(m,1H),7.89-7.72(m,4H),7.46(s,1H),7.37-7.26(m,1H),7.06-7.01(m,1H),4.85-4.59(m,2H),3.99-3.56(m,2H),2.79-2.66(m,2H)。LCMS:[M+H]⁺＝379.2。

(4- (3-aminopropyl) -3-chlorophenyl) (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indole-2 (9H) -yl) Ketone：

¹H NMR(400MHz,DMSO-d₆):δ11.26(br,1H),7.47～7.43(m,3H),7.34～7.32(m,2H),6.99(s,1H),4.80～4.59(m,2H),3.95～3.47(m,3H),2.95～2.56(m,6H),1.69～1.62(m,2H)。LCMS:[M+H]⁺＝402.1。

(6-chloro-4- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chlorophenyl) carbaldehyde Ketones：

¹H NMR(400MHz,DMSO-d₆):δ11.23～10.89(m,1H),7.56～7.27(m,6H),7.28～6.87(m,1H),6.64～6.59(m,0.5H),5.07～5.02(m,0.5H),4.74～4.43(m,2.5H),3.81～3.71(m,1.5H),3.56(dd,J＝13.2,4.4Hz,1H),3.17～3.02(m,1H)。LCMS:[M+H]⁺＝375.1。

(6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chlorophenyl) carbaldehyde Ketones：

¹H NMR(400MHz,DMSO-d₆):δ11.14～10.89(m,1H),7.56～7.27(m,6H),7.05(d,J＝8.4Hz,1H),5.63～4.74(m,2H),3.89～3.87(m,1H),3.80～3.57(m,2H),2.80～2.73(m,1H),2.65(d,J＝4.4Hz,1H)。LCMS:[M+H]⁺＝375.1。

(6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chlorophenyl) carbaldehyde Ketones：

¹H NMR(400MHz,DMSO-d₆):δ11.17～10.86(m,1H),7.58～7.25(m,6H),7.07(dd,J＝8.4,2.0Hz,1H),5.80(dd,J＝9.2,4.0Hz,0.8H),4.86～4.56(m,1.2H),3.69～3.44(m,4H),2.83～2.65(m,2H),2.20～1.96(m,2H)。LCMS:[M+H]⁺＝389.3。

6-chloro-2- (3-chlorobenzoyl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-1-carboxylic acid Amines as pesticides：

¹H NMR(400MHz,DMSO-d₆):δ11.04～10.74(m,1H),8.18(s,1H),7.62～7.34(m,6H),7.09～7.07(m,1H),5.94(s,0.8H),5.12～4.82(m,0.3H),3.83～3.59(m,1.8H),2.78～2.69(m,5.3H)。LCMS:[M+H]⁺＝402.1。

6-chloro-2- (3-chlorobenzoyl) -N- (2-hydroxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole- 1-carboxamides：

¹H NMR(400MHz,DMSO-d₆)δ7.59-7.45(m,5H),7.40-7.30(m,1H),7.08(d,J＝7.6Hz,1H),6.06(s,1H),4.00-3.95(m,1H),3.81-3.75(m,1H),3.69-3.62(m,2H),3.48-3.35(m,3H),2.91-2.76(m,2H).LCMS:[M+H]⁺＝432.2。

(5-chloro-2, 3-dihydroxyphenyl) (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) methanones：

¹H NMR(400MHz,DMSO-d₆):δ11.13～10.86(m,1H),7.43～7.28(m,2H),7.04(d,J＝8.4Hz,1H),6.85(s,1H),6.63(s,1H),4.81～4.46(m,2H),3.94～3.52(m,2H),2.73～2.68(m,2H)。LCMS:[M+H]⁺＝377.0。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-4, 5-dihydroxyphenyl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.11(br,1H),10.11(s,1H),9.62(s,1H),7.45(d,J＝2Hz,1H),7.34(d,J＝8Hz,1H),7.05～7.02(m,1H),6.91～6.84(m,2H),4.71(s,2H),3.72(br,2H),2.74(s,2H)。LCMS:[M+H]⁺＝377.0。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (4-chloro-3-hydroxyphenyl) methanones：

¹H NMR(400MHz,DMSO-d₆):δ11.16～10.84(m,1H),10.59(br,1H),7.46～7.27(m,3H),7.05～6.87(m,3H),4.79～4.62(m,2H),4.04～3.62(m,2H),2.74～2.68(m,2H)。LCMS:[M+H]⁺＝361.0。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-hydroxy-4- (trifluoromethyl) benzene Yl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.18～10.84(m,2H),7.61(d,J＝7.6Hz,1H),7.46(s,1H),7.37～7.30(m,1H),7.06～6.98(m,3H),4.82～4.55(m,2H),3.97～3.60(m,2H),2.78～2.73(m,2H)。LCMS:[M+H]⁺＝395.1。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-hydroxy-5- (trifluoromethyl) benzene Yl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.17～10.86(m,1H),10.52(s,1H),7.47(d,J＝1.6Hz,1H),7.38～7.28(m,1H),7.19(d,J＝11.2Hz,2H),7.11(s,1H),7.06(d,J＝8.0Hz,1H),4.83～4.60(m,2H),3.98～3.61(m,2H),2.74(s,2H)。LCMS:[M+H]⁺＝395.1。

(6-chloro-4- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-5-hydroxybenzene Yl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.21～10.90(m,1H),10.06(br,1H),7.55～7.51(m,1H),7.35～7.27(m,1H),3.90(d,J＝1.6Hz,2H),7.04(d,J＝8.0Hz,1H),6.74(s,1H),5.01～4.40(m,3.5H),3.80～3.42(m,2.5H),3.12～3.02(m,1H)。LCMS:[M-H]^-＝389.1。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-5-hydroxy-4-tolyl) methyl Ketones：

¹H NMR(400MHz,DMSO-d₆):δ11.16～10.83(m,1H),10.20(s,1H),7.46(d,J＝2.0Hz,1H),7.35～7.28(m,1H),7.05(d,J＝8.0Hz,1H),6.86～6.78(m,1H),4.78～4.58(m,2H),3.93～3.59(m,2H),2.74～2.71(m,2H),2.21(s,3H)。LCMS:[M+H]⁺＝375.1。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3, 4-dichloro-5-hydroxyphenyl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.16～10.82(m,1H),7.46(s,1H),7.45～7.30(m,1H),7.13(s,1H),7.05～6.98(m,2H),4.79～4.60(m,2H),3.94～3.62(m,2H),2.74(s,2H)。LCMS:[M+H]⁺＝395.0。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-4- (hydroxymethyl) phenyl) carbaldehyde Ketones：

¹H NMR(400MHz,DMSO-d₆):δ11.17～10.84(m,1H),7.65(d,J＝7.6Hz,1H),7.50～7.45(m,3H),7.36～7.29(m,1H),7.05(d,J＝8.0Hz,1H),5.52～4.82(m,2H),4.61(s,2H),3.96～3.62(m,2H),2.75(s,2H)。LCMS:[M+H]⁺＝375.2。

N- (3-chloro-5- (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-2-carbonyl) phenyl) methanesulfonyl Amines as pesticides：

¹H NMR(400MHz,DMSO-d₆):δ11.17～10.87(m,1H),7.46(d,J＝1.6Hz,1H),7.37～7.33(m,2H),7.23～7.20(m,2H),7.05(d,J＝7.6Hz,1H),4.81～4.60(m,2H),3.96～3.62(m,2H),3.10(s,3H),2.51(s,2H)。LCMS:[M+H]⁺＝438.0。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-5- (2-hydroxyethyl) phenyl) Ketone：

¹H NMR(400MHz,DMSO-d₆):δ11.16～10.86(m,1H),7.46～7.44(m,2H),7.34～7.26(m,3H),7.06(d,J＝8.4Hz,1H),4.82～4.60(m,3H),3.96～3.62(m,4H),2.78～2.73(m,4H)。LCMS:[M+H]⁺＝389.1。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (4- (trifluoromethyl) phenyl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.20～10.83(m,1H),7.87(d,J＝8.0,Hz,2H),7.71(d,J＝7.6Hz,2H),7.46(s,1H),7.38～7.27(m,1H),7.07～7.02(m,1H),4.86～4.55(m,2H),4.01～3.59(m,2H),2.80～2.74(m,2H)。LCMS:[M+H]⁺＝379.1。

(6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-5-hydroxyphenyl) methanones：

¹H NMR(400MHz,DMSO-d₆):δ11.16～10.86(m,1H),10.21(br,1H),7.46(d,J＝2.0Hz,1H),7.36～7.30(m,1H),7.06(d,J＝7.6Hz,1H),6.90～6.76(m,3H),4.79～4.55(m,2H),3.94～3.60(m,2H),3.32～2.72(m,2H)。LCMS:[M+H]⁺＝361.1。

2-amino-1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-2- (3-chloro-5-hydroxybenzene Alkyl) ethanones：

¹H NMR(400MHz,DMSO-d₆):δ11.08～11.02(m,1H),9.92(br,1H),7.42～7.40(m,1H),7.32～7.29(m,1H),7.03(dd,J＝8.4,2.0Hz,1H),6.90～6.82(m,1H),6.73～6.64(m,2H),4.92～4.39(m,3H),4.04～3.65(m,2H),2.69～2.62(m,1H),2.33～2.26(m,1H),2.19(br,2H)。LCMS:[M+H]⁺＝390.0。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-2- (4-chlorophenyl)-3-hydroxypropyl Alk-1-ones：

¹H NMR(400MHz,DMSO-d₆):δ11.08～10.96(m,1H),7.41～7.27(m,6H),7.02(dd,J＝8.8,2.4Hz,1H),4.84～4.72(m,2H),4.46～3.78(m,4H),3.52(dd,J＝10.0,5.6Hz,1H),2.67～2.62(m,1.2H),2.29～2.24(m,0.8H)。LCMS:[M+H]⁺＝389.3。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-2- (4-chlorophenyl) -3-hydroxybutyl Alk-1-ones：

¹H NMR(400MHz,DMSO-d₆):δ11.08～10.96(m,1H),7.43～7.28(m,6H),7.02～6.99(m,1H),4.92～4.42(m,3H),4.17～4.09(m,1H),4.01～3.99(m,1H),3.85～3.80(m,2H),2.68～2.62(m,1H),2.28～2.24(m,1H),1.11～1.07(m,3H)。LCMS:[M+H]⁺＝403.2。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-2- (4-chlorophenyl) -4-hydroxybutyl Alk-1-ones：

¹H NMR(400MHz,DMSO-d₆):δ11.07～10.95(m,1H),7.40～7.28(m,6H),7.02(dd,J＝8.8,2.0Hz,1H),4.89～4.42(m,3H),4.33～3.21(m,1H),3.93～3.68(m,2H),3.32～3.29(m,2H),2.68～2.62(m,1H),2.27～2.07(m,2H),1.76～1.69(m,1H)。LCMS:[M+H]⁺＝403.3。

1- (1- (aminomethyl) -6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -2- (4-chlorobenzene 2-hydroxy-2-carbonylEthanone hydrochloride：

¹H NMR(400MHz,DMSO-d₆):δ11.40～11.05(m,1H),8.58～8.14(m,3H),7.55～7.05(m,7H),8.56～8.47(m,1H),5.85～5.57(m,2H),4.77～4.11(m,1H),3.44～3.38(m,1H),3.29～3.16(m,1H),2.68～2.59(m,1H),2.47～2.33(m,1H)。LCMS:[M+H]⁺＝404.0。

1- (6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -2- (4-chlorobenzene 2-hydroxyacetophenone：

¹H NMR(400MHz,DMSO-d₆):δ11.09～10.91(m,1H),7.44～7.24(m,6H),7.06～7.00(m,1H),6.17～6.40(m,3H),5.11～4.12(m,1H),4.21～4.11(m,1H),3.82～3.66(m,2H),3.44～3.05(m,1H),2.66～2.19(m,2H)。LCMS:[M-H]^-＝405.0。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (4-chlorophenyl) -2, 3-dihydroxy Propan-1-ones：

¹H NMR(400MHz,DMSO-d₆):δ11.06～11.01(m,1H),7.43～7.08(m,6H),7.05(dd,J＝8.4,1.6Hz,1H),5.59(br,1H),5.15～5.12(m,1H),4.92～4.52(m,4H),3.90～3.66(m,2H),2.76～2.61(m,2H)。LCMS:[M+H]⁺＝405.0。

1- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -3- (3-chlorophenyl) -2, 3-dihydroxy Propan-1-ones：

¹H NMR(400MHz,DMSO-d₆):δ11.05～11.00(m,1H),7.42～7.23(m,6H),7.04(dd,J＝8.4,1.6Hz,1H),5.54～5.52(m,1H),5.17～5.11(m,1H),4.89～4.48(m,4H),3.87～3.63(m,2H),2.74～2.60(m,2H).LCMS:[M+H]⁺＝405.0。

2-amino-N- (3-chloro-5- (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-2-carbonyl) phenyl) Acetamide formate salt：

¹H NMR(400MHz,DMSO-d₆):δ11.22～10.90(m,1H),8.32(br,1H),7.91(s,1H),7.70～7.62(m,1H),7.46(d,J＝8.4Hz,1H),7.36(d,J＝8.4Hz,1H),7.21(s,1H),7.05(d,J＝7.6Hz,1H),4.82～4.60(m,2H),3.62(s,2H),3.44(s,2H),2.76(s,2H)。LCMS:[M+H]⁺＝417.2。

3-amino-N- (3-chloro-5- (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-2-carbonyl) phenyl) Propionamide formate salt：

¹H NMR(400MHz,DMSO-d₆):δ11.25～10.96(m,1H),8.41(s,1H),7.88(s,1H),7.62～7.58(m,1H),7.46(d,J＝2.0Hz,1H),7.37～7.30(m,1H),7.20(s,1H),7.05(d,J＝8.4Hz,1H),4.82～4.59(m,2H),3.95～3.62(m,2H),2.98(s,2H),2.76(s,2H),2.62(s,2H)。LCMS:[M+H]⁺＝431.2。

(6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (2, 3-dichlorobenzene Yl) Methanone formate salt：

¹H NMR(400MHz,DMSO-d₆):δ11.23～10.92(m,1H),8.50(s,0.2H),7.87～7.66(m,1H),7.54～7.29(m,4H),7.11～7.04(m,1H),5.69～4.84(m,2H),4.60～3.85(m,2H),3.73～3.41(m,2H),2.81～2.59(m,2H)。LCMS:[M+H]⁺＝409.2。

(6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) (3-chloro-4-hydroxy- 5-tolyl) methanone：

¹H NMR(400MHz,DMSO-d₆):δ11.11(br,1H),8.44(s,0.59H),7.44(d,J＝2.0Hz,1H),7.34～7.29(m,1H),7.19(s,1H),7.06(dd,J＝8.4,2.0Hz,3H),5.69～5.0(m,1H),3.84(s,2H),3.35(s,2H),2.68(s,2H),2.22(s,3H)。LCMS:[M+H]⁺＝405.3。

2-amino-1- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl-2- (2, 4-dichlorobenzene) Yl) ethane-1-one formate ¹H NMR (400MHz, methanol-d)₄):δ7.68-7.57(m,1H),7.38-7.14(m,4H),7.03-6.98(m,1H),5.55-5.49(m,1H),5.00-4.95(m,1H),4.73-4.63(m,1H),4.24-3.60(m,2H),2.78-2.00(m,2H)。LCMS:[M+H]⁺＝410.0。

2-amino-1- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -2- (3, 4-dichloro-benzene)Phenyl) ethane-1-one formate salt ¹H NMR (400MHz, methanol-d)₄):δ8.09-8.07(m,1H),7.94-7.10(m,6H),5.90-5.67(m,2H),4.05-3.31(m,4H),3.01-1.54(m,2H)。LCMS:[M+H]⁺＝439.9。

1- (2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -1- (3, 4-dichloro Phenyl) -2-oxoethyl) guanidinium formate salt ¹H NMR(400MHz,Methanol-d₄):δ8.51(brs,1H),7.69-6.99(m,6H),6.07-5.62(m,2H),4.10-4.04(m,1H),3.56-3.50(m,1H),3.31-2.15(m,2H),1.75-1.38(m,3H)。LCMS:[M+H]⁺＝466.0。

General scheme 12

(N- (3- (3-aminopropionamide) -5-chlorobenzyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole Representatives of the synthesis of indole-2-carboxamides: to a solution of 3-amino-5-chlorobenzonitrile (1.0g, 6.55mmol, 1.0 equiv.), 3- ((tert-butoxycarbonyl) amino) propionic acid (1.24g, 6.55mmol, 1.0 equiv.) and HATU (2.98g, 7.86mmol, 1.2 equiv.) in DMF (15mL) at 25 ℃ was added DIEA (2.5g, 19.65mmol, 3.0 equiv.). The reaction mixture was then stirred at 25 ℃ for 1 h. TLC showed that 3-amino-5-chlorobenzonitrile was completely consumed and a new spot was formed. The reaction mixture was diluted with water (100mL) and extracted with ethyl acetate (100 mL. times.3). The combined organic phases were concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA ═ 5/1-3/1) to give tert-butyl (3- ((3-chloro-5-cyanophenyl) amino) -3-oxopropyl) carbamate (1.5g, yield: 70.8%) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ10.42(s,1H),7.98(d,J＝1.6Hz,1H),7.92(s,1H),7.71–7.67(m,1H),6.90(t,J＝5.2Hz,1H),3.32(s,2H),3.22(dd,J＝12.8,6.8Hz,2H),1.37(s,9H)。

To a solution of tert-butyl (3- ((3-chloro-5-cyanophenyl) amino) -3-oxopropyl) carbamate (500mg, 1.54mmol, 1.0 eq) in methanol (10.0mL) was added Raney nickel (180mg, 3.08mmol, 2.0 eq) and NH₃·H₂O (0.1 mL). At H₂The reaction was stirred at 25 ℃ for 4 h. LCMS showed complete consumption of starting material and the desired product quality was detected. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl (3- ((3- (aminomethyl) -5-chlorophenyl) amino) -3-oxopropyl) carbamate as a yellow oil (460mg, yield: 90.9%). LCMS: [ M + H]⁺＝328.1。

To a solution of tert-butyl (3- ((3- (aminomethyl) -5-chlorophenyl) amino) -3-oxopropyl) carbamate (240mg, 0.73mmol, 1.0 eq) in dichloromethane (5.0mL) at 0 deg.C was added triethylamine (221mg, 2.2mmol, 3.0 eq) and bis (trichloromethyl) carbonate (65.0mg, 0.22mmol, 0.3 eq). After 30min, 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] was added to the reaction mixture]Indole hydrochloride (178mg, 0.73mmol, 1.0 equiv). The reaction mixture was then stirred at 25 ℃ for 3 h. LCMS showed complete consumption of starting material and the desired product quality was detected. The reaction was quenched with water (20mL) and extracted with ethyl acetate (30 mL. times.3). The combined organic phases were concentrated in vacuo. The residue was then subjected to preparative high performance liquid chromatography (mobile phase: 0.1% HCOOH/CH)₃CN/H₂O) to give (3- ((3-chloro-5- ((6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indole-2-carboxamide) methyl) phenyl) amino) -3-oxopropyl) carbamic acid tert-butyl ester (130mg, yield: 31.7%). LCMS (liquid Crystal Module) [ M + H-100 ]]⁺＝460.1。

To (3- ((3-chloro-5- ((6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b))]Indole-2-carboxamide) methyl) phenyl) amino) -3-oxopropyl) carbamic acid tert-butyl ester (60mg, 0.10mmol, 1.0 eq) to a solution in dichloromethane (5.0mL) was added HCl/dioxane (1.0mL, 4.0M). The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated in vacuo. The obtained residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1%HCOOH/CH₃CN/H₂O) purification to give N- (3- (3-aminopropionamide) -5-chlorobenzyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] as a pale yellow solid]Indole-2-carboxamide (13.30mg, yield: 27.0%).¹H NMR(400MHz,DMSO-d6)δ11.18(s,1H),10.53(s,1H),8.41(s,2H),7.72(s,1H),7.46–7.25(m,4H),7.01(d,J＝13.6Hz,2H),4.59(s,2H),4.22(d,J＝4.8Hz,2H),3.70(s,2H),3.01(s,2H),2.74–2.61(m,4H)。LCMS:[M+H]⁺＝460.1。

N- (3- (3-aminopropionamide) -4-chlorobenzyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole- 2-carboxamide formate salt：

¹H NMR(400MHz,DMSO-d₆)δ11.09(s,1H),8.32(s,1H),7.69(s,1H),7.45–7.34(m,3H),7.31(d,J＝8.5Hz,1H),7.08(d,J＝8.3Hz,1H),7.02(dd,J＝8.5,2.1Hz,1H),4.57(s,2H),4.23(d,J＝5.5Hz,2H),3.69(t,J＝5.5Hz,2H),2.99(t,J＝6.6Hz,2H),2.72–2.57(m,4H)。LCMS:[M+H]⁺＝460.1,462.1。

N- (3- (2-Aminoacetamide) -4-chlorobenzyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole- 2-carboxamide formate salt：

¹H NMR(400MHz,DMSO-d₆)δ11.07(s,1H),8.13(d,J＝27.5Hz,2H),7.46–7.35(m,3H),7.30(d,J＝8.6Hz,1H),7.08–7.02(m,1H),7.01(d,J＝2.1Hz,0H),4.57(s,2H),4.24(d,J＝5.6Hz,2H),3.69(t,J＝5.6Hz,2H),3.43(s,2H),2.68(t,J＝5.4Hz,2H)。LCMS:[M+H]⁺＝446.1,448.1。

1- (aminomethyl) -6-chloro-N- (3-chlorophenyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole-2-carboxylic acid Amine formate salt：

¹H NMR(400MHz,DMSO-d₆)δ8.19(s,1H),7.65(s,1H),7.49(d,J＝2.0Hz,1H),7.34(s,2H),7.27(t,J＝8.0Hz,1H),7.10–6.96(m,2H),5.37(s,1H),4.36(d,J＝11.5Hz,1H),3.20(s,2H),3.15–3.05(m,1H),2.69(d,J＝17.5Hz,2H)。LCMS:[M+H]⁺＝389.0,391.0。

N- (3- (3-aminopropionamide) -5-chlorobenzyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole- 2-carboxamide formate salt：

¹H NMR(400MHz,DMSO-d₆)δ11.18(s,1H),10.53(s,1H),8.41(s,2H),7.72(s,1H),7.46–7.25(m,4H),7.01(d,J＝13.6Hz,2H),4.59(s,2H),4.22(d,J＝4.8Hz,2H),3.70(s,2H),3.01(s,2H),2.74–2.61(m,4H)。LCMS:[M+H]⁺＝460.1,462.1。

1- (aminomethyl) -6-chloro-N- (3-chlorobenzyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole-2-carboxylic acid Amine formate salt：

¹H NMR(400MHz,DMSO-d₆)δ11.28(s,1H),8.38(s,1H),7.58(s,1H),7.47(s,1H),7.38–7.24(m,5H),7.06(d,J＝7.2Hz,1H),5.40(s,1H),4.30(s,2H),4.19(d,J＝12.8Hz,1H),3.93(s,1H),3.17(dd,J＝38.4,22.4Hz,4H),2.75–2.54(m,4H)。LCMS:[M+H]⁺＝403.1,405.1。

6-chloro-N- (2-chlorophenyl) -1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxylic acid Amines as pesticides：

¹H NMR(400MHz,DMSO-d₆):δ11.15(s,1H),8.71(s,1H),7.74(d,J＝8.4Hz,1H),7.48-7.00(m,7H),5.98(brs,1H),5.25(dd,J＝8.8,3.2Hz,1H),4.43(d,J＝13.2Hz,1H),4.00-3.79(m,2H),3.30-3.15(m,2H),2.73-2.71(m,2H)。LCMS:[M-H]^-＝388.1。

General scheme 13

6-chloro-N- (4-chlorophenyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxamidine hydrochloride (6- chloro-N-(4-chlorophenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)- Representative Synthesis of Carboximidamide hydrochloride)：

N- (4-chlorophenyl) -1H-imidazole-1-carboxamidine: to a solution of 4-chloroaniline (500mg, 3.92mmol) in THF (8mL) was added di (1H-imidazol-1-yl) methanimine (757mg, 4.7mmol) at room temperature and stirred for 16H. The reaction suspension was concentrated and purified by silica gel chromatography eluting with EtOAc to give N- (4-chlorophenyl) -1H-imidazole-1-carboxamidine as a white solid (300mg, yield: 35%).

6-chloro-N- (4-chlorophenyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxamidine hydrochloride: to a solution of N- (4-chlorophenyl) -1H-imidazole-1-carboxamidine (100mg, 0.45mmol) in DMF (4mL) was added 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole hydrochloride (94mg, 0.45mmol) and NaHCO₃(190mg, 2.26 mmol). The reaction mixture was stirred at 65 ℃ under argon for 4h, then poured into water, extracted with EtOAc, washed with brine,with Na₂SO₄Drying and evaporating. The residue was purified by preparative high performance liquid chromatography (mobile phase 0.1% TFA/CH)₃CN/H₂O) purification to give 6-chloro-N- (4-chlorophenyl) -3, 4-dihydro-1H-pyrido [3,4-b as a white solid]Indole-2 (9H) -carboxamidine (hydrochloride, 28.15mg, yield: 17%).¹H NMR(400MHz,DMSO-d₆):δ11.36(d,J＝5.2Hz,1H),10.22～10.17(m,1H),8.21(s,2H),7.52～7.48(m,3H),7.36～7.31(m,3H),7.07(dd,J＝2.0,8.8Hz,1H),4.79(s,2H),3.90～3.87(m,2H),2.89(s,2H)。LCMS:[M+H]⁺＝359.1。

6-chloro-N- (4-chlorobenzyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxamidine hydrochloride：

¹H NMR(400MHz,DMSO-d₆):δ11.37(s,1H),8.72(s,1H),8.03(s,2H),7.50(d,J＝2.4Hz,1H),7.45～7.40(m,4H),7.35(d,J＝8.4Hz,1H),7.07(dd,J＝1.6,10.0Hz,2H),4.73(s,2H),4.53(d,J＝5.2Hz,2H),3.85～3.82(m,2H),2.83(s,2H)。LCMS:[M+H]⁺＝373.2。

6-chloro-N- (3, 4-dichlorobenzyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxamidine hydrochloride：

¹H NMR(400MHz,DMSO-d₆):δ11.29(s,1H),8.55(s,1H),7.96(s,2H),7.66(d,J＝8.4Hz,2H),7.51(s,1H),7.38～7.33(m,2H),7.08～7.05(m,1H),4.70(s,2H),4.51～4.49(d,J＝5.2Hz,2H),3.82(t,2H),2.82(s,2H)。LCMS:[M+H]⁺＝407.0。

General scheme 14

Chlorosulfonic acid was slowly added to a solution of arylamine in anhydrous DCM at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 30min and then warmed to room temperature for 1 h. The precipitate was collected by filtration and dried under high vacuum. The solid was suspended in toluene and phosphorus pentachloride was added. The mixture was stirred at 100 ℃ for 2h, then cooled to room temperature and filtered. The solid residue was washed three times with toluene. The filtrate was evaporated and dried under vacuum. In the next step unpurified crude sulfonyl chloride (sulfoamyl chloride) was used. To a mixture of1, 2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole (tryptoline) (1.0 eq) and DIPEA (3.0 eq) in DCM was added sulfonyl chloride (prepared above, 1.2 eq). The reaction mixture was stirred at room temperature for 12h, concentrated, and purified by flash chromatography on silica gel to give the desired product (15% -70% yield).

6-chloro-N- (4-chlorobenzyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b]Representative indole-2-sulfonamides Synthesis (PCT International application No. 2002050041, 6 months and 27 days 2002)：

To a solution of (4-chlorophenyl) methylamine (1.374g, 12mmol) in anhydrous DCM (10mL) at 0 deg.C was slowly added chlorosulfonic acid (0.266mL, 4 mmol). The reaction mixture was stirred at 0 ℃ for 30min and then warmed to room temperature for 1 h. The precipitate was collected by filtration and dried under high vacuum. The solid was suspended in toluene (6mL) and phosphorus pentachloride (833mg, 4mmol) was added. The mixture was stirred at 100 ℃ for 2h, then cooled to room temperature and filtered. The solid residue was washed with toluene (3X 5 mL). The filtrate was evaporated and dried under high vacuum. Unpurified crude sulfonyl chloride (0.864g, 3.6mmol, 90%) was used in the next step. To 1,2,3, 4-tetrahydro-9H-pyridine [3,4-b ]]To a mixture of isoindole (48.6mg, 0.2mmol) and DIPEA (0.104mL, 0.6mmol) in DCM (2mL) was added sulfonyl chloride (prepared above, 58mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 12h, concentrated and purified by flash chromatography on silica gelTo obtain 6-chloro-N- (4-chlorobenzyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole-2-sulfonamide (5.4mg, 13% yield).¹H NMR (500MHz, chloroform-d) δ 7.90(s,1H),7.44(d, J ═ 1.9Hz,1H),7.26(d, J ═ 2.3Hz,1H),7.24(d, J ═ 2.5Hz,2H),7.20(s,1H),7.19(d, J ═ 6.3Hz,1H),7.14(dd, J ═ 8.6,2.1Hz,1H),4.43(s,2H),4.17(s,2H),3.62(t, J ═ 5.8Hz,2H),2.82(td, J ═ 5.8,4.9,2.8Hz, 2H).

General scheme 15

The compound 6-chloro-N- (4-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxamides (Orchidaceae) Synthetic representation of the target-A4-1)：

6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxylic acids: to 2-amino-3- (5-chloro-1H-indol-3-yl) propionic acid (979mg, 4.1mmol, 1.0 eq.), H₂SO₄(410mg, 4.18mmol, 1.02 eq) in H₂To the mixture in O (16mL) was added 30% formaldehyde (1.6 mL). The mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS. By NH₃·H₂Adjusting pH value to 6-7, collecting solid, and using H₂O washing to give 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as an off-white solid]Indole-3-carboxylic acid: (1.08g, yield: 100%). LCMS: [ M + H]⁺＝250.1。

2- (tert-Butoxycarbonyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxylic acids: reacting 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-3-carboxylic acid (1.08g, 4.32mmol, 1.0 equiv.), Boc₂A mixture of O (1.4g, 6.48mmol, 1.5 equiv), 1N NaOH in water in THF/i-PrOH (80mL/80mL) was stirred at room temperature for 4 h. The reaction was monitored by LC-MS. The solution was concentrated under reduced pressure and the pH was adjusted to 7 with 1N aqueous HClExtracted with EtOAc (3X 50 mL). The combined organic layers were combined and washed with water (2X 50mL), then brine (2X 50mL), then anhydrous Na₂SO₄Dried and concentrated. The residue was washed with petroleum ether, ethyl acetate (100:1) to give 2- (tert-butoxycarbonyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as an off-white solid]Indole-3-carboxylic acid (2.05g, 100%). LCMS: [ M + H]⁺＝360.1。

6-chloro-3- ((4-chlorophenyl) carbamoyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxylic acid Tert-butyl ester: 2- (tert-butyloxycarbonyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]A mixture of indole-3-carboxylic acid (350mg, 1mmol, 1.0 equiv.), 4-chloroaniline (153mg, 1.2mmol, 1.2 equiv.), HATU (570mg, 1.5mmol, 1.5 equiv.), and DIEA (387mg, 3mmol, 3.0 equiv.) in DMF (3mL) was stirred at room temperature for 16 h. Reaction was monitored by LC-MS with H₂Quenched with O and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with water (2X 20mL) and brine (2X 20mL), over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography (petroleum ether: EtOAc ═ 3:1) to give 6-chloro-3- ((4-chlorophenyl) carbamoyl) -3, 4-dihydro-1H-pyrido [3,4-b ] as a pale yellow solid]Indole-2 (9H) -carboxylic acid tert-butyl ester (22mg, yield: 5%).

6-chloro-N- (4-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxamides: reacting 6-chloro-3- ((4-chlorophenyl) carbamoyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]A solution of indole-2 (9H) -carboxylic acid tert-butyl ester (22mg, 0.048mmol, 1.0 equiv.) in 4N HCl/dioxane (4mL) was stirred at room temperature for 1H. The reaction was monitored by LC-MS. The solution was concentrated and purified by preparative high performance liquid chromatography (mobile phase: 0.1% NH)₄OH/MeCN/H₂O) purification to give 6-chloro-N- (4-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as a white solid]Indole-3-carboxamide (4.37mg, yield: 25%).¹H NMR(400MHz,DMSO-d₆):δ7.66–7.62(m,2H),7.39(d,J＝2.0Hz,1H),7.35–7.32(m,2H),7.24(d,J＝8.4Hz,1H),7.02–7.00(m,1H),4.15–4.05(m,2H),3.76–3.72(m,1H),3.11–3.06(m,1H),2.90–2.83(m,1H)。LCMS:[M+H]⁺＝360.1。

6-chloro-N- (3-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxamides：

¹H NMR(400MHz,DMSO-d₆):δ10.95(br,1H),10.13(br,1H),7.92(t,J＝2.0Hz,1H),7.60–7.58(m,1H),7.44(d,J＝1.6Hz,1H),7.35(t,J＝8.0Hz,1H),7.29(d,J＝8.4Hz,1H),7.13–7.11(m,1H),7.02–6.99(m,1H),4.00(s,2H),3.70–3.64(m,1H),2.97–2.92(m,1H),2.85(br,1H),2.78–2.72(m,1H)。LCMS:[M+H]⁺＝360.1。

6-chloro-N- (4-chlorobenzyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxamides：

¹H NMR(400MHz,DMSO-d₆):10.91(br,1H),8.48(t,J＝6.0Hz,1H),7.41–7.27(m,6H),7.01–6.98(m,1H),4.31(d,J＝6.0Hz,2H),3.95–3.92(m,2H),3.53–3.49(m,1H),2.90–2.85(m,1H),2.70–2.64(m,2H)。LCMS:[M+H]⁺＝374.1。

6-chloro-N- (3-chlorobenzyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxamides：

¹H NMR(400MHz,DMSO-d₆):δ10.92(br,1H),8.52(br,1H),7.41–7.23(m,6H),7.00(d,J＝8.8Hz,1H),4.33(d,J＝6.0Hz,2H),3.95(s,2H),3.53(br,1H),2.90–2.88(m,1H),2.71–2.65(m,2H)。LCMS:[M+H]⁺＝374.1。

General scheme 16

The compound 3, 4-dichloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethanes Yl) representative Synthesis of Anilines：

3- (3, 4-dichlorophenyl) oxazolidin-2-one: to 3, 4-dichloroaniline (800mg, 4.94mmol) and K₂CO₃(1.7g, 12.35mmol) to a suspension in MeCN (10mL) was added chloroethyl chloroformate (2-chloroethyl carbonate) (883mg, 6.18 mmol). The reaction mixture was stirred at room temperature for 1h, then at 80 ℃ for 16 h. The reaction mixture is poured into H₂In O, collecting the obtained precipitate, and using H₂O washing and vacuum drying gave 3- (3, 4-dichlorophenyl) oxazolidin-2-one as a white solid (600mg, yield: 52%).¹H NMR(400MHz,DMSO-d₆):δ7.87(d,J＝2.4Hz,1H),7.63(d,J＝8.8Hz,1H),7.55～7.53(m,1H),4.43(t,J＝16Hz,2H),4.04(t,J＝15.6Hz,2H)。

3, 4-dichloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) aniline: 3- (3, 4-dichlorophenyl) oxazolidin-2-one (50mg, 0.22mmol) and 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]A mixture of indole in DMSO (1mL) was stirred at 120 ℃ for 16 h. The reaction mixture was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₄HCO₃/CH₃CN/H₂O) purification to give 3, 4-dichloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b) as a yellow solid]Indol-2 (9H) -yl) ethyl) aniline (18.8mg, yield: 22%).¹H NMR(400MHz,DMSO-d₆):δ10.91(d,J＝5.2Hz,1H),7.37(d,J＝5.6Hz,1H),7.29～7.21(m,2H),6.98(s,1H),6.78(d,J＝4.4Hz,1H),6.59(s,1H),5.99(s,1H),3.65(d,J＝5.2Hz,2H),3.21(s,2H),2.80～2.66(m,6H)。LCMS:[M+H]⁺＝394.0。

N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) -4- (trifluoromethyl) Aniline：

¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),7.26～7.38(m,4H),6.98～7.00(m,1H),6.70(d,J＝8.4Hz,2H),6.27(s,1H),3.68(s,2H),3.26(s,2H),2.68～2.84(m,6H)。LCMS:[M+H]⁺＝394.0。

General scheme 17

To a solution of 2-bromoacetyl chloride (1.0 eq) and DMAP (0.1 eq) in anhydrous DCM at 0 ℃ was slowly added arylamine (1.0 eq) and stirred at 0 ℃ for 3 h. The mixture was then diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-bromoacetamide as a white solid which was carried on to the next step without further purification (yield 80%). To a solution of1, 2,3, 4-tetrahydro-9H-pyridoindole (1.0 eq) and DIPEA (3.0 eq) in anhydrous THF was added 2-bromoacetamide (1.2 eq) and heated to reflux for 2H. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel to give the desired product (35% -80% yield).

2-bromo-N- (4-chlorophenyl) acetamide (Bioorganic)&Medicinal Chemistry Letters,22(5), 1985-1988；2012)：

To 0 ℃ 4-chloroaniline (256mg, 2mmol) and 4-bisTo a solution of methylaminopyridine (25mg, 0.2mmol) in anhydrous DCM (5mL) was added 2-bromoacetyl chloride (0.166mL, 2mmol) slowly. The reaction mixture was stirred at 0 ℃ for 3h, then diluted with DCM, washed with water and brine, dried over sodium sulfate and concentrated to give 2-bromo-N- (4-chlorophenyl) acetamide as a white solid which was used directly in the next step without further purification (400mg, 1.6mmol, 80%).¹H NMR (500MHz, chloroform-d) delta 8.15(s,1H), 7.54-7.45 (m,2H), 7.41-7.30 (m,2H),4.04(s, 2H).

2- (6-chloro-8-fluoro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (4-chlorophenyl) acetyl Amine (PCT International application No. 2008025694, 6 months 3 2008)：

To 6-chloro-8-fluoro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]To a solution of indole hydrochloride (39mg, 0.15mmol) and DIPEA (0.08mL, 0.45mmol) in anhydrous THF (2mL) was added 2-bromo-N- (4-chlorophenyl) acetamide (45mg, 0.18mmol) and heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel to give 2- (6-chloro-8-fluoro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (4-chlorophenyl) acetamide (20mg, 0.0525mmol, 35%).¹H NMR (500MHz, chloroform-d) δ 7.58-7.48 (m,2H), 7.32-7.17 (m,3H), 6.98-6.83 (m,1H),3.85(t, J ═ 2.4Hz,1H),3.40(d, J ═ 1.1Hz,4H),3.02(t, J ═ 5.7Hz,2H), 2.88-2.75 (m, 1H).

General scheme 18

5-chloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) -6-methylpyridine Representative Synthesis of Pyrid-2-Amines：

2-chloro-N- (5-chloro-6-methylpyridin-2-yl) acetamide: in N₂Next, 5-chloro-6-methylpyridin-2-amine (500mg, 3.51mmol) and Et₃N (1.2g, 11.57mmol) in CH₂Cl₂To a solution at 0 deg.C (10mL) was added 2-chloroacetyl chloride (436mg, 3.86mmol) dropwise. The reaction was stirred at room temperature for 3 h. The reaction solution was then washed with brine (2X 10mL) and anhydrous Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography, eluting with petroleum ether ethyl acetate ═ 5:1, to give 2-chloro-N- (5-chloro-6-methylpyridin-2-yl) acetamide in the form of a white solid (500mg, yield: 65%). LCMS: [ M + H]⁺＝219.0。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-N- (5-chloro-6-methylpyridine-2- Yl) acetamide: reacting 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]A mixture of indole hydrochloride (150mg, 0.62mmol), 2-chloro-N- (5-chloro-6-methylpyridin-2-yl) acetamide (149mg, 0.68mmol), DIEA (399mg, 3.08mmol) and NaI (115mg, 0.62mmol) in DMF (3mL) was stirred at 50 ℃ for 16 h. Then the reaction solution was poured into water, and the resulting precipitate was collected to obtain 2- (6-chloro-3, 4-dihydro-1H-pyrido [3,4-b ] in the form of a white solid]Indol-2 (9H) -yl) -N- (5-chloro-6-methylpyridin-2-yl) acetamide (210mg, yield: 87%). LCMS: [ M + H]⁺＝389.0。

5-chloro-N- (2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethyl) -6-methylpyridine Pyridin-2-amines: to 2- (6-chloro-3, 4-dihydro-1H-pyrido [3,4-b ]]Indol-2 (9H) -yl) -N- (5-chloro-6-methylpyridin-2-yl) acetamide (170mg, 0.44mmol) in dry THF (10mL) was added BH dropwise₃THF (1M, 1.75mL, 1.75 mmol). The reaction was stirred at 50 ℃ for 16h and saturated NH₄And (4) quenching by Cl. EtOAc (20mL) was added and the resulting mixture was washed with brine (2X 20mL) and anhydrous Na₂SO₄Dried and concentrated. The residue is prepared byType high performance liquid chromatography (mobile phase: 0.1% NH)₄HCO₃/H₂O/MeCN) to obtain 2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b) in the form of a white solid]Indol-2 (9H) -yl) -N- (5-chloro-6-methylpyridin-2-yl) acetamide (35.04mg, yield: 21%).¹H NMR(400MHz,DMSO-d₆):δ10.93(s,1H),7.39(d,J＝1.6Hz,1H),7.35(d,J＝8.4Hz,1H),7.29(d,J＝8.8Hz,1H),7.00(dd,J＝8.4,2.0Hz,1H),6.54(t,J＝5.6Hz,1H),6.38(d,J＝8.8Hz,1H),3.67(s,2H),3.45～3.40(m,2H),2.81(t,J＝5.6Hz,2H),2.72(t,J＝6.4Hz,2H),2.67(t,J＝5.2Hz,2H),2.33(s,3H)。LCMS:[M+H]⁺＝375.1。

5-chloro-N2- (2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl group Pyridine-2, 6-diamine hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.54(brs,1H),11.17(brs,1H),7.57-7.37(m,4H),7.14-7.11(m,1H),6.00-5.98(m,1H),4.91-4.89(m,1H),3.93～3.02(m,8H),1.72(d,J＝5.6Hz,3H)。LCMS:[M+H]⁺＝390.2。

(6-chloro-2- (2- ((5-chloro-6-ethoxypyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO-d₆):δ10.84(brs,1H),7.41-7.29(m,3H),7.00(dd,J＝8.4Hz,2.0Hz,1H),6.68(d,J＝4.8Hz,1H),6.05(d,J＝8.8Hz,1H),4.75-4.72(m,1H),4.33-4.24(m,2H),3.74-3.60(m,2H),3.35-3.13(m,2H),3.14-2.43(m,6H),1.28(d,J＝7.2Hz,3H)。LCMS:[M+H]⁺＝435.2。

(6-chloro-2- (2- ((5-chloro-6-methoxypyridin-2-yl) amino)) Ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO-d₆):δ10.84(brs,1H),7.41-7.29(m,3H),7.00(dd,J＝8.8Hz,2.0Hz,1H),6.71-6.68(m,1H),6.06(d,J＝8.4Hz,1H),4.75～4.72(m,1H),3.82(s,3H),3.75-3.50(m,3H),3.43-3.38(m,2H),3.17-3.11(m,1H),2.91-2.70(m,4H),2.50-2,40(s,1H)。LCMS:[M+H]⁺＝421.2。

(6-chloro-2- (2- ((5-chloro-6- (methylamino) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyridine And [3,4-b ]]Indol-1-yl) methanolate hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ10.84(brs,1H),7.40(d,J＝1.6Hz,1H),7.30(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.00(dd,J＝8.8Hz,2.0Hz,1H),6.24(t,J＝5.6Hz,1H),5.95-5.93(m,1H),5.65(d,J＝8.4Hz,1H),4.75-4.72(m,1H),3.75-3.57(m,3H),3.17-3.10(m,1H),2.91-2.86(m,1H),2.79-2.67(m,6H),2.50-2.43(m,1H)。LCMS:[M+H]⁺＝420.2。

(3-chloro-6- ((2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl group Amino) pyridin-2-yl) methanol

¹H NMR(400MHz,DMSO-d₆):δ10.94(brs,1H),7.39(d,J＝8.4Hz,H),7.39(s,1H),7.27(d,J＝8.8Hz,1H),6.99(d,J＝8.4Hz,1H),6.66(br,1H),6.46(d,J＝8.8Hz,1H),4.86-4.84(m,1H),4.44(d,J＝4.8Hz,2H),3.85-3.82(m,1H),3.48-3.44(m,2H),3.10-3.07(m,2H),2.83-2.76(m,2H),2.70-2.66(m,2H),1.35(d,J＝6.4Hz,3H)。LCMS:[M+H]⁺＝405.2。

2- (6-chloro-2- (2- ((5-chloro-6-methylpyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) ethan-1-ol

¹H NMR(400MHz,DMSO-d₆):δ10.92(brs,1H),7.39(s,1H),7.33(d,J＝8.8Hz,1H),7.28(d,J＝8.4Hz,1H),7.00(dd,J＝1.6Hz,8.4Hz,1H),6.54-6-50(m,1H),6.33(d,J＝8.8Hz,1H),4.76(br,1H),3.89-3.86(m,1H),3.67-3.53(m,4H),3.13-3.08(m,1H),2.92-2.88(m,1H),2.77-2.63(m,4H),2.32(s,3H),1.92～1.85(m,2H)。LCMS:[M+H]⁺＝419.2。

5-chloro-N- (2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) -6- (trifluoro Methyl) pyridin-2-amine formate salt

¹H NMR(400MHz,DMSO-d6):δ10.96(brs,1H),8.25(s,1H),7.64(d,J＝8.8Hz,1H),7.38(d,J＝1.6Hz,1H),7.29(d,J＝8.4Hz,1H),7.01(dd,J＝2.0Hz,8.4Hz,1H),6.82(d,J＝9.2Hz,1H),3.67(brs,2H),3.50-3.45(m,2H),2.84-2.80(m,2H),2.76-2.72(m,2H),2.68-2.66(m,2H)。

¹⁹F NMR(376.5MHz,DMSO-d6):δ-64.71LCMS:[M+H]⁺＝429.1。

(6-chloro-2- (2- ((3, 5-dichloropyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4- b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,DMSO-d6):δ10.84(brs,1H),8.21(brs,1H),8.03(d,J＝2.0Hz,1H),7.80(d,J＝2.4Hz,1H),7.40(d,J＝2.0Hz,1H),7.32(d,J＝8.4Hz,1H),7.00(dd,J＝2.0Hz,8.4Hz,1H),6.68-6.66(m,1H),3.78～3.60(m,3H),3.56～3.44(m,2H),3.18～3.12(m,1H),2.90～2.86(m,1H),2.81～2.67(m,3H),2.47～2.43(m,1H)。LCMS:[M+H]⁺＝427.0。

(6-chloro-2- (2- ((5-chloro-2-methylpyridin-3-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO-d₆):δ11.87(brs,1H),7.66(d,J＝2.0Hz,1H),7.42(d,J＝1.6Hz,1H),7.31(d,J＝8.8Hz,1H),7.00(dd,J＝8.8Hz,2.0Hz,1H),6.94(d,J＝1.6Hz,1H),5.47(t,J＝4.8Hz,1H),4.86-4.83(m,1H),3.77-3.65(m,3H),3.23-3.13(m,3H),3.92-2.85(m,3H),2.76-2.72(m,1H),2.50-2.45(m,1H),2.28(s,3H)。LCMS:(M+H)⁺＝405.1。

(6-chloro-2- (2- ((3, 5-dichloro-6-methylpyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyridine And [3,4-b ]]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,DMSO-d₆):δ10.83(brs,1H),8.15(s,1H),7.68(s,1H),7.40(d,J＝1.6Hz,1H),7.32(d,J＝8.4Hz,1H),7.01(dd,J＝8.8Hz,2.0Hz,1H),6.56(t,J＝5.2Hz,1H),3.81～3.77(m,1H),3.74～3.70(m,1H),3.67～3.61(m,1H),3.56～3.46(m,2H),3.18～3.09(m,1H),2.91～2.88(m,1H),2.80～2.70(m,3H),2.50～2.44(m,1H),2.36(s,3H)。LCMS:[M+H]⁺＝441.3。

(6-chloro-2- (2- ((3, 5-dichloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methanolate hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.50(s,1H),10.85-10.51(m,1H),8.15(s,1H),7.62-7.55(m,2H),7.39(d,J＝8.4Hz,1H),7.12(d,J＝8.8Hz,1H),5.81-5.67(m,1H),4.87-4.81(m,1H),4.27-3.53(m,8H),3.02(br,2H)。LCMS:[M+H]⁺＝495.1。

(6-chloro-2- (2- ((6-ethyl-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO-d₆):δ10.86(s,1H),8.26(s,1H),7.54(d,J＝8.8Hz,1H),7.40(d,J＝1.6Hz,1H),7.30(d,J＝8.8Hz,1H),7.14(s,1H),7.00(dd,J＝8.4Hz,2.0Hz,1H),6.40(d,J＝8.8Hz,1H),3.74-3.63(m,3H),3.47(d,J＝4.8Hz,2H),3.15-3.11(m,1H),2.92-2.89(m,1H),2.81-2.64(m,5H),2.45-2.33(m,2H),1.18(t,J＝7.2Hz,3H)。LCMS:[M+H]⁺＝453.2。

5-chloro-N- (2- (6-chloro-4-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) - 6-Ethylpyridin-2-amine formate salt

¹H NMR(400MHz,MeOD)δ8.61-8.39(m,1H),7.49(d,J＝2.0Hz,1H),7.34(d,J＝8.8Hz,1H),7.26(d,J＝8.4Hz,1H),7.03(dd,J＝8.4Hz,2.0Hz,1H),6.37(d,J＝8.8Hz,1H),4.10-3.90(m,2H),3.62(t,J＝6.0Hz,2H),3.31-3.29(m,2H),3.08-3.04(m,2H),2.70-2.65(m,3H),1.39(d,J＝6.4Hz,3H),1.14(t,J＝7.6Hz,3H)。LCMS:[M+H]⁺＝403.2。

5-chloro-N- (2- (6-chloro-1- (dimethylamino) methyl) -4-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3,4- b]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,MeOD)δ7.54-7.44(m,2H),7.27-7.23(m,1H),7.00-6.95(m,1H),6.67(d,J＝8.8Hz,1H),3.90-3.80(m,1H),3.56-3.45(m,2H),3.20-2.99(m,2H),2.93-2.68(m,4H),2.51(br,1H),2.45-2.35(m,6H),1.32(d,J＝6.8Hz,3H)。LCMS:[M+H]⁺＝500.1。

(6-chloro-2- (2- ((4-chloro-3- (trifluoromethyl) phenyl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido) [3,4-b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,MeOD)δ8.24(brs,1H),7.41(d,J＝2.0Hz,1H),7.30-7.25(m,2H),7.06-7.01(m,2H),6.83(dd,J＝9.2Hz,2.8Hz,1H),4.13(brs,1H),3.91-3.88(m,2H),3.53-3.43(m,1H),3.39(t,J＝6.0Hz,2H),3.23-3.18(m,1H),3.14-3.07(m,2H),2.99-2.88(m,1H),2.72-2.68(m,1H)。LCMS:[M+H]⁺＝458.1。

5-chloro-N- (2- (6-chloro-1- (tetrahydrofuran-2-yl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole- 2-yl) ethyl) -6-methylpyridin-2-amine formate salt

¹H NMR(400MHz,MeOD):δ8.28(brs,1H),7.40(dd,J＝16.0Hz,5.2Hz,2H),7.30(d,J＝8.4Hz,1H),7.04(dd,J＝8.4Hz,2.0Hz,1H),6.40(d,J＝8.8Hz,1H),4.28-4.22(m,1H),4.02-3.98(m,1H),3.91-3.78(m,2H)3.67-3.58(m,1H),3.53-3.49(m,2H),3.33-3.30(m,1H),3.12-2.93(m,3H),2.74-2.65(m,1H),2.36(s,3H),2.23-2.17(m,1H),2.04-1.90(m,1H),1.89-1.85(m,2H)。LCMS:[M+H]⁺＝445.2。

(6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -4-methyl-2, 3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,MeOD):δ8.25(brs,1H),7.57-7.52(m,2H),7.29(dd,J＝12.0Hz,8.0Hz,1H),7.08-7.03(m,1H),6.74-6.69(m,1H),4.32-4.14(m,1H),4.05-3.84(m,2H),3.75-3.60(m,3H),3.38-3.34(m,1H),3.30-2.76(m,3H),1.43-1.35(m,3H)。LCMS:[M+H]⁺＝475.0。

(6-chloro-2- (2- ((5-chloro-6-ethylpyridin-2-yl) amino) ethyl) -4-methyl-2, 3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,MeOD):δ8.35(brs,1H),7.54(s,1H),7.38-7.27(m,2H),7.09-7.05(m,1H),6.42-6.36(m,1H),4.32-4.27(m,1H),4.09-3.92(m,2H),3.79–3.70-3.35(m,3H),3.30-3.10(m,1H),2.90(br,1H),2.71-2.64(m,2H),1.43-1.36(m,3H),1.14(t,J＝7.6Hz,3H)。LCMS:[M+H]+＝433.1。

6- ((2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) amino) -substituted N, N, 2-trimethylnicotinamide formate salt

¹H NMR(400MHz,MeOD):δ8.40(brs,1H),7.46(d,J＝2.0Hz,1H),7.31(dd,J＝8.8Hz,1.2Hz,2H),7.11(dd,J＝8.8Hz,2.0Hz,1H),6.51(d,J＝8.4Hz,1H),4.74-4.71(m,1H),3.82-3.74(m,3H),3.62-3.42(m,2H),3.41-3.32(m,1H),3.05-3.29(m,5H),2.87(s,3H),2.06(s,3H),1.71(d,J＝6.8Hz,3H)。LCMS:[M+H]⁺＝426.3。

N- (2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) -6-methyl 5- (Morpholinylmethyl) pyridin-2-aminedicarboxylate

¹H NMR(400MHz,MeOD):δ8.34(brs,2H),7.47-7.42(m,2H),7.33(d,J＝8.4Hz,1H),7.13(dd,J＝8.4Hz,2.0Hz,1H),6.53(d,J＝8.8Hz,1H),4.72-4.70(m,1H),3.83-3.79(m,1H),3.73-3.71(m,2H),3.65-3.61(m,4H),3.62-3.46(m,2H),3.37(br,3H),3.07-3.03(m,2H),2.45-2.42(m,4H),2.10(s,3H),1.72(d,J＝6.8Hz,3H)。LCMS:[M+H]⁺＝454.2。

(6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (methyl) amino) ethyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,MeOD):δ7.60(d,J＝8.0Hz,1H),7.35(d,J＝2.0Hz,1H),7.24(d,J＝12.0Hz,1H),6.99(dd,J＝8.0Hz,2.0Hz,1H),6.80(d,J＝8.0Hz,1H),3.87-3.73(m,5H),3.30-3.24(m,1H),3.10(s,3H),3.02-2.97(m,1H),2.92-2.90(m,2H),2.88-2.78(m,1H),2.58-2.53(m,1H)。LCMS:[M+H]⁺＝473.1。

(6- ((2- (6-chloro-1-methyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) amine Base) ion-exchange material2-methylpyridin-3-yl) methanol

¹H NMR(400MHz,MeOD)δ7.40(d,J＝8.4Hz,1H),7.35(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.00(dd,J＝8.8Hz,2.0Hz,1H),6.36(d,J＝8.4Hz,1H),4.48(s,2H),3.96(br,1H),3.57-3.38(m,2H),3.02-2.60(m,6H),2.37(s,3H),1.48(d,J＝6.8Hz,3H)。LCMS:[M+H]⁺＝373.2。

2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -3- ((5-chloro-6-ethylpyridine- 2-yl) amino) propan-1-ol formate salt

¹H NMR(400MHz,DMSO)δ10.89(s,1H),8.39(brs,1H),7.37-7.31(m,2H),7.26(d,J＝8.8Hz,1H),6.98(dd,J＝8.4Hz,2.0Hz,1H),6.43(br,1H),6.37(d,J＝8.8Hz,1H),4.57(br,1H),4.00-3.90(m,2H),3.68-3.59(m,2H),3.59-3.56(m,2H),3.01-2.95(m,4H),2.70-2.60(m,3H),1.17(t,J＝7.6Hz,3H)。LCMS:[M+H]⁺＝419.1。

(6-chloro-2- (2- ((5-chloro-6-cyclopropylpyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),8.16(s,1H),7.40(d,J＝2.0Hz,1H),7.30(dd,J＝8.8Hz,1.6Hz,2H),7.00(dd,J＝8.4Hz,2.0Hz,1H),6.57-6.54(m,1H),6.27(d,J＝8.8Hz,1H),3.72-3.59(m,3H),3.37-3.28(m,2H),3.17-3.09(m,1H),2.89-2.84(m,1H),2.77-2.67(m,3H),2.48-2.44(m,1H),2.30-2.24(m 1H),0.95-0.89(m,4H)。LCMS:[M+H]⁺＝431.2。

(6-chloro-2- (2- ((5-chloro-6-propylpyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),8.14(s,1H),7.40(d,J＝4.0Hz,1H),7.32(dd,J＝12.0Hz,8.0Hz,2H),7.00(dd,J＝8.0Hz,2.0Hz,1H),6.57(t,J＝6.0Hz,1H),6.35(d,J＝8.0Hz,1H),3.74-3.60(m,3H),3.40-3.36(m,3H),3.17-3.11(m,1H),2.91-2.88(m,1H),2.79-2.74(m,2H),2.64-2.60(m,2H),2.48-2.44(m,1H),1.66-1.60(m,2H),0.90(t,J＝8.0Hz,3H)。LCMS:[M+H]⁺＝433.2。

(6-chloro-2- (2- ((6-chloro-5-methylpyridazin-3-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyridine- [3, 4-b]indol-1-yl) methanol formate salt

¹H NMR(400MHz,DMSO-d₆)δ10.83(s,1H),8.25(br,1H),7.40(s,1H),7.30(d,J＝8.8Hz,1H),7.00(d,J＝8.4Hz,1H),6.90-6.84(m,2H),3.76-3.60(m,3H),3.48-3.42(m,2H),3.18-3.11(m,2H),2.98-2.67(m,4H),2.19(s,3H)。LCMS:[M+H]⁺＝406.1。

(6-chloro-2- (2- ((6-methoxy-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methanol formate salt

¹H NMR(400MHz,DMSO-d₆)δ10.84(s,1H),8.16(s,1H),7.51(d,J＝12.0Hz,1H),7.40(d,J＝2.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.00(dd,J＝8.0,4.0Hz,1H),6.11(d,J＝8.0Hz,1H),4.75(br,1H),3.86(s,3H),3.77-3.60(m,3H),3.51-3.43(m,2H),3.18-3.11(m,1H),2.93-2.88(m,1H),2.81-2.70(m,3H),2.48-2.44(m,1H)。LCMS:[M+H]⁺＝455.1。

(6-chloro-2- (2- ((5-ethyl-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.47(d,J＝8.8Hz,1H),7.40(s,1H),7.30(d,J＝8.4Hz,1H),7.00(dd,J＝8.4Hz,1.6Hz,1H),6.78-6.71(m,2H),4.72-4.69(m,1H),3.72-3.61(m,3H),3.40-3.33(m,2H),3.18-3.11(m,1H),2.92-2.88(m,1H),2.81-2.71(m,3H),2.57-2.52(m,2H),2.45-2.43(m,1H),1.11(t,J＝7.2Hz,3H)。LCMS:[M+H]⁺＝453.1。

(6- ((2- (6-chloro-1- (hydroxymethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl group Amino) -2- (trifluoromethyl) pyridin-3-yl) dimethylphosphine oxide

¹H NMR(400MHz,MeOD):δ8.04(brs,1H),7.40(s,1H),7.27(d,J＝8.8Hz,1H),7.05(d,J＝8.4Hz,1H),6.80(brs,1H),4.43-3.44(m,6H),3.20-2.70(m,5H),1.83(s,3H),1.79(s,3H)。LCMS:[M+H]⁺＝501.2。

2- (6-chloro-4-ethyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- ((5-chloro-6-ethyl) Pyridino-2-yl) methyl) ethan-1-amine

¹H NMR(400MHz,MeOD)δ7.73(d,J＝8.0Hz,1H),7.40(d,J＝2.0Hz,1H),7.22(dd,J＝8.4Hz,2.8Hz,2H),6.99(dd,J＝8.4Hz,2.0Hz,1H),3.95(s,2H),3.67-3.54(m,2H),2.94-2.80(m,8H),2.70-2.66(m,1H),2.04-1.91(m,1H),1.70-1.66(m,1H),1.15(t,J＝7.6Hz,3H),0.98(t,J＝7.6Hz,3H)。LCMS:[M+H]⁺＝431.2。

N- (2- (1- (((azetidin-3-ylmethyl) amino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-aminetricarboxylate

¹H NMR(400MHz,MeOD)δ8.41(brs,2H),7.54(d,J＝8.8Hz,1H),7.38(s,1H),7.25(d,J＝8.8Hz,1H),7.03(dd,J＝8.8Hz,1.6Hz,1H),6.70(d,J＝9.2Hz,1H),4.13-4.05(m,3H),3.87-3.82(m,2H),3.55(t,J＝6.0Hz,2H),3.13-2.87(m,10H),2.58-2.53(m,1H)。LCMS:[M+H]⁺＝527.1。

5-chloro-N- (2- (6-chloro-1- (pyrrolidin-2-yl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole-2- Yl) ethyl) -6-methylpyridin-2-amine

¹H NMR(400MHz,DMSO-d⁶)δ10.24(brs,1H),7.32-7.22(m,3H),6.98(d,J＝8.0Hz,1H),6.76-6.73(m,1H),6.26(d,J＝8.8Hz,1H),4.03-4.00(m,1H),3.51-3.36(m,3H),3.29-3.15(m,2H),2.99-2.70(m,4H),2.43-2.05(m,5H),1.80-1.60(m,2H),1.55-1.40(m,2H)。LCMS:[M+H]⁺＝444.2。

5-chloro-N- (2- (6-chloro-1- (1-methylpyrrolidin-2-yl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole Indol-2-yl) ethyl) -6-methylpyridin-2-amine

¹H NMR(400MHz,DMSO)δ10.41(brs,1H),8.27(brs,1H),7.42-7.32(m,3H),6.97(dd,J＝8.4Hz,2.0Hz,1H),6.57(s,1H),6.33(d,J＝8.8Hz,1H),3.82(brs,1H),3.53-3.20(m,3H),3.19-3.05(m,1H),2.94-2.86(m,1H),2.73-2.60(m,5H),2.39(s,3H),2.34(s,3H),2.18-1.97(m,1H),1.69-1.67(m,1H),1.50-1.48(m,1H),1.29-1.17(m,2H)。LCMS:[M+H]⁺＝458.2。

(6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (cyclopropyl) amino) ethyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO):δ10.75(brs,1H),7.82(brs,1H),7.37-7.32(m,2H),7.21(brs,1H),7.00(brs,1H),4.60(brs,1H),3.90-3.46(m,5H),3.20-3.10(m,1H),2.90-2.60(m,5H),2.44(br,1H),0.94(brs,2H),0.67(brs,2H)。LCMS:[M+H]⁺＝499.2。

2- (6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) propane-1, 3-diol

¹H NMR(400MHz,CD₃OD)δ8.47(br,1H),7.52(d,J＝8.8Hz,1H),7.42(d,J＝1.2Hz,1H),7.29(d,J＝8.8Hz,1H),7.06(dd,J＝8.4Hz,1.6Hz,1H),6.69(d,J＝8.8Hz,1H),4.25(d,J＝8.8Hz,1H),3.92-3.80(m,2H),3.74-3.52(m,5H),3.50-3.41(m,1H),3.13-2.87(m,3H),2.70-2.66(m,1H),2.21(br,1H)。LCMS:[M+H]⁺:503.2。

N- (2- (1- (2-aminoethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) - 5-chloro-6- (trifluoromethyl) pyridin-2-aminedicarboxylate

¹H NMR(400MHz,DMSO-d₆):δ11.14(brs,1H),8.38(brs,2H),7.63(d,J＝8.8Hz,1H),7.40(d,J＝2.0Hz,2H),7.29(d,J＝8.4Hz,1H),7.02(dd,J＝8.4Hz,2.0Hz,1H),6.81(d,J＝9.2Hz,1H),3.86～3.83(m,1H),3.48～3.41(m,2H),3.11～3.09(m,1H),2.90～2.71(m,6H),2.47～2.43(m,3H),2.05～1.99(m,2H).¹⁹F NMR(376MHz,CDCl₃):δ-64.68。LCMS:[M+H]⁺＝472.2。

(6-chloro-2- (2- ((6-methyl-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) methanol

¹H NMR(400MHz,DMSO-d₆):δ10.85(s,1H),7.54(d,J＝8.8Hz,1H),7.40(d,J＝1.6Hz,1H),7.30(d,J＝8.4Hz,1H),7.13(brs,1H),7.00(dd,J＝8.4Hz,2.0Hz,1H),6.40(d,J＝8.8Hz,1H),4.75～4.73(m,1H),3.77～3.62(m,3H),3.48～3.45(m,2H),3.15～3.12(m,1H),2.92～2.89(m,1H),2.78～2.73(m,3H),2.45～2.44(m,1H),2.40(s,3H).¹⁹F NMR(376MHz,CDCl₃):δ-57.60。LCMS:[M+H]⁺＝439.2。

5-chloro-N- (2- (6-chloro-1, 1-dimethyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl Representative Synthesis of 6-methylpyridin-2-amine: 2- (5-chloro-1H-indol-3-yl) ethan-1-amine (1.386g, 6mmol), acetone (0.384mL, 5.2mmol) andTi(OiPr)₄the mixture was heated to 80 ℃ under argon and incubated for 3 h. Adding CF to the mixture at 0 deg.C₃COH and (CF)₃CO)₂O, and then the mixture was heated at 70 ℃ for 3 h. The reaction mixture was diluted with MeOH (100mL) and the TiO removed by a short silica gel column₂. The eluate was concentrated in vacuo to a volume of about 50mL and the residue was taken up in CHCl₃And (4) extracting. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel to give the title compound (366mg, 30%).¹H NMR (500MHz, chloroform-d) δ 7.86(s,1H),7.43(d, J ═ 2.0Hz,1H),7.21(d, J ═ 8.5Hz,1H),7.08(dd, J ═ 8.5,2.0Hz,1H),3.20(t, J ═ 5.7Hz,2H),2.66(t, J ═ 5.7Hz,2H),1.47(s, 6H). LCMS: [ M + H]⁺＝235.1。

To 6-chloro-1, 1-dimethyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole (75mg, 0.3mmol), 2-bromo-N- (5-chloro-6-methylpyridin-2-yl) acetamide (79mg, 0.36mmol) and KI (50mg, 0.3mmol) in anhydrous CH₃DIPEA (0.156mL, 0.9mmol) was added to the mixture in CN. The mixture was heated to reflux overnight. The reaction was quenched with water, extracted with ethyl acetate, washed with brine, and washed with Na₂SO₄And (5) drying. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate ═ 5:1 to 3:1) to give the title compound (61mg, 48%).¹H NMR (500MHz, chloroform-d) δ 9.82(s,1H),8.10(d, J ═ 8.7Hz,1H),7.96(s,1H),7.63(d, J ═ 8.7Hz,1H),7.47(d, J ═ 2.0Hz,1H),7.25(d, J ═ 8.6Hz,1H),7.14(dd, J ═ 8.6,2.1Hz,1H),3.39(s,2H),3.02(t, J ═ 5.7Hz,2H),2.84(t, J ═ 5.7Hz,2H),2.50(s,3H),1.50(s, 6H). LCMS: [ M + H]⁺＝417.0。

To 2- (6-chloro-1, 1-dimethyl-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]To a mixture of indol-2-yl) -N- (5-chloro-6-methylpyridin-2-yl) acetamide (10mg, 0.024mmol) in 1mL anhydrous THF was added 10. mu.L of 10M BH₃A THF solution of (1). The reaction mixture was heated to reflux overnight. The reaction was quenched with methanol, concentrated under reduced pressure, and purified by silica gel flash chromatography (DCM/methanol ═ 20:1) to give the title compound (6.4mg, 66%).¹H NMR (500MHz, chloroform-d) δ 7.91(s,1H),7.41(d, J ═ 2.0Hz,1H),7.32(d, J ═ 8.7Hz,1H),7.21(d, J ═ 8.5Hz,1H), and,1H),7.08(dd,J＝8.6,2.0Hz,1H),6.21(d,J＝8.7Hz,1H),5.14(d,J＝17.8Hz,1H),3.37(t,J＝6.0Hz,2H),2.92(t,J＝5.7Hz,2H),2.78(t,J＝5.9Hz,2H),2.67(t,J＝5.7Hz,2H),2.42(s,3H),1.39(s,6H)。LCMs:[M+H]⁺＝403.1。

general scheme 19

6-chloro-2- (2- (4-chlorophenoxy) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Representative of indoles Synthesis of：

2- (4-chlorophenoxy) acetic acid ethyl ester: to 4-dichlorophenol (1.0g, 7.81mmol) and K at 0 deg.C₂CO₃(2.2g, 15.62mmol) to a suspension in DMF (10mL) was added ethyl 2-bromoacetate (1.9g, 11.72 mmol). The reaction was stirred at room temperature for 16H, then poured into H₂O (15mL), the resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated to give ethyl 2- (4-chlorophenoxy) acetate (1.2g, yield: 71.8%) as a yellow oil.¹H NMR(400MHz,DMSO-d₆):δ7.35～7.31(m,2H),7.00～6.94(m,2H),4.93(s,2H),4.20～4.12(m,2H),1.23-1.18(m,3H)。

2- (4-chlorophenoxy) ethanol: to a solution of ethyl 2- (4-chlorophenoxy) acetate (1.86g, 8.7mmol) in anhydrous THF (10mL) at 0 deg.C was added LiBH dropwise₄(2M in THF, 8.7mL, 17.4 mmol). The reaction was stirred at room temperature for 2h, then saturated NH₄The Cl was quenched and the resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with Na₂SO₄Drying and concentration gave the product, 2- (4-chlorophenoxy) ethanol (1.28g, yield: 85.6%) as a yellow oil.¹H NMR(400MHz,DMSO-d₆):δ7.33(dd,J＝6.8,2.0Hz,2H),6.97(dd,J＝6.4,2.0Hz,2H),4.87(t,J＝5.6Hz,1H),3.97(t,J＝4.4Hz,2H),3.72～3.68(m,2H)。

2- (4-chlorophenoxy) methanesulfonic acid ethyl ester: to 2- (4-chlorophenoxy) ethanol (500mg, 2.906mmol) and Et at 0 deg.C₃N (882g, 8.718mmol) in CH₂Cl₂To the solution in (10mL) was added MsCl (663mg, 5.813mmol) dropwise. The reaction was stirred at room temperature for 2H, then H₂Quenching with O (10mL) and CH₂Cl₂(3X 10 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated to give the product ethyl 2- (4-chlorophenoxy) methanesulfonate as a yellow oil (324mg, yield: 61.8%).¹H NMR(400MHz,DMSO-d₆):δ7.36(dd,J＝6.8,2.0Hz,2H),7.03(dd,J＝5.6,3.6Hz,2H),4.53(dd,J＝4.4,2.8Hz,2H),4.26(dd,J＝4.4,2.4Hz,2H),3.23(s,3H)。

6-chloro-2- (2- (4-chlorophenoxy) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indoles: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole hydrochloride (100mg, 0.413mmol), NaI (124mg, 0.826mmol) and K₂CO₃(685mg, 4.956mmol) to a solution in DMF (10mL) was added ethyl 2- (3, 4-dichlorophenoxy) methylsulfonate (234mg, 0.826 mmol). The mixture was stirred at 100 ℃ for 3H and then with H₂O (10mL) was quenched and extracted with EtOAc (3X 10 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated. The residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₃/H₂O/CH₃CN/H₂O) purification to give 6-chloro-2- (2- (4-chlorophenoxy) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as a yellow oil]Indole (35.38mg, yield: 11.9%).¹H NMR(400MHz,DMSO-d₆):δ10.95(s,1H),7.39～7.27(m,4H),7.02～6.98(m,2H),4.17(t,J＝5.6Hz,2H),3.73(s,2H),2.97～2.85(m,4H),2.67(t,J＝5.2Hz,2H)。LCMS:[M+H]⁺＝361.1。

6-chloro-2- (2- (3-chlorophenoxy) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole formate salt：

¹H NMR(400MHz,DMSO-d₆):δ10.94(s,1H),8.19(s,1H),7.39(d,J＝2.0Hz,1H),7.33～7.27(m,2H),7.07(t,J＝2.0Hz,1H),7.01～6.94(m,2H),4.21(t,J＝5.6Hz,2H),3.74(s,2H),2.96(t,J＝5.6Hz,2H),2.87(t,J＝5.6Hz,2H),2.67(t,J＝5.6Hz,2H)。LCMS:[M+H]⁺＝361.0。

6-chloro-2- (2- (3, 4-dichlorophenoxy) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indoles：

¹H NMR(400MHz,DMSO-d₆):δ10.94(s,1H),7.53～7.27(m,4H),7.01～6.99(m,2H),4.22(s,2H),3.73(s,2H),2.95～2.85(m,4H),2.67(s,2H)。LCMS:[M+H]⁺＝395.0。

General scheme 20

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3, 5-dichlorophenyl) ethanone Representative Synthesis of Formate salts：

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3, 5-dichlorophenyl) ethanone: to 2-bromo-1- (3, 5-dichlorophenyl) ethan-1-one (500mg, 1.9mmol) and 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]To a solution of indole hydrochloride (310mg, 1.9mmol) in DMF (10mL) was added DIEA (0.7 mL). The resulting mixture was stirred at room temperature for 2h, then poured into water and extracted with EtOAc (3X 20 mL). The organic layer was treated with saturated chlorineWashed with aqueous sodium hydroxide solution and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography using CH₂Cl₂MeOH 200:1 elution gave 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] as a brown oil]Indol-2-yl) -1- (3, 5-dichlorophenyl) ethan-1-one (128mg, yield: 26%). LCMS: [ M + H]⁺＝393.0,395.0。

2- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl-1- (3, 5-dichlorophenyl) ethanone: to 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]To a solution of indol-2-yl) -1- (3, 5-dichlorophenyl) ethan-1-one (120mg, 0.31mmol) in EtOH (10mL) was added NaBH₄(23mg, 0.61 mmol). The reaction solution was stirred at room temperature for 2 h. The solvent was evaporated and the residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% HCOOH/CH)₃CN/H₂O) purification to give 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b) as a white solid]Indol-2-yl) -1- (3, 5-dichlorophenyl) ethane-1-ol (33.56mg, yield: 28%).¹H NMR(400MHz,DMSO-d₆):δ10.94(s,1H),8.32(s,1H),7.46～7.44(m,3H),7.38(d,J＝2.0Hz,1H),7.28(d,J＝8.8Hz,1H),7.00(dd,J＝8.4,2.0Hz,1H),4.86(t,J＝5.6Hz 1H),3.77～3.68(m,2H),2.89～2.67(m,5H),2.65～2.62(m,2H)。LCMS:[M+H]⁺＝395.2。

2- (6-chloro-1- (hydroxymethyl) -3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -1- (3, 4-di Chlorophenyl) ethanolate salt：

¹H NMR(400MHz,DMSO-d₆):δ10.87(s,1H),8.24(s,1H),7.66～7.63(m,1H),7.58～7.54(m,1H),7.43～7.36(m,2H),7.31～7.28(m,1H),7.02(dd,J＝4.8,2.0Hz,1H),4.79～4.73(m,1H),3.85～3.77(m,2H),3.68(d,J＝6.4Hz,1H),3.63～3.55(m,2Hz),3.18～3.05(m,1H),2.90～2.85(m,1H),2.82～2.75(m,1H),2.73～2.62(m,2H),2.46～2.41(m,1H)。LCMS:[M+H]⁺＝427.0。

General scheme 21

3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -1- (4-chlorophenyl) propane-1, 2- Representative Synthesis of diols：

To 1- (6-chloro-3, 4-dihydro-1H-pyrido [3,4-b ]]Indol-2 (9H) -yl) -3- (4-chlorophenyl) -2, 3-dihydroxypropan-1-one (150mg, 0.37mmol) in dry THF (5mL) was added BH dropwise₃THF (1M, 1.11mL, 1.11 mmol). The reaction was stirred at room temperature for 16h and saturated NH₄And (4) quenching by Cl. EtOAc (20mL) was added and the resulting mixture was washed with brine (2X 20mL) and anhydrous Na₂SO₄Dried and concentrated. The residue was passed through (mobile phase: 0.1% NH)₄HCO₃/H₂O/MeCN) to give 3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b) as a white solid]Indol-2 (9H) -yl) -1- (4-chlorophenyl) propane-1, 2-diol (29.92mg, yield: 21%).¹H NMR(400MHz,DMSO-d₆):δ10.89(s,1H),7.38～7.26(m,6H),7.00(d,J＝7.2Hz,1H),5.42(s,1H),4.61(s,2H),3.81～3.62(m,3H),2.77～2.59(m,5H),2.41～2.36(m,1H)。LCMS:[M+H]⁺＝391.3。

3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) -1- (3-chlorophenyl) propane-1, 2- Diols：

¹H NMR(400MHz,DMSO-d₆):δ10.89(s,1H),7.42～7.26(m,6H),7.00(d,J＝8.0Hz,1H),5.46～5.42(m,1H),4.63(d,J＝3.2Hz,2H),3.82～3.63(m,3H),2.79～2.50(m,5H),2.44～2.39(m,1H)。LCMS:[M+H]⁺＝391.3。

General scheme 22

3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Generation of indol-2 (9H) -yl) dihydrofuran-2 (3H) -one Epitopic Synthesis: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole hydrochloride (400mg, 1.66mmol) in CH₂Cl₂To a solution in (10mL) and DMSO (2mL) was added 3-bromodihydrofuran-2 (3H) -one (274mg, 1.66mmol) and DIEA (1g, 8.3 mmol). The reaction mixture was stirred at room temperature for 16H, then filtered to give 3- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) dihydrofuran-2 (3H) -one (320mg, yield: 66%). LCMS: [ M + H]⁺＝391.0。

3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) dihydrofuran-2 (3H) -one: to a solution of 3-chloroaniline (88mg, 0.7mmol) in anhydrous THF (5mL) at-78 deg.C was added 2M LDA (0.9mL, 1.8 mmol). The reaction was stirred at-78 ℃ for 30min and then warmed to room temperature. 3- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] in THF (2mL)]Indol-2-yl) dihydrofuran-2 (3H) -one (200mg, 0.7mmol) was added to the reaction and stirred at room temperature for 2H. The reaction was then treated with saturated ammonium chloride (10mL) and extracted with ethyl acetate (3X 10 mL). The combined organics were washed with Na₂SO₄Dried and concentrated. The residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₃/CH₃CN/H₂O) purification to obtain 2- (6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) -N- (3-chlorophenyl) -4-hydroxybutyramide (20.34mg, yield: 7%).¹H NMR(400MHz,DMSO-d₆):δ10.92(s,1H),10.20(s,1H),7.88(s,1H),7.51～7.49(m,1H),7.37～7.26(m,3H),7.11～7.09(m,1H),7.00～6.79(m,1H),4.59(t,1H),3.90(m,2H),3.66～3.41(m,3H),2.93～2.65(m,4H),1.98～1.87(m,2H)。LCMS:[M+H]⁺＝418.1。

General scheme 23

3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) propionic acid: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]To a solution of indole hydrochloride (300mg, 1.23mmol) in DMF (5mL) was added oxetan-2-one (89mg, 1.23mmol) and DIEA (476mg, 3.69 mmol). The reaction was stirred at room temperature for 16h and then poured into water. The resulting mixture was adjusted to pH ≈ 6 with 3M aqueous hydrochloric acid, extracted with EtOAc, washed with brine, and Na₂SO₄Drying and evaporating to obtain 3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) propionic acid (100mg, yield: 29%).

3- (6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) propionic acid: to 3- (6-chloro-3, 4-dihydro-1H-pyrido [3,4-b ]]To a solution of indol-2 (9H) -yl) propionic acid (80mg, 0.287mmol) in DMF (4mL) was added 3-chloroaniline (73mg, 0.574mmol), HATU (218mg, 0.574mmol) and DIEA (111mg, 0.861 mmol). The reaction was stirred at room temperature for 1h, then poured into water, extracted with EtOAc, washed with brine, washed with Na₂SO₄Dried and concentrated. Subjecting the residue to preparative high performance liquid chromatography (0.1% HCOOH/CH)₃CN/H₂O) purification to give 3- (6-chloro-3, 4-dihydro-1H-pyrido [3,4-b ] as a white solid]Indol-2 (9H) -yl) -N- (3-chlorophenyl) propionamide (100mg, yield: 90%).¹H NMR(400MHz,DMSO-d₆):δ10.97(s,1H),10.29～10.27(m,1H),8.16(d,J＝6.0Hz,0.6H),7.83(s,1H),7.43～7.38(m,2H),7.31～7.27(m,2H),7.08(dd,J＝1.2,8.0Hz,1H),6.99(dd,J＝2.0,8.8Hz,1H),3.68(s,2H),2.94～2.90(m,2H),2.84～2.82(m,2H),2.68～2.67(m,2H),2.63～2.59(m,2H)。LCMS:[M+H]⁺＝388.2。

General scheme 24

6-chloro-N- (3-chloro-5-methoxybenzyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxamides: to (3-chloro-5-methoxyphenyl) methylamine (255mg, 1.491mmol) and Et at 0 deg.C₃N (905mg, 8.946mmol) in THF (8mL) was added CDI (265mg, 1.640 mmol). The mixture was stirred at 0 ℃ for 1 h. Then 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] is added]Indole hydrochloride (361mg, 1.491mmmol), the mixture was stirred at 0 ℃ for 1h and at 65 ℃ for 2 h. The reaction mixture was then filtered and the filtrate was concentrated. The residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₄HCO₃/CH₃CN/H₂O) purification to give 6-chloro-N- (3-chloro-5-methoxybenzyl) -3, 4-dihydro-1H-pyrido [3,4-b ] in the form of a colorless oil]Indole-2 (9H) -carboxamide (330mg, yield: 55%).¹H NMR(400MHz,DMSO-d₆):δ11.07(s,1H),7.44～7.30(m,3H),7.03(dd,J＝8.4,2.0Hz,1H),6.88～6.79(m,3H),4.59(s,2H),4.23(d,J＝5.6Hz,2H),3.72～3.68(m,5H),2.68(s,2H)。LCMS:[M+H]⁺＝404.2。

6-chloro-N- (3-chloro-5-hydroxybenzyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxamides: to 6-chloro-N- (3-chloro-5-methoxybenzyl) -3, 4-dihydro-1H-pyrido [3,4-b ] at 0 deg.C]Indole-2 (9H) -carboxamide (100mg, 0.249mmol) in anhydrous CH₂Cl₂(5mL) to the solution BBr₃(2.5 mL). The reaction was stirred at room temperature for 2h, then saturated NaHCO₃And (4) quenching. The resulting solution was taken up in saturated NaHCO₃Adjusted to pH 8-9 and extracted with EtOAc (3X 10 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated. The residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₃·H₂O/CH₃CN/H₂O) purification to give 6-chloro-N- (3-chloro-5-hydroxybenzyl) -3, 4-dihydro-1H-pyrido [3,4-b ] as a white solid]Indole-2 (9H) -carboxamide (19.95mg, yield: 10.3%).¹H NMR(400MHz,DMSO-d₆):δ11.08(s,1H),7.44(d,J＝1.6Hz,1H),7.32～7.30(m,2H),7.04(dd,J＝8.8,2.0Hz,1H),6.72(s,1H),6.63(s,2H),4.58(s,2H),4.18(d,J＝5.6Hz,2H),3.69(d,J＝5.6Hz,2H),2.68(s,2H)。LCMS:[M+H]⁺＝390.1。

General scheme 25

4-Nitrophenyl (6- (trifluoromethyl) pyridin-3-yl) carbamates: to 6- (trifluoromethyl) pyridin-3-amine (500mg, 3.08mmol) in CH at room temperature₂Cl₂To the solution (20mL) was added phenyl p-nitrochloroformate (620mg, 3.08mmol) and pyridine (244mg, 3.08mmol), and the mixture was stirred for 2 hours. The mixture was then poured into water with CH₂Cl₂Extraction, washing with brine and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography, eluting with petroleum ether: EtOAc ═ 4:1, to give 4-nitrophenyl (6- (trifluoromethyl) pyridin-3-yl) carbamate (350mg, yield: 35%).

6-chloro-N- (6- (trifluoromethyl) pyridin-3-yl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carbaryl Amides of carboxylic acids: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] at room temperature]Indole hydrochloride (100mg, 0.306mmol) in CH₂Cl₂To a solution in (2mL) was added 4-nitrophenyl (6- (trifluoromethyl) pyridin-3-yl) carbamate (63mg, 0.306mmol), Et₃N (218mg, 0.574mmol) and stirred for 2 h. The reaction was concentrated and the residue was purified by preparative high performance liquid chromatography (mobile phase 0.1% NH)₄HCO₃/CH₃CN/H₂O) purification to give 6-chloro-N- (6- (trifluoromethyl) pyridin-3-yl) -3, 4-dihydro-1H-pyrido [3, 4-b) as a white solid]Indole-2 (9H) -carboxamide (35.18mg, yield: 29%).¹H NMR(400MHz,DMSO-d₆):δ11.14(s,1H),9.35(s,1H),8.84(d,J＝2.4Hz,1H),8.18(dd,J＝2.4,8.8Hz,1H),7.79(d,J＝8.4Hz,1H),7.48(d,J＝2.0Hz,1H),7.34(d,J＝8.8Hz,1H),7.05(dd,J＝2.0,8.4Hz,1H),4.73(s,2H),3.87-3.85(m,2H),2.80-2.77(m,2H)。LCMS:[M+H]⁺＝395.1。

General scheme 26

6-chloro-N- (4-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Representative indole-1-carboxamides Synthesis of：

2- (tert-Butoxycarbonyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-1-carboxylic acid: to 6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-1-carboxylic acid (2.0g, 8.0mmol) and NaOH (960mg, 24.0mmol) in H₂O (40mL) and CH₂Cl₂(10mL) of the mixture was added Boc₂O (2.6g, 12.0 mmol). The mixture was stirred at 40 ℃ for 4 h. The reaction was then cooled to 10 ℃ and adjusted to pH 6. The precipitate was collected by filtration and dried in vacuo to give 2- (tert-butoxycarbonyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as a white solid]Indole-1-carboxylic acid (2.1g, yield: 75%).¹H NMR(400MHz,DMSO-d₆):δ13.41(br,1H),11.16(m,1H),7.47(s,1H),7.39(d,J＝8.8Hz,1H),7.09(dd,J＝8.4,1.6Hz,1H),5.56～5.47(m,1H),4.34～4.22(m,1H),3.30～3.12(m,2H),2.78～2.60(m,2H),1.45～1.42(m 9H)。

6-chloro-1- ((4-chlorophenyl) carbamoyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxylic acid Tert-butyl ester: to 2- (tert-butoxycarbonyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] at 0 deg.C]To a mixture of indole-1-carboxylic acid (200mg, 0.57mmol, 1.0 equiv.), 3(109mg, 0.86mmol, 1.5 equiv.), and HATU (433mg, 1.14mmol, 2.0 equiv.) in DMF (10mL) was added DIEA (221mg, 1.71mmol, 3.0 equiv.). The mixture was stirred at room temperature for 3h, then poured into water (30mL) and extracted with EtOAc (3X 60 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Purifying the residue by silica gel column chromatography with petroleum ether and ethyl acetate2:1 elution gave 6-chloro-1- ((4-chlorophenyl) carbamoyl) -3, 4-dihydro-1H-pyrido [3,4-b ] as a white solid]Indole-2 (9H) -carboxylic acid tert-butyl ester (140mg, yield: 53%).¹H NMR(400MHz,DMSO-d₆):δ11.17～11.02(m,1H),10.71～10.62(m,1H),7.72～7.68(m,2H),7.50(br,1H),7.41(d,J＝8.0Hz,1H),7.09(dd,J＝8.4,2.0Hz,1H),5.76～5.63(m,1H),4.26～4.22(m,1H),3.63～3.51(m,1H),2.85～2.76(m,1H),2.71～2.62(m,1H),1.45～1.36(m,9H)。

6-chloro-N- (4-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-1-carboxamides: to 6-chloro-1- ((4-chlorophenyl) carbamoyl) -3, 4-dihydro-1H-pyrido [3,4-b]Indole-2 (9H) -carboxylic acid tert-butyl ester (120mg, 0.26mmol) in CH₂Cl₂To the mixture (9mL) was added TFA (3 mL). The mixture was stirred at room temperature for 3 h. The solvent was evaporated in vacuo. The residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% NH)₃·H₂O/CH₃CN/H₂O) purification to give 6-chloro-N- (4-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as a white solid]Indole-1-carboxamide (65mg, yield: 69%).¹H NMR(400MHz,DMSO-d₆):δ10.94(s,1H),10.25(s,1H),7.75(d,J＝8.8Hz,2H),7.43-7.34(m,4H),7.02(dd,J＝8.4Hz,2.0Hz,1H),4.70(d,J＝6.0Hz,1H),3.22-3.19(m,1H),3.08-3.04(m,2H),2.66-2.63(m,2H)。LCMS:[M+H]⁺＝360.1。

6-chloro-N- (3-chlorophenyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-1-carboxamide hydrochloride：

¹H NMR(400MHz,DMSO-d₆):δ11.75(s,1H),11.60(s,1H),10.31(br,1H),9.60(br,1H),7.90～7.88(m,1H),7.71(d,J＝8.4Hz,1H),7.60(d,J＝1.6Hz,1H),7.46～7.41(m,2H),7.25～7.14(m,2H),5.64(s,1H),3.81～3.75(m,1H),3.60～3.54(m,1H),3.08～3.02(m,1H),2.97～2.90(m,1H)。LCMS:[M+H]⁺＝360.1。

General scheme 27

(2- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) amino) -2-oxoethyl) carbamic acid tert-butyl ester：

To N- (2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine (200mg, 0.44mmol) in DMF (5mL) was added DIPEA (171mg, 1.32mmol) and (tert-butoxycarbonyl) glycine (100mg, 0.57mmol) and HATU (251mg, 0.66 mmol). The resulting mixture was stirred at 16 ℃ for 2 h. The mixture was diluted with ethyl acetate (50mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated to give crude (2- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a light yellow oil]Indol-1-yl) methyl) amino) -2-oxoethyl) carbamic acid tert-butyl ester (300mg, crude). LCMS: [ M + H]⁺615.0。

2-amino-N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) acetamides

To (2- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) amino) -2-oxoethyl) carbamic acid tert-butyl ester (230mg, 0.37mmol) to a solution in DCM (80mL) was added TFA (TFA)1 mL). The mixture was stirred at 16 ℃ for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to give 2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] as a white solid]Indol-2-yl) -N- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) acetamide (30.52 mg).¹H NMR(400MHz,DMSO-d₆)δ11.03(s,1H),7.93-7.89(m,1H),7.64(d,J＝12.0Hz,1H),7.42(d,J＝4.0Hz,1H),7.30(d,J＝8.0Hz,1H),7.18-7.15(m,1H),7.02(dd,J＝8.0Hz,2.0Hz,1H),6.80(d,J＝8.0Hz,1H),3.81(dd,J＝8.0Hz,4.0Hz,1H),3.74-3.68(m,1H),3.42-3.38(m,2H),3.28-3.22(m,1H),3.18-3.13(m,1H),3.07(s,2H),2.92(dd,J＝8.0Hz,4.0Hz,1H),2.81-2.71(m,3H),2.47-2.45(m,1H),1.89(brs,2H)。LCMS:[M+H]⁺:515.1。

(2S) -2, 6-diamino-N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethane) Yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) hexanamide：

¹H NMR(400MHz,MeOD)δ7.53(d,J＝8.8Hz,1H),7.38(d,J＝1.6Hz,1H),7.24(dd,J＝8.8Hz,2.8Hz,1H),7.02(d,J＝8.8Hz,1H),6.71(d,J＝9.2Hz,1H),3.88-3.86(m,1H),3.69-3.66(m,1H),3.56-3.47(m,3H),3.24-3.15(m,1H),2.97-2.91(m,2H),2.87-2.81(m,2H),2.61-2.53(m,3H),1.50-1.12(m,7H)。LCMS:[M+H]⁺＝586.3。

(2S) -2, 4-diamino-N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethane) Yl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) butanamide：

¹H NMR(400MHz,DMSO-d₆):δ11.11-11.08(m,1H),8.33(s,2H),8.10-8.09(m,1H),7.63(d,J＝8.8Hz,1H),7.41(s,1H),7.30(dd,J＝8.8Hz,2.0Hz,1H),7.32-7.26(m,1H),7.02(d,J＝8.8Hz,1H),6.80(d,J＝8.8Hz,1H),3.82-3.78(m,1H),3.67-3.55(m,2H),3.42-3.38(m,2H),3.30-3.23(m,3H),3.19-3.13(m,2H),2.93-2.72(m,5H),2.49-2.46(m,1H),1.87-1.83(m,1H),1.55-1.53(m,1H)。LCMS:[M+H]⁺＝558.3。

N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) acetamides

¹H NMR(400MHz,MeOD)δ7.53(d,J＝8.8Hz,1H),7.37(s,1H),7.25(d,J＝8.4Hz,1H),7.01(d,J＝8.4Hz,1H),6.70(d,J＝8.8Hz,1H),3.87-3.84(m,1H),3.73-3.67(m,1H),3.48-3.42(m,3H),3.30-2.85(m,5H),2.56-2.52(m,1H),1.87(s,3H)。LCMS:[M+H]⁺＝500.2。

(2S) -2-amino-N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methyl) -3-hydroxypropionamide hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.63～11.47(m,1H),11.15～10.74(m,1H),9.08～8.94(d,J＝58Hz,1H),8.28(s,3H),7.73～7.68(m,2H),7.57(s,1H),7.42～7.40(m,1H),7.15～7.13(m,1H),6.88～6.83(m,1H),5.60(br,1H),4.95～4.84(m,1H),4.16～3.49(m,10H),3.22～3.05(m,3H).¹⁹F NMR(376MHz,CDCl₃):δ-64.57。LCMS:[M+H]⁺＝545.3。

(2S) -2-amino-N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methyl) -5-guanidinoPentamide formate salt

¹H NMR(400MHz,MeOD-d₆):δ7.53(d,J＝6.8Hz,1H),7.46～7.24(m,2H),7.14～7.00(m,1H),6.77～6.72(m,1H),5.67～5.64(m,1H),4.08～3.37(m,7H),3.18～2.56(m,7H),1.62～1.29(m,4H)。LCMS:[M+H]⁺＝644.2。

2-amino-N- ((6-chloro-2- (2- ((5, 6-dichloropyridin-2-yl) (methyl) amino) ethyl) -2,3,4, 9-tetra Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) acetamide dihydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.63～11.59(m,1H),11.32～10.95(m,1H),8.96～8.80(m,1H),8.20～8.13(m,3H),7.75(d,J＝8.8Hz,1H),7.58(s,1H),7.43(d,J＝8.8Hz,1H),7.15(d,J＝8.0Hz,1H),6.76(d,J＝8.8Hz,1H),4.95(br,1H),4.20～4.09(m,2H),3.99～3.83(m,3H),3.67～3.61(m,4H),3.43～3.33(m,1H),3.24～3.21(m,1H),3.06(br,4H)。LCMS:[M+H]⁺＝497.1。

General scheme 28

The compound 1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Synthesis of indol-1-yl) methyl) -3- (2- (dimethylamino) ethyl) urea

2-isocyanato-N, N-dimethylethane-1-amines

To a solution of CDI (1.84g, 11.34mmol) in toluene (5mL) at 5-10 deg.C was added N¹,N¹-a solution of dimethylethane-1, 2-diamine (1g, 11.34mmol) in toluene (2 mL). The reaction solution was stirred at 5-10 ℃ for 3h, then at 20-25 ℃ for 3h to give a clear colorless solution. The resulting solution was used directly in the next step.

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) -3- (2- (dimethylamino) ethyl) urea

To N- (2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine (250mg, 0.23mmol) and Et₃To a solution of N (234.1mg, 1.16mmol) in THF (5mL) was added a solution of 2-isocyanato-N, N-dimethylethan-1-amine (53mg, 0.23mmol) prepared previously in toluene (0.14 mL). The resulting mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% HCOOH/CH)₃CN/H₂O) purification to give 1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indol-1-yl) methyl) -3- (2- (dimethylamino) ethyl) urea (53.31mg, yield: 20%).¹H NMR(400MHz,DMSO-d₆):δ11.01(s,1H),8.16(s,1H),7.65(d,J＝9.2Hz,1H),7.41(d,J＝2.0Hz,1H),7.30(d,J＝8.4Hz,1H),7.19(t,J＝5.2Hz,1H),7.03(dd,J＝8.8Hz,2.0Hz,1H),6.83(d,J＝8.8Hz,1H),6.12(t,J＝5.2Hz,1H),6.02(dd,J＝6.4Hz,4.0Hz,1H),3.75～3.72(m,1H),3.63～3.58(m,1H),3.46～3.35(m,4H),3.24～3.09(m,4H),2.87～2.83(m,1H),2.76～2.71(m,2H),2.43～2.39(m,2H),2.27(s,6H).¹⁹F NMR(376MHz,CDCl₃):δ-64.66。LCMS:[M+H]⁺＝572.3。

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) urea

¹H NMR(400MHz,DMSO-d₆)δ11.02(brs,1H),7.62(d,J＝8.0Hz,1H),7.40(d,J＝4.0Hz,1H),7.29(d,J＝8.0Hz,1H),7.18(t,J＝4.0Hz,1H),7.01(dd,J＝8.0Hz,2.0Hz,1H),6.82(d,J＝12.0Hz,1H),5.92(brs,1H),5.55(brs,2H),3.72-3.71(m,1H),3.63-3.61(m,1H),3.43-3.39(m,3H),3.16-3.12(m,2H),2.86-2.83(m,1H),2.76-2.73(m,3H)。LCMS:[M+H]⁺:501.2。

General scheme 29

The compound N- (2- (1- (sulfamethanamine) -6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indole-2 (9H) Synthesis of-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine

(Chlorosulfonyl) carbamic acid tert-butyl ester

To a solution of chlorosulfonyl isocyanate (160mg, 1.09mmol) in DCM (10mL) was added dropwise a solution of t-BuOH (80mg, 1.09mmol) in DCM (5mL) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h. The resulting solution was used directly in the next step.

(N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) sulfamoyl) carbamic acid tert-butyl ester

To N- (2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] at 0 deg.C]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine (500mg, 1.09mmol) and Et₃A solution of tert-butyl (chlorosulfonyl) carbamate (prepared in the previous step) in DCM (15mL) was added dropwise to a solution of N (1.1g, 10.9 mmol). After stirring at room temperature for 4h, the mixture was poured into water and extracted with DCM. The organic solution was washed with brine and Na₂SO₄Dried and evaporated. The residue was purified by silica gel column chromatography to give (N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indol-1-yl) methyl) sulfamoyl) carbamic acid tert-butyl ester (600mg, yield: 86%). LCMS: [ M + H]⁺＝637.3。

N- (2- (1- (sulfamoylaminomethyl) -6-chloro-3, 4-dihydro-1H-pyrido [3, 4-b)]Indol-2 (9H) -yl) ethanes Yl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine

To (N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) at room temperature]Indol-1-yl) methyl) sulfamoyl) carbamic acid tert-butyl ester (400mg, 0.627mmol) in DCM (15mL)To the solution was added TFA (1 mL). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with DCM. The organic solution was washed with saturated NaHCO₃And brine, then Na₂SO₄Dried and evaporated. The residue was purified by preparative high performance liquid chromatography to give N- (2- (1- (sulfamomethyl) -6-chloro-3, 4-dihydro-1H-pyrido [3,4-b ] as a white solid]Indol-2 (9H) -yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine (46mg, yield: 14%).¹H NMR(400MHz,DMSO-d₆):δ10.94(s,1H),7.64(d,J＝8.8Hz,1H),7.42(d,J＝1.6Hz,1H),7.31(d,J＝8.4Hz,1H),7.25(t,J＝5.2Hz,1H),7.03(dd,J＝8.8Hz,2.0Hz,1H),6.80(d,J＝9.2Hz,1H),6.61(s,2H),6.15～6.11(m,1H),3.90～3.86(m,1H),3.45～3.40(m,2H),3.31～3.25(m,1H),3.22～3.15(m,1H),3.12～3.06(m,1H),2.97～2.89(m,1H),2.82～2.68(m,3H),2.47～2.43(m,1H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.65。LCMS:[M+H]⁺＝537.1。

General scheme 30

3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Representative Synthesis of indol-1-yl) methyl) -1-methyl-1H-imidazol-3-ium: reacting (6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methanol (300mg, 0.65mmol, 1.0 eq) was dissolved in THF (20mL) and SOCl was added₂(155g, 1.30mmol, 2 equiv.). The reaction was stirred at 20 ℃ for 16 h. The reaction mixture was concentrated to give crude 5-chloro-N- (2- (6-chloro-1- (chloromethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b) as a brown solid]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine (300mg, 73.47% yield), which was used without further purification. LCMS: [ M + H]⁺＝477.1。

3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazol-3-ium。

Reacting 5-chloro-N- (2- (6-chloro-1- (chloromethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ]]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine (150mg, 0.31mmol, 1.0 eq) was dissolved in 1-methyl-1H-imidazole (10mL) and the solution was stirred at 25 ℃ for 18H. The reaction solution was directly purified by preparative high performance liquid chromatography (HCOOH) to give 3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a brown solid]Indol-1-yl) methyl) -1-methyl-1H-imidazol-3-ium (20.19mg, yield: 12.26%).¹H NMR(400MHz,MeOD):δ8.68(brs,0.5H),8.55(brs,1H),7.66(brs,1H),7.56-7.52(m,2H),7.45(brs,1H),7.27(d,J＝8.4Hz,1H),7.14(d,J＝8.4Hz,1H),6.62(d,J＝8.8Hz,1H),5.77(brs,1H),3.79(s,3H),3.54-3.39(m,3H),3.28-3.23(m,2H),3.11(br,2H),2.90-2.83(m,3H)。LCMS:[M+H]⁺＝523.2。

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (methyl) amino) ethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -4- (dimethylamino) pyridin-1-ium

¹H NMR(400MHz,MeOD):δ8.50(br,1H),8.07(d,J＝7.6Hz,2H),7.63-7.55(m,2H),7.27-7.23(m,1H),7.15-7.12(m,1H),6.84(d,J＝8.0Hz,2H),6.73-6.70(m,1H),5.65(brs,1H),3.61-3.54(m,2H),3.53-3.41(m,3H),3.20(s,6H),3.15-3.03(m,2H),2.94(s,3H),2.85-2.80(m,3H)。LCMS:[M+H]⁺＝577.3。

3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (methyl) amino) ethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazol-3-ium

¹H NMR(400MHz,MeOD):δ8.62(brs,1H),8.51(brs,1H),7.65-7.62(m,2H),7.54(d,J＝2.0Hz,1H),7.50(d,J＝1.6Hz,1H),7.27(d,J＝8.8Hz,1H),7.14(d,J＝8.8Hz,2.0Hz,1H),6.75(d,J＝9.2Hz,1H),5.75(d,J＝2.0Hz,1H),3.84(s,3H),3.70-3.63(m,1H),3.56-3.42(m,3H),3.39-3.32(m,1H),3.14-3.07(m,1H),3.02-2.93(m,4H),2.87-2.77(m,3H)。LCMS:[M+H]⁺＝537.2。

5-amino-2- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (methyl) amino) ethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methyl) -1-methyl-1H-pyrazole-2-ium chloride

¹H NMR(400MHz,MeOD):δ7.60(d,J＝9.2Hz,1H),7.38(d,J＝1.6Hz,1H),7.22(d,J＝8.4Hz,1H),7.16(d,J＝2.4Hz,1H),6.98(dd,J＝8.4Hz,2.0Hz,1H),6.79(d,J＝9.2Hz,1H),5.50(d,J＝2.0Hz,1H),4.56(dd,J＝7.2Hz,2.0Hz,1H),3.84-3.73(m,2H),3.60(s,3H),3.27-3.20(m,1H),3.17-3.06(m,5H),3.00-2.87(m,5H)。LCMS:[M+H]⁺＝552.2。

3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) -1- (2-hydroxyethyl) -1H-imidazole-3-ium chloride trihydrochloride

¹H NMR(400MHz,DMSO-d₆):δ14.76(s,0.5H),11.85～11.72(m,1.5H),9.49～8.94(m,1.5H),7.95～7.84(m,2.5H),7.75～7.66(m,3H),7.41(d,J＝8.4Hz,1H),7.18(d,J＝8.0Hz,1H),6.89(d,J＝8.8Hz,1H),6.56(br,1H),4.26～4.06(m,4.5H),3.72(br,6H),3.49～3.38(m,4.5H).¹⁹F NMR(376MHz,CDCl₃):δ-64.65。LCMS:[M+]⁺＝553.3。

1- (2-aminoethyl) -3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methyl) -1H-imidazole-3-chloride dihydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.76～11.45(m,2H),9.01(br,0.6H),8.58～8.44(m,3H),8.00～7.71(m,5H),7.39(br,1H),7.18(br,1H),6.87(d,J＝8.8Hz,1H),6.50(br,0.4H),4.49(br,3H),4.14(br,1H),3.85～3.75(m,2H),3.43～3.36(m,9H).¹⁹F NMR(376MHz,CDCl₃):δ-64.64。LCMS:[M+]⁺＝552.2。

3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) -1- (2- (dimethylamino) ethyl) -1H-imidazole-3-ium chloride trihydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.80～11.61(m,2H),11.00～10.60(m,1H),9.68～9.20(m,1H),8.01～7.72(m,5H),7.40～7.38(m,1H),7.20(d,J＝7.6Hz,1H),6.89(d,J＝9.2Hz,1H),6.58(br,1H),4.69～4.48(m,3H),4.15～4.12(m,1H),3.84～3.75(m,6H),3.51～3.39(m,5H),2.82(s,6H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.64。LCMS:[M+]⁺＝580.2。

3- (2- (6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) ethyl) -1-methyl-1H-imidazole-3-ium chloride dihydrochloride

¹H NMR(400MHz,DMSO-d₆):11.72～11.69(m,1H),11.22(br,0.5H),10.81(br,0.5H),9.52(s,0.5H),9.26(s,0.5H),7.92～7.66(m,5H),7.37(d,J＝8.8Hz,1H),7.17～7.12(m,1H),6.84(dd,J＝8.4Hz,6.8Hz,1H),6.62-6.57(m,0.5H),6.18(dd,J＝11.2Hz,3.2Hz,0.5H),3.89(d,J＝13.6Hz,3H),3.68～3.13(m,11H),2.89～2.79(m,1.5H),2.54～2.50(m,0.5H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.68。LCMS:[M+]⁺＝537.1。

1- (azetidin-3-yl) -3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (methyl) amino) Yl) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1H-imidazole-3-chloronium hydrochloride

¹H NMR(400MHz,MeOD-d₄):δ8.15-8.14(m,1H),7.91(s,1H),7.75-7.69(m,2H),7.37(d,J＝8.4Hz,1H),7.23(dd,J＝8.8Hz,1.6Hz,1H),6.96(d,J＝9.2Hz,1H),6.45-6.38(m,1H),5.59(t,J＝7.2Hz,1H),4.66-4.55(m,5H),4.26-4.06(m,3H),3.96-3.91(m,1H),3.63-3.56(m,4H),3.49-3.38(m,2H),3.15(s,3H)。LCMS:[M]⁺＝578.0。

1- (azetidin-3-ylmethyl) -3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (methyl) Yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1H-imidazole-3-ylium chloride salt Acid salts

¹H NMR(400MHz,MeOD-d₄):δ8.91(brs,1H),7.80～7.39(m,4H),7.39～7.36(d,J＝8.8Hz,1H),7.23～7.21(d,J＝7.6Hz,1H),6.98～6.96(d,J＝8.8Hz,1H),6.52(brs,1H),4.32(s,3H),4.28～3.89(m,9H),3.61～3.34(m,6H),3.19(s,3H)。LCMS:[M]⁺＝592.1。

3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) (sulfo) amino) ethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1- (2-hydroxyethyl) -1H-imidazole-3-ium chloride

¹H NMR(400MHz,MeOD-d₄):δ8.84～8.77(m,1H),7.86(d,J＝9.2Hz,1H),7.76(d,J＝9.2Hz,1H),7.60～7.51(m,3H),7.28～7.25(m,1H),7.14～7.11(m,1H),5.82～5.76(m,1H),4.28～4.20(m,2H),4.0～3.94(m,2H),3.82～3.78(m,2H),3.58～3.35(m,3H),3.10～2.82(m,5H)。¹⁹F NMR(400MHz,MeOD-d₄):δ-67.14。LCMS:[M]⁺＝552.9。

1- (azetidin-3-ylmethyl) -3- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) Yl) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1H-imidazole-3-ium chloride

¹H NMR(400MHz,CD₃OD):δ7.01(d,J＝8.4Hz,2H),7.60-7.52(m,2H),7.29-7.11(m,2H),6.73(d,J＝8.8Hz,1H),6.39(brs,1H),4.96-4.89(m,1H),4.43(s,2H),4.19-4.08(m,3H),4.0-3.95(m,2H),3.85-3.80(m,3H),3.64-3.43(m,5H),3.38-3.31(m,2H)。LCMS:[M]⁺＝578.1。

General scheme 31

(1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Representative Synthesis of indol-1-yl) methyl) pyrrolidin-2-yl) methanol

To 5-chloro-N- (2- (6-chloro-1- (chloromethyl) -3, 4-dihydro-1H-pyrido [3, 4-b) at room temperature]Indol-2 (9H) -yl) -ethyl) -6- (trifluoromethyl) pyridin-2-amine (100mg, 0.209mmol) and K₂CO₃(57mg, 0.418mmol) to a mixture in acetonitrile (10mL) was added pyrrolidin-2-ylmethanol (422mg, 4.18mmol), and the mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative high performance liquid chromatography to give two isomers. Diastereomer 1: 18.72mg, 17% yield, white solid.¹H NMR(400MHz,DMSO-d₆):δ10.67(s,1H),7.63(d,J＝8.8Hz,1H),7.40(d,J＝1.6Hz,1H),7.31(d,J＝8.8Hz,1H),6.99(br,1H),6.98(dd,J＝8.8Hz,2.4Hz,1H),6.79(d,J＝8.8Hz,1H),4.25-4.16(m,2H),3.45-3.41(m,2H),3.24-3.21(m,1H),3.07-2.74(m,11H),2.65-2.55(m,1H),1.75-1.53(m,4H)。LCMS:[M+H]⁺542.1. Diastereomer 2: 11.3mg, 11% yield, white solid.¹H NMR(400MHz,DMSO)δ10.77(s,1H),7.63(d,J＝8.8Hz,1H),7.44(d,J＝1.6Hz,1H),7.29(d,J＝8.4Hz,1H),7.20-7.16(m,1H),6.98(dd,J＝8.4Hz,2.0Hz,1H),6.76(d,J＝9.2Hz,1H),4.48-4.46(m,1H),4.11(brs,1H),3.47-3.36(m,2H),3.27-3.03(m,6H),2.90-2.66(m,5H),2.59-2.54(m,1H),2.44-2.24(m,1H),1.61-1.46(m,4H)。LCMS:[M+H]⁺:542.1。

5-chloro-N- (2- (6-chloro-1- ((cyclopropyl)Amino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indole Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,MeOD):δ7.50(d,J＝8.8Hz,1H),7.37(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),6.98(dd,J＝8.4Hz,2.0Hz,1H),6.70(d,J＝8.8Hz,1H),3.84(d,J＝4.4Hz,1H),3.60-3.48(m,2H),3.28-3.21(m,2H),2.90-2.82(m,5H),2.57-2.50(m,1H),1.85-1.82(m,1H),0.43-0.27(m,4H)。LCMS:[M+H]⁺:498.1。

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) piperidin-4-ol formate salt

¹H NMR(400MHz,MeOD):δ8.45(brs,1H),7.55(d,J＝8.8Hz,1H),7.50(d,J＝2.0Hz,1H),7.32(d,J＝8.8Hz,1H),7.11(dd,J＝8.8Hz,2.0Hz,1H),6.71(d,J＝8.8Hz,1H),4.25(d,J＝4.4Hz,1H),3.78(br,1H),3.71-3.62(m,3H),3.48-3.42(m,1H),3.27-3.01(m,7H),2.89-2.82(m,3H),1.96-1.91(m,2H),1.74-1.70(m,2H)。LCMS:[M+H]⁺:542.2。

N- (2- (1- ((azetidin-3-ylamino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)] Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-aminetricarboxylate

¹H NMR(400MHz,MeOD):δ8.51(brs,1H),7.64(d,J＝8.8Hz,1H),7.55-7.50(m,1H),7.41-7.24(m,1H),7.13-7.10(m,1H),6.82(d,J＝8.8Hz,1H),4.72(brs,2H),4.44(d,13.2Hz,2H),4.29(d,10.0Hz,2H),4.10-3.91(m,3H),3.89-3.53(m,4H),3.40-3.34(m,2H),2.99-2.82(m,3H)。LCMS:[M+H]⁺:513.2。

5-chloro-N- (2- (6-chloro-1- ((3-methylpiperazin-1-yl) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4- b]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,MeOD):δ8.45(brs,0.5H),7.54(d,J＝8.4Hz,1H),7.43(s,1H),7.30(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,1H),6.82(d,J＝7.6Hz,1H),4.14(brs,1H),3.90-3.39(m,8H),3.30-2.90(m,7H),2.69(br,1H),2.48(br,1H),1.30-1.17(m,3H)。LCMS:[M+H]⁺:541.1。

((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) methyl) proline

¹H NMR(400MHz,DMSO-d₆):δ11.31(s,1H),7.73(d,J＝9.2Hz,1H),7.63(br,1H),7.49-7.47(m,1H),7.36(d,J＝8.8Hz,1H),7.10(dd,J＝8.8Hz,2.0Hz,1H),6.83(d,J＝8.8Hz,1H),4.37-4.35(m,1H),3.77-3.50(m,6H),3.40-3.32(m,,2H),3.29-3.17(m,2H),3.05-3.00(m,2H),2.83-2.81(m,1H),2.67-2.50(m,1H),2.17-2.14(m,1H),1.95-1.90(m,1H),1.76-1.64(m,2H)。LCMS:[M+H]⁺:556.2。

2- (4- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) piperazin-1-yl) ethan-1-ol

¹H NMR(400MHz,DMSO-d₆):δ10.65(brs,1H),7.63(d,J＝9.2Hz,1H),7.42(d,J＝2.0Hz 1H),7.33(d,J＝8.4Hz,1H),7.19(d,J＝4.8Hz,1H),6.99(dd,J＝8.8Hz,2.0Hz,1H),6.78(d,J＝9.2Hz,1H),4.24(br,1H),3.78-3.76(m,1H),3.46-3.39(m,4H),3.14-2.92(m,4H),2.83-2.60(m,7H),2.50-2.49(m,1H),2.39-2.31(m,6H)。LCMS:[M+H]⁺:571.3。

5-chloro-N- (2- (6-chloro-1- (((3,3, 3-trifluoropropyl) amino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido) [3,4-b]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,CD₃OD)δ7.53(d,J＝8.0Hz,1H),7.41(d,J＝2.0Hz,1H),7.25(d,J＝8.0Hz,1H),7.02(dd,J＝8.0Hz,2.0Hz,1H),6.70(d,J＝12.0Hz,1H),3.80(d,J＝4.0Hz,1H),3.56-3.54(m,2H),3.30-3.24(m,2H),2.91-2.86(m,5H),2.74-2.70(m,1H),2.60-2.53(m,2H),2.33-2.22(m,2H)。LCMS:[M+H]⁺:554.2。

2,2' - (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) azanedi (ethane-1-ol) (2,2' - ((6-chloro-2- (2-) ((5-chloro-6-(trifluoromethyl)pyridin-2-yl)amino)ethyl)-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)methyl)azanediyl)bis(ethan-1-ol))

¹H NMR(400MHz,CDCl₃)δ10.07(brs,1H),7.47(d,J＝8.8Hz,1H),7.40(d,J＝1.2Hz,1H),7.21(d,J＝8.4Hz,1H),7.05(dd,J＝8.4Hz,1.6Hz,1H),6.54(d,J＝8.8Hz,1H),5.48(brs,1H),4.28(d,J＝8.8Hz,1H),3.81-3.75(m,2H),3.66-3.63(m,2H),3.52-3.50(m,2H),3.28-3.24(m,1H),3.17-3.13(m,1H),3.00-2.75(m,10H)。LCMS:[M+1]⁺:546.1。

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) pyrrolidin-3-ol

¹H NMR(400MHz,DMSO-d₆)δ10.92(d,J＝4.0Hz,1H),8.15(s,1H),7.63(d,J＝8.8Hz,1H),7.45(s,1H),7.31-7.28(m,1H),7.23(d,J＝2.8Hz,1H),7.00(dd,J＝8.4Hz,1.6Hz,1H),6.79(dd,J＝8.8Hz,4.8Hz,1H),4.73(br,1H),4.15(br,1H),3.82(br,1H),3.45-3.40(m,2H),3.21-3.12(m,1H),3.08-3.03(m,1H),2.92-2.52(m,9H),2.45-2.39(m,1H),1.98-1.92(m,1H),1.55-1.50(m,1H)。LCMS:[M+H]⁺:528.2。

N- (2- (1- ((3-aminopyrrolidin-1-yl) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)] Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-aminetricarboxylate

¹H NMR(400MHz,DMSO-d₆)δ11.41(br,1H),8.05-7.75(m,2H),7.74-7.70(m,1H),7.65-7.45(m,2H),7.39-7.33(m,1H),7.10-7.06(m,1H),6.84(dd,J＝8.4Hz,4.0Hz,1H),4.06-3.93(m 1H),3.88-3.50(m,8H),3.20-2.90(m,4H),2.85-2.50(m,2H),2.48-2.10(m,2H),1.78-1.70(m,1H)。LCMS:[M+1]⁺:527.1。

N- (2- (1- (azetidin-1-ylmethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole-2- Yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridine-2-carbamic acidSalt (salt)

¹H NMR(400MHz,CD₃OD)δ8.51(brs,1H),7.55(d,J＝8.0Hz,1H),7.52(d,J＝4.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.15(dd,J＝8.0,2.0Hz,1H),6.71(d,J＝12.0Hz,1H),4.43(d,J＝4.0Hz,1H),4.18-4.12(m,2H),3.97(brs,2H),3.60-3.57(m,2H),3.49-3.38(m,2H),3.02-2.97(m,5H),2.71-2.64(m,1H),2.47-2.40(m,2H)。LCMS:[M+1]⁺:498.2。

5-chloro-N- (2- (6-chloro-1- ((4, 4-difluoropiperidin-1-yl) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b]indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,CD₃OD)δ7.50(d,J＝8.0Hz,1H),7.38(d,J＝2.0Hz,1H),7.27(d,J＝8.0Hz,1H),7.00(dd,J＝8.0Hz,2.0Hz,1H),6.67(d,J＝8.0Hz,1H),4.03-4.01(m,1H),3.56-3.55(m,2H),3.16-3.09(m,3H),2.93-2.88(m,5H),2.79-2.73(m,4H),2.03-1.98(m,4H)。LCMS:[M+1]⁺:562.3。

5-chloro-N- (2- (6-chloro-1- ((pyrrolidin-3-ylamino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4- b]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-aminedicarboxylate

¹H NMR(400MHz,CD₃OD)δ8.34(br,2H),7.55(d,J＝9.2Hz,1H),7.41(d,J＝2.0Hz,1H),7.26(d,J＝8.4Hz,1H),7.02(dd,J＝8.4Hz,2.0Hz,1H),6.72(d,J＝8.8Hz,1H),3.93(br,1H),3.66-3.60(m,2H),3.48-3.40(m,3H),3.31-3.30(m,1H),3.30-3.20(m,1H),3.13-3.12(m,1H),3.09-2.82(m,8H),2.10-2.05(m,1H),3.05-1.95(m,1H)。LCMS:[M+1]⁺:527.2。

5-chloro-N- (2- (6-chloro-1- ((pyrrolidin-3-ylamino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4- b]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-aminedicarboxylate

¹H NMR(400MHz,CD₃OD)δ8.34(br,2H),7.55(d,J＝9.2Hz,1H),7.41(d,J＝2.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.02(dd,J＝8.4Hz,2.0Hz,1H),6.72(d,J＝9.2Hz,1H),3.93(br,1H),3.63-3.58(m,2H),3.50-3.33(m,3H),3.27-2.76(m,9H),1.98-1.73(m,2H)。LCMS:[M+1]⁺:527.2。

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) azetidin-3-ols

¹H NMR(400MHz,DMSO-d₆)δ10.95(brs,1H),7.64(d,J＝8.8Hz,1H),7.44(s,1H),7.30(d,J＝8.0Hz,2H),7.00(dd,J＝8.4Hz,1.6Hz,1H),6.79(d,J＝5.2Hz,1H),5.25(br,1H),4.15(t,J＝6.0Hz,1H),3.54-3.48(m,4H),3.03-2.97(m,2H),2.94-2.85(m,5H),2.84-2.74(m,3H),2.62-2.60(m,1H)。LCMS:[M+H]⁺:514.10。

N- (2- (1- ((3-Aminoazetidin-1-yl) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4- b]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,DMSO-d₆)δ10.90(brs,1H),7.63(d,J＝8.8Hz,1H),7.43(s,1H),7.34-7.29(m,2H),6.99(d,J＝8.4Hz,1H),6.79(d,J＝8.8Hz,1H),3.52-3.45(m,2H),3.45-3.39(m,3H),2.97-2.89(m,3H),2.85-2.72(m,7H),2.67-2.50(m,1H)。¹⁹F NMR(376.5MHz,DMSO-d₆)δ-64.72。LCMS:[M+H]⁺:513.20。

5-chloro-N- (2- (6-chloro-1- ((oxetan-3-ylamino) methyl) -1,3,4, 9-tetrahydro-2H-pyrido) [3,4-b]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,DMSO-d₆)δ10.91(brs,1H),7.65(d,J＝8.0Hz,1H),7.42(d,J＝2.0Hz,1H),7.29-7.27(m,2H),6.98(dd,J＝8.0Hz,2.0Hz,1H),6.85(d,J＝8.0Hz,1H),4.56-4.53(m,1H),4.26(t,J＝6.0Hz,1H),4.05-4.02(m,1H),3.95-3.90(m,1H),3.78-3.70(m,2H),3.44-3.42(m,2H),3.10-3.08(m,1H),3.04-2.99(m,2H),2.85-2.71(m,4H),2.56-2.54(m,2H)。LCMS:[M+H]⁺:514.2。

5-chloro-N- (2- (6-chloro-1- (2- (dimethylamino) ethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole Indole-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-aminecarboxylate

¹H NMR(400MHz,DMSO-d₆):δ10.95(brs,1H),8.24(s,1H),7.64(d,J＝9.2Hz,1H),7.39(d,J＝2.0Hz,1H),7.30～7.24(m,2H),7.01(dd,J＝8.4Hz,2.0Hz,1H),6.79(d,J＝9.2Hz,1H),3.78～3.74(m,1H),3.44～3.39(m,2H),3.14～3.08(m,1H),2.90～2.85(m,1H),2.75～2.69(m,3H),2.58～2.53(m,1H),2.47～2.41(m,1H),2.34～2.27(m,1H),2.21(s,6H),1.93～1.77(m,2H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.72。LCMS:[M+H]⁺:500.2。

5-chloro-N- (2- (6-chloro-1- (2- (methylamino) ethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole- 2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-aminedicarboxylic acid salt

Diastereomer 1:¹H NMR(400MHz,DMSO-d₆):δ11.79～11.69(m,1H),11.53～11.43(m,1H),9.22(br,2H),7.83(br,1H),7.73～7.68(m,1H),7.56(d,J＝2.0Hz,1H),7.44～7.39(m,1H),7.15(dd,J＝8.4Hz,1.6Hz,1H),6.88～6.83(m,1H),5.14～5.03(m,1H),3.89～3.66(m,4H),3.40～3.21(m,4H),3.04～3.00(m,2H),2.77～2.70(m,1H),2.59-2.57(m,3H),2.44～2.33(m,1H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.57。LCMS:[M+H]⁺:486.2。

diastereomer 2:¹H NMR(400MHz,DMSO-d₆):δ11.89～11.76(m,1H),10.70～10.55(m,1H),10.31～10.30(m,1H),10.06～9.73(m,1H),7.74～7.70(m,3H),7.44(d,J＝8.8Hz,1H),7.19～7.15(m,1H),6.84(d,J＝8.8Hz,1H),5.38(br,0.6H),4.67(br,0.4H),3.67～3.03(m,9.5H),2.89～2.74(m,2H),2.65～2.55(m,3H),2.25～2.19(m,0.5H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.68。LCMS:[M+H]⁺:486.1。

n1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) -N2, N2-dimethylethane-1, 2-diamine diformate

¹H NMR(400MHz,DMSO-d₆):δ11.13(brs,1H),8.31(brs,2H),7.64(d,J＝8.8Hz,1H),7.42(d,J＝2.0Hz,1H),7.29(d,J＝8.4Hz,1H),7.24(br,1H),6.97(dd,J＝8.4Hz,2.0Hz,1H),6.79(d,J＝8.8Hz,1H),3.79(br,1H),3.68-3.65(m,1H),3.44-3.41(m,2H),3.11-3.03(m,2H),2.86-2.80(m,4H),2.72-2.61(m,3H),2.51-2.40(m,2H),2.38-2.17(m,1H),2.09(s,6H)。¹⁹F NMR(376MHz,CDCl₃):δ-64.71。LCMS:[M+H]⁺:529.3。

N- (2- (1- (((azetidin-2-ylmethyl) amino) methyl) -6-chloro-3, 4-dihydro-1H-pyrido [3, 4-) b]Indol-2 (9H) -yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,MeOD-d₄):δ7.60～7.53(m,2H),7.40～7.38(m,1H),7.20～7.17(m,1H),6.84～6.81(m,1H),5.42(d,J＝7.6Hz,1H),5.02～5.00(m,1H),4.13～3.79(m,9H),3.71～3.62(m,3H),3.22～3.17(m,2H),2.73～2.61(m,2H)。¹⁹F NMR(400MHz,MeOD-d₄):δ-67.23。LCMS:[M+1]⁺＝527.1。

5-chloro-N- (2- (6-chloro-1- (((pyrrolidin-2-ylmethyl) amino) methyl) -3, 4-dihydro-1H-pyrido [3, 4-b]indol-2 (9H) -yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,MeOD-d₄):δ7.52(dd,J＝12.8Hz,8.8Hz,2H),7.38(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,2.0Hz,1H),6.83(d,J＝8.8Hz,1H),5.49(d,J＝7.6Hz,1H),4.21-4.15(m,2H),3.97-3.87(m,5H),3.76-3.61(m,4H),3.49-3.43(m,2H),3.21-3.16(m,2H),2.43-2.41(m,1H),2.17-1.98(m,3H)。LCMS:[M+1]⁺＝541.5。

1-carbamimidoyl-N- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4 ]-b]Indol-1-yl) methyl) azetidine-3-carboxamide (1-Carbamimidoyl-N- ((6-chloro-2-(2-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)amino)ethyl)-2,3, 4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl)azetidine-3-carboxamide)

¹H NMR(400MHz,MeOD-d₄):δ7.60-7.50(m,2H),7.35(d,J＝8.4Hz,1H),7.14(dd,J＝8.4Hz,1.6Hz,1H),6.82(d,J＝8.8Hz,1H),4.96-4.89(m,1H),4.20-3.72(m,10H),3.59-3.55(m,1H),3.45-3.42(m,1H),3.30-3.31(m,1H),3.17-3.00(m,2H)。LCMS:[M+1]⁺＝583.2。

3- ((((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-l-ethyl) 1H-pyrido [3,4-b]Indol-1-yl) methyl) amino) methyl azetidine-1-carboxamidine (3- ((((6-Chloro-2-) (2-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)amino)ethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl)amino)methyl)azetidine-1- carboximidamide)

¹H NMR(400MHz,MeOD-d₄):δ7.58-7.52(m,2H),7.38(d,J＝8.4Hz,1H),7.17(dd,J＝8.8Hz,2.0Hz,1H),6.80(d,J＝8.8Hz,1H),5.22-5.21(m,1H),4.36-4.31(m,2H),4.12-4.07(m,2H),3.97-3.69(m,6H),3.59-3.47(m,4H),3.34-3.30(m,1H),3.22-3.13(m,1H),3.07-3.02(m,1H)。LCMS:[M+1]⁺＝569.2。

N- (2-aminoethyl) -3- ((((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) - 2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methyl) amino) methyl) azetidines-1-carboxamides

¹H NMR(400MHz,MeOD-d₄):δ7.56-7.54(m,1H),7.46(s,1H),7.34-7.31(m,1H),7.11(s,1H),6.82-6.73(m,1H),4.20-4.07(m,1H),3.85-3.80(m,1H),3.73-3.69(m,4H),3.66-3.61(m,3H),3.56-3.38(m,4H),3.31-3.02(m,7H),2.94-2.69(m,1H),2.68(brs,1H)。LCMS:[M+1]⁺＝615.2。

N- (2- (1- (((azetidin-3-ylmethyl) amino) methyl) -6-chloro-3, 4-dihydro-1H-pyrido [3, 4-) b]Indol-2 (9H) -yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,MeOD-d₄):δ7.62～7.60(m,2H),7.43(d,J＝8.8Hz,1H),7.23(dd,J＝8.8,2.0Hz,1H),6.84(d,J＝8.8Hz,1H),5.05(br,1H),4.32～4.27(m,1H),4.20～3.93(m,8H),3.71～3.55(m,4H),3.48～3.31(m,3H),3.30～3.20(m,1H)。¹⁹F NMR(400MHz,MeOD-d₄):δ-67.25。LCMS:[M+1]⁺＝527.0。

5-chloro-N- (2- (6-chloro-1- ((((S) -pyrrolidin-3-ylmethyl) amino) methyl) -3, 4-dihydro-1H-pyridine And [3,4-b ]]Indol-2 (9H) -yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹H NMR(400MHz,DMSO-d₆):δ11.02(d,J＝14.8Hz,1H),8.31(s,1.5H),7.64(d,J＝8.0Hz,1H),7.43(d,J＝1.6Hz,1H),7.33-7.30(m,2H),6.98(dd,J＝8.4Hz,2.0Hz,1H),6.84(d,J＝8.8Hz,1H),3.79(s,1H),3.43(d,J＝4.8Hz,2H),3.20-3.13(m,5H),3.12-3.04(m,6H),2.81-2.54(m,1.5H),2.51-2.33(m,2.6H),1.92-1.90(m 1H),1.52-1.49(m,1H)。LCMS:[M-1]^-＝539.2。

3- (2- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetra-ethyl) Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) amino) ethyl) -1-methyl-1H-imidazole-3-chloronium hydrochloride

¹H NMR(400MHz,MeOD-d₄):δ8.56(s,1H),7.53～7.49(m,2H),7.40～7.38(d,J＝8Hz,2H),7.26～7.24(d,J＝8Hz,2H),7.04～7.02(m,1H),6.71～6.68(d,J＝8.8Hz,1H),4.22～4.21(m,2H),3.94～3.86(m,1H),3.62～3.47(m,5H),3.12～2.57(m,10H)。LCMS:[M]⁺＝566.1。

General scheme 32

((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Representative Synthesis of indol-1-yl) methyl) di-tert-butyl phosphate

To (6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] at 0 deg.C]Indol-1-yl) methanol (1g, 2.1mmol) in THF (20mL) was added NaH (210mg, 5.25mmol) and the mixture was stirred at room temperature for 2 h. Di-tert-butyl phosphate (505mg, 2.94mmol) in THF (4mL) was added dropwise to the mixture at 0 deg.C. The mixture was then stirred at room temperature overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic solution is treated with Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography (PE: EA ═ 1:1) to give ((6-chloro-2- (ii) as a yellow solid2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) di-tert-butyl phosphate (600mg, 44% yield). The solid was used directly in the next step without further purification.

((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) phosphoric acid di-tert-butyl ester (600mg, 0.923mmol) in TFA (1mL) and DCM (20mL) was stirred at 0 ℃ to room temperature overnight. The reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography to give (6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a yellow solid]Indol-1-yl) methyl dihydrogen phosphate (67.77mg, 13% yield).¹H NMR(400MHz,DMSO)δ12.16(br,1H),7.86-7.83(m,1H),7.55-7.53(m,1H),7.37(s,1H),7.25(d,J＝8.4Hz,1H),7.00(d,J＝9.2Hz,1H),6.96(d,J＝8.8Hz,2H),4.04-3.83(m,4H),3.20-3.05(m,3H),2.84-2.67(m,4H)。LCMS:[M+H]⁺:539.1。

General scheme 33

The compound 3-amino-1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Synthesis of indol-1-yl) methyl) -1-methylpyrrolidine-1-chloronium hydrochloride Represents: at 70 deg.C, 5-chloro-N- (2- (6-chloro-1- (chloromethyl) -1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ]]Indol-2-yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine (100mg, 0.21mmol) was added to a solution of tert-butyl pyrrolidin-3-ylcarbamate (240mg, 1.26mmol) in MeCN (1 ml). The reaction was then stirred at 70 ℃ overnight. Purifying the mixture by preparative high performance liquid chromatography to obtainTo (1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (60mg, yield: 45.64%). LCMS: [ M + H]⁺＝627.3。

3- ((tert-Butoxycarbonyl) amino) -1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) Ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methylpyrrolidine-1-ium iodide

Reacting (1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]A solution of indol-1-yl) methyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (60mg, 0.096mmol) and MeI (2mL) in acetone (0.5mL) was stirred in a sealed tube at 40 ℃ overnight. Purifying the mixture by preparative high performance liquid chromatography to obtain 3- ((tert-butoxycarbonyl) amino) -1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) -1-methylpyrrolidine-1-ium iodide (2mg, 2.71%). LCMS: [ M]⁺＝641.2。

Amino-1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methylpyrrolidine-1-chloronium hydrochloride

Reacting 3- ((tert-butoxycarbonyl) amino) -1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) -1-methylpyrrolidine-1-ium iodide (2mg, 0.003mmol) was dissolved in HCl/ethyl acetate (10mL) and stirred at room temperature overnight. Concentrating the reaction mixture and removing the residueThe retentate was purified by preparative high performance liquid chromatography to give 3-amino-1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indol-1-yl) methyl) -1-methylpyrrolidine-1-chloronium hydrochloride (1.21mg, yield: 42%).¹H NMR(400MHz,MeOD-d₆):δ7.62(d,J＝8.8Hz,1H),7.48(s,1H),7.35(d,J＝8.4Hz,1H),7.13～7.08(m,1H),6.82(dd,J＝8.8Hz,1.2Hz,1H),4.81(m,1H),4.06～3.78(m,9H),3.54(s,3H),3.34～3.30(m,2H),3.12～2.58(m,4H),2.39(br,1H),1.95-1.92(m,1H)。LCMS:[M]⁺＝541.2。

1- ((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) -3-hydroxy-1-methylpyrrolidine-1-chloronium hydrochloride

¹H NMR(400MHz,MeOD-d₄):δ11.13～11.11(m,1H),7.75～7.72(d,J＝8.8Hz,2H),7.54(s,1H),7.37～7.35(d,J＝8.4Hz,1H),7.08～7.05(m,1H),6.90～6.88(d,J＝8.8Hz,1H),4.93～4.87(m,1H),4.67～4.65(m,1H),4.23(s,1H),3.99～3.64(m,8H),3.44～3.43(m,4H),3.22～3.17(m,2H),2.93～2.90(m,1H),2.70～2.38(m,2H),2.32～1.71(m,2H)。LCMS:[M]⁺＝542.2。

General scheme 34

The compound (6-chloro-2- ((1- (5, 6-dichloropyridin-2-yl) pyrrolidin-2-yl) methyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Synthesis of indol-1-yl) methanol: to a solution of 2-chloro-6-fluoropyridine (3.0g, 22.81mmol, 1.0 equiv.) and proline methyl ester hydrochloride (5.7g, 34.21mmol, 1.5 equiv.) in DMSO (40mL) was added DIPEA (14.7g, 114.03mmol,5.0 equivalents). The mixture was stirred at 120 ℃ for 16 h. Water (20mL) was then added, and the mixture was extracted with EtOAc (4X 50 mL). The combined organic layers were washed with brine (5X 50mL) and Na₂SO₄Dried and concentrated. The residue was purified by column chromatography (SiO)₂Purification of EtOAc ═ 10: 1-5: 1) afforded (6-chloropyridin-2-yl) proline methyl ester (3.3g, 60% yield) as a pale yellow oil.

To (6-chloropyridin-2-yl) proline methyl ester (2.8g, 11.61mmol, 1.0 eq) in CH₃To a solution in CN (20mL) was added NCS (1.6g, 12.19mmol, 1.05 equiv) in portions. The reaction was stirred at 50 ℃ for 5 h. Subjecting the mixture to column chromatography (SiO)₂Ethyl acetate (10: 1) to give methyl (5, 6-dichloropyridin-2-yl) proline as a pale yellow oil (2.5g, 78% yield).¹H NMR:(400MHz,DMSO-d₆)δ7.72(d,J＝8.8Hz,1H),6.52(d,J＝8.8Hz,1H),4.47-4.44(m,1H),3.61(s,3H),3.53-3.38(m,2H),2.03-1.99(m,1H)。LCMS:[M+H]⁺＝275.0。

(1- (5, 6-dichloropyridin-2-yl) pyrrolidin-2-yl) methanol

To a solution of (5, 6-dichloropyridin-2-yl) proline methyl ester (1.9g, 6.98mmol, 1.0 eq) in THF (20mL) at 0 deg.C was added LiAlH₄(800mg, 20.95mmol, 3.0 equiv.). The reaction was stirred at room temperature for 3 h. The mixture was quenched with NaOH (aq.15%, 800. mu.L) and water (2.5 mL). The residue was purified by column chromatography (SiO)₂EtOAc ═ 5:1) to give (1- (5, 6-dichloropyridin-2-yl) pyrrolidin-2-yl) methanol as a colourless oil (1.5g, 88% yield). LCMS: [ M + H]⁺＝247.0。

1- (5, 6-dichloropyridin-2-yl) pyrrolidine-2-carbaldehyde

To a solution of (1- (5, 6-dichloropyridin-2-yl) pyrrolidin-2-yl) methanol (700mg, 2.833mmol, 1.0 equiv.) in DMSO (10mL) was added Et₃N (2.87g, 28.33mmol, 10.0 equiv.) and PCC (1.35g, 8.498mmol, 3.0 equiv.). The mixture was stirred at 35 ℃ for 3 h. Subjecting the mixture to hydrogenation with H₂O (10mL) was washed, and the aqueous layer was extracted with EtOAc (3X 10 mL). The combined organic phases were washed with brine (4X 30mL) and Na₂SO₄Dried and concentrated. The residue was purified by column chromatography (SiO)₂PE: EtOAc ═ 10:1) purification afforded 1- (5, 6-dichloropyridin-2-yl) pyrrolidine-2-carbaldehyde as a light brown oil (161mg, 23% yield). LCMS: [ M + H]⁺＝245.0。

(6-chloro-2- ((1- (5, 6-dichloropyridin-2-yl) pyrrolidin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyridine And [3,4-b ]]Indol-1-yl) methanol

To 1- (5, 6-dichloropyridin-2-yl) pyrrolidine-2-carbaldehyde (113mg, 0.46mmol, 1.0 eq.) and (6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indol-1-yl) methanol (120mg, 0.51mmol, 1.1 equiv.) in THF (5mL) was added 3 drops of CH₃COOH. The mixture was stirred at 40 ℃ for 2 h. Add NaBH portionwise at room temperature₃CN (157mg, 1.38mmol, 3.0 equiv.). The mixture was stirred at 40 ℃ for 2 h. The reaction mixture was diluted with EtOAc (20mL) and washed with brine (10 mL). Adding Na to the solution₂SO₄Dried and concentrated. The residue was purified by preparative high performance liquid chromatography to give (6-chloro-2- ((1- (5, 6-dichloropyridin-2-yl) pyrrolidin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indol-1-yl) methanol (37.33mg, yield: 17%).¹H NMR(400MHz,DMSO-d₆):δ10.80(s,1H),7.61(d,J＝8.8Hz,1H),7.37(d,J＝2，0Hz,1H),7.32(d,J＝8.4Hz,1H),6.99(dd,J＝8.8Hz,2.0Hz,1H),6.42(d,J＝8.8Hz,1H),4.64-4.61(m,1H),4.13-4.03(m,2H),3.72-3.62(m,2H),3.44-3.39(m,1H),3.20-3.12(m,2H),2.95-2.91(m,1H),2.75-2.63(m,2H),2.47-2.34(m,2H),2.08-1.91(m,4H)。LCMS:[M+H]⁺＝467.2。

3- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) pyrrolidin-2-yl) methyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazole-3-chloronium hydrochloride

¹H NMR(400MHz,MeOD-d₄)δ8.92(d,J＝38.1Hz,1H),7.97–7.44(m,5H),7.30(d,J＝8.7Hz,1H),7.18(d,J＝8.8Hz,1H),6.78(s,1H),4.51(s,1H),3.95(s,6H),3.51(d,J＝27.7Hz,4H),2.08(t,J＝50.5Hz,5H),1.29(s,2H)。LCMS:[M+1]⁺＝563.2。

1- (azetidin-3-yl) -N- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) pyrrolidine- 2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) methylamine

¹H NMR(400MHz,CD₃OD)δ7.75(d,J＝9.0Hz,1H),7.58(s,1H),7.43(d,J＝8.7Hz,1H),7.22(d,J＝8.7Hz,1H),6.84(d,J＝9.1Hz,1H),4.96(s,4H),4.22–3.95(m,7H),3.61(m,8H),2.41–2.13(m,5H)。LCMS:[M+1]⁺＝567.2。

3- ((6-chloro-2- (((2S,4R) -1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -4-hydroxypyrrolidine-2-) Yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazol-3-ium

Diastereomer 1:¹H NMR(400MHz,DMSO-d₆):δ9.03(s,1H),7.63-7.52(m,3H),7.40-7.41(m,1H),7.32(d,J＝8.4Hz,1H),7.09-7.06(m,1H),6.59-6.54(m,1H),4.60-4.27(m,4H),3.99(s,3H),3.65-3.47(m,3H),3.16-3.08(m,3H),3.01-2.79(m,1H),2.52-2.33(m,2H),2.10-2.05(m,1H),1.70-1.63(m,1H)。LCMS:[M]⁺＝579.0。

diastereomer 2:¹H NMR(400MHz,DMSO-d₆):δ8.95(s,1H),7.64-7.59(m,3H),7.59-7.40(m,2H),7.39-7.27(m,1H),7.08-7.05(m,1H),6.64(d,J＝9.2Hz,1H),4.55-4.40(m,3H),4.03-3.94(m,4H),3.57-3.35(m,6H),3.13-3.02(m,1H),2.50-2.46(m,1H),2.19-2.18(m,1H),1.91-1.89(m,1H),1.69-1.66(m,1H)。LCMS:[M]⁺＝579.0。

(3R,5S) -5- ((1- (((azetidin-3-ylmethyl) amino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyri-dine Pyrido [3,4-b]Indol-2-yl) methyl) -1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-ol

¹H NMR(400MHz,DMSO-d₆):δ7.75-7.72(m,1H),7.55-7.50(m,1H),7.40-7.38(m,1H),7.18-7.16(m,1H),6.85-6.83(m,1H),4.70-4.62(m,3H),4.23-3.94(m,6H),3.79-3.72(m,6H),3.20-3.11(m,3H),2.39-2.37(m,2H)。LCMS:[M+1]⁺＝583.2。

(6-chloro-2- (1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -2,3,4, 9-tetrahydro-1H- Pyrido [3,4-b]Indol-1-yl) methanolate hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.38～11.35(m,1H),10.95(brs,1H),7.86(d,J＝8.8Hz,1H),7.60(s,1H),7.43(d,J＝8.8Hz,1H),7.15(d,J＝8.0Hz,1H),6.85(d,J＝9.2Hz,1H),5.89(brs,1H),4.75～4.70(m,1H),4.19～4.05(m,4H),3.82～3.71(m,4H),3.03(brs,2H),2.60～2.54(m,2H)。¹⁹F NMR(376MHz,DMSO-d₆):δ-64.73。LCMS:[M+H]⁺＝485.1。

(6-chloro-2- (1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methanolate hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ12.15～11.21(m,2H),7.92(d,J＝8.8Hz,1H),7.60(s,1H),7.41(d,J＝8.4Hz,1H),7.15(dd,J＝8.8Hz,2.0Hz,1H),6.84(d,J＝8.8Hz,1H),5.89～5.69(m,1H),4.86～4.29(m,6H),4.06(d,J＝2.0Hz,2H),3.79～3.42(m,3H),3.05～2.89(m,2H)。¹⁹F NMR(376MHz,DMSO-d₆):δ-64.73。LCMS:[M+H]⁺＝471.1。

(6-chloro-2- ((1- (5, 6-dichloropyridin-2-yl) azetidin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyri-dine Pyrido [3,4-b]Indol-1-yl) methanolate hydrochloride

¹H NMR(400MHz,DMSO-d₆):δ11.52～11.50(m,1H),10.43～9.85(m,1H),7.86～7.83(m,1H),7.59～7.56(m,1H),7.41(dd,J＝8.8Hz,2.4Hz,1H),7.15(d,J＝8.4Hz,1H),6.62～6.53(m,1H),5.87～5.75(m,1H),4.93～4.77(m,2H),4.19～3.66(m,8H),3.12～3.07(m,2H),2.54～2.50(m,1H),2.37～2.31(m,1H)。LCMS:[M+H]⁺＝451.0。

6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indole hydrochloric acidSalt (salt)

¹H NMR(500MHz,DMSO-d₆)δ11.36(d,J＝19.5Hz,1H),10.64(s,1H),10.33(s,1H),8.00(d,J＝8.7Hz,1H),7.55(s,1H),7.40(s,1H),7.34(d,J＝9.2Hz,1H),7.11(d,J＝8.5Hz,1H),5.45(d,J＝49.1Hz,1H),4.89–4.63(m,1H),4.52(s,1H),4.21(m,2H),4.01(m,2H),3.88(s,1H),3.67(s,1H),3.57(m,1H),3.29(m,2H),3.09(m,3H),2.91(s,1H)。LCMS:[M+H]⁺＝484.1。

6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -4-methylpiperazin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indoles

¹H NMR (500MHz, chloroform-d) δ 7.50(d, J ═ 9.0Hz,1H),7.40(d, J ═ 2.0Hz,1H),7.28(dd, J ═ 8.6,2.1Hz,1H),7.11(dd, J ═ 8.6,2.1Hz,1H),6.64(d, J ═ 9.1Hz,1H),4.81(s,1H),3.88(d, J ═ 15.1Hz,1H),3.75(d, J ═ 15.2Hz,1H),3.68(d, J ═ 12.7Hz,1H),3.17(qd, J ═ 8.2,3.3 dt, 2H),3.09(dd, J, 12.3,9.5, 1H),3.17 (dd, J ═ 8.2,3.3, 2H),3.09(dd, J ═ 12.3.5, 1H), 1H, 3.5 (d, 3.7, 3.5H), 3.7, 7H, 1H, 23.7, 7H, 1H, 3.7, 3.7.7, 7H, 1H, 3.7H, 1H, 3.7H, 1H. LCMS: [ M + H]⁺＝498.1。

6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -4-ethylpiperazin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indoles

¹H NMR (500MHz, chloroform-d) δ 7.69(s,1H),7.48(d, J ═ 9.0Hz,1H),7.40(d, J ═ 2.0Hz,1H),7.20(d,J＝8.5Hz,1H),7.06(dd,J＝8.5,1.9Hz,1H),6.64(d,J＝9.1Hz,1H),4.74(s,1H),3.94(d,J＝15.3Hz,1H),3.78(d,J＝15.3Hz,1H),3.66(d,J＝12.0Hz,1H),3.31(d,J＝11.3Hz,1H),3.17(td,J＝12.3,3.6Hz,1H),3.10(dd,J＝12.3,9.5Hz,1H),2.98(ddt,J＝20.7,14.6,7.7Hz,3H),2.77–2.60(m,2H),2.51(dd,J＝12.2,7.2Hz,1H),2.46(dd,J＝12.2,4.0Hz,1H),2.41–2.32(m,1H),2.13(td,J＝11.8,3.7Hz,1H),2.10–2.01(m,1H),1.12(t,J＝7.2Hz,3H)。LCMS:[M+H]⁺＝512.1。

2- (3- ((6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol

¹H NMR (500MHz, chloroform-d) δ 7.78(s,1H),7.51(d, J ═ 9.1Hz,1H),7.40(d, J ═ 2.0Hz,1H),7.19(d, J ═ 8.5Hz,1H),7.06(dd, J ═ 8.6,2.1Hz,1H),6.65(d, J ═ 9.1Hz,1H),4.78(d, J ═ 9.6Hz,1H),3.88(d, J ═ 15.1Hz,1H),3.76(d, J ═ 15.2Hz,1 ddh), 3.71(d, J ═ 11.3,7.4,3.9Hz,2H),3.65(d, J ═ 11.2,5.5,4, 3.35H, 3.78 (d, J ═ 11.3,7.4,3.9, 2H),3.65(d, J ═ 11.2,5, 4, 3.5, 3.2H, 3.6, 1H, 1, 1.6, 1H, 1, 2.50-2.41 (m,1H),2.34(td, J ═ 11.7,3.7Hz,1H),2.23(dd, J ═ 11.4,3.7Hz, 1H). LCMS; [ M + H ]]⁺＝528.2。

2- ((l 2-chlorophenyl) amino) -1- (3- ((6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole-2- Yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

¹H NMR (500MHz, methanol-d)₄)δ7.83(d,J＝9.1Hz,1H),7.46(d,J＝2.0Hz,1H),7.31(d,J＝8.7Hz,1H),7.22(d,J＝9.3Hz,2H),7.10(dd,J＝8.7,2.0Hz,1H),5.56(s,1H),4.70(s,2H),4.50(d,J＝14.1Hz,1H),4.29(d,J＝15.8Hz,1H),4.08(dd,J＝29.4,15.3Hz,2H),3.95(d,J＝16.0Hz,1H),3.87(dd,J＝31.5,10.4Hz,1H),3.79–3.69(m,2H),3.65(q,J＝5.3,4.9Hz,2H),3.61–3.51(m,2H),3.45–3.36(m,1H),3.25–3.18(m,1H),3.14(d,J＝15.7Hz,1H)。LCMS:[M+H]⁺＝512.1。

N- (2- (3- ((6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) methyl) -4- (5-chloro- 6- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) ethyl) -l 2-chloramine

¹H NMR(500MHz,DMSO-d₆)δ11.39(s,1H),8.12(d,J＝9.1Hz,1H),7.56–7.51(m,1H),7.39(d,J＝8.6Hz,1H),7.11(dd,J＝8.7,2.1Hz,1H),6.94(d,J＝9.2Hz,1H),4.60(d,J＝28.0Hz,2H),4.37–4.19(m,2H),3.94(d,J＝34.6Hz,1H),3.84–3.53(m,10H),3.44(dd,J＝8.7,7.2Hz,2H),3.01(s,3H)。

1- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Representative Synthesis of indol-1-yl) methyl) guanidines

To a solution of 4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -3-formylpiperazine-1-carboxylic acid tert-butyl ester (1.0g, 2.5mmol, 1.0 eq) in DMF (10mL) was added 1- (azidomethyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b [ -b ]]Indole (670.0mg, 2.5mmol, 1.0 equiv.). The reaction was stirred at 40 ℃ for 14 h. Then NaBH is added₃CN (488.0mg, 7.5mmol, 3.0 eq), and the reaction was stirred at room temperature for 30 min. The mixture was concentrated and purified by silica gel column chromatography to give 3- ((1- (azidomethyl) -6-chloro) as a yellow solid-1,3,4, 9-tetrahydro-2H-pyrido [3,4-b]Indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1.1g, yield: 68.0%). LCMS (liquid Crystal Module) [ M +1 ]]⁺＝639.2。

To 3- ((1- (azidomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1.1g, 1.7mmol, 1.0 eq) in THF/H₂To a solution in O (10mL) was added triphenylphosphine (670.0mg, 2.6mmol, 1.5 equiv.). The mixture was stirred at 70 ℃ for 16 h. The reaction was concentrated and extracted with EtOAc (50mL × 3). The organic layer was washed with Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography to give 3- ((1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyridine- [3, 4-b) as a yellow solid]Indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1.0g, 70.0% yield). LCMS (liquid Crystal Module) [ M +1 ]]⁺＝613.3。

To 3- ((1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]To a solution of indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (500.0mg, 0.8mmol, 1.0 equiv) in DCM (10mL) were added DIEA (210.0mg, 1.6mmol, 2.0 equiv) and tert-butyl (E) - (((tert-butoxycarbonyl) imino) (1H-imidazol-1-yl) methyl) carbamate (301.1mg, 1.0mmol, 1.2 equiv). The mixture was stirred at room temperature for 16H, then concentrated to give (E) -3- ((1- ((2, 3-bis (tert-butoxycarbonyl) guanidino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b-as a white solid]Indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (700.0mg crude product, yield:>99％)。LCMS:[M+1]⁺＝855.2。

to a solution of (E) -3- ((1- ((2, 3-bis (tert-butoxycarbonyl) guanidino) -methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indol-2-yl) methyl) -4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1.6g, 1.8mmol, 1.0 eq) in DCM (15mL) was added TFA (5 mL). The mixture was stirred at room temperature for 3h and then purified by preparative high performance liquid chromatography to give two diastereomers: diastereomer 1(450.0mg, yield: 43%) and diastereomer 2(400.0mg, yield: 38.0%) as yellow solids. Each diastereomer can be further separated into two enantiomers by separation by chiral Supercritical Fluid Chromatography (SFC).

Diastereomer 1:¹H NMR(400MHz,CD₃OD)δ7.71(d,J＝8.0Hz,1H),7.37(s,1H),7.26(d,J＝8.6Hz,1H),7.08-7.02(m,2H),4.28–4.12(m,2H),3.87(d,J＝13.1Hz,1H),3.62–3.47(m,3H),3.40–3.30(m,4H),3.23–3.15(m,2H),3.03-3.09(m,1H),2.73-2.89(m,2H),2.53-2.50(m,1H)。LCMS:[M+1]⁺＝555.2。

diastereomer 2:¹H NMR(400MHz,CD₃OD)δ7.75(d,J＝9.1Hz,1H),7.33(d,J＝1.8Hz,1H),7.23(d,J＝8.6Hz,1H),7.09–6.99(m,2H),5.20(s,1H),4.21(d,J＝13.6Hz,1H),4.05–3.95(m,1H),3.82(d,J＝12.9Hz,1H),3.63–3.50(m,4H),3.31-3.10(m,4H),2.96–2.86(m,3H),2.52-2.48(m,1H)。LCMS:[M+1]⁺＝555.2。

3- ((6-chloro-2- ((4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazole-3-chloronium hydrochloride

Diastereomer 1:¹H NMR(400MHz,DMSO-d₆):δ9.09-9.02(m,1H),7.79(d,J＝8.8Hz,1H),7.64-7.56(m,2H),7.44(s,1H),7.31(d,J＝8.4Hz,1H),7.15-7.08(m,2H),4.88-4.70(m,2H),4.44-4.38(m,3H),3.94(s,1H),3.55-3.52(m,2H),3.45-3.39(m,3H),3.31-3.22(m,3H),3.18-2.90(m,4H),2.60-2.56(m,1H)。LCMS:[M]⁺＝578.0。

diastereomer 2:¹H NMR(400MHz,DMSO-d₆):δ9.22-9.12(m,1H),8.00(s,1H),7.82-7.79(m,1H),7.72-7.65(m,1H),7.52(s,1H),7.45(d,J＝1.6Hz,1H),7.32(d,J＝8.4Hz,1H),7.17-7.08(m,2H),4.76-4.67(m,2H),4.41-4.33(m,2H),3.95(s,1H),4.53-3.36(m,4H),3.32-3.12(m,3H),3.01(s,3H),3.97-2.94(m,2H),2.87(s,2H),2.70-2.60(m,1H)。LCMS:[M]⁺＝578.0。

3- ((6-chloro-2- ((4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) morpholin-3-yl) methyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazole-3-ium chloride

¹H NMR(400MHz,CD₃OD):δ8.90(s,1H),7.59-7.52(m,2H),7.51-7.34(m,2H),7.22-7.18(m,1H),7.01-6.97(m,1H),6.88-6.84(m,1H),4.81(s,3H),4.59(s,2H),3.91-3.86(m,4H),3.76-3.57(m,4H),3.36(s,3H),2.88-2.60(m,3H)。LCMS:[M]⁺＝579.0。

1- (2-amino-2-oxoethyl) -3- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piper-ine) Oxazin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1H-imidazole-3-ium chloride

Diastereomer 1:¹H NMR(400MHz,CD₃OD):δ9.14(s,1H),7.73(d,J＝8.8Hz,1H),7.64-7.67m,2H),7.44(s,1H),7.31(d,J＝8.0Hz,1H),7.07-7.10(m,2H),5.20(s,2H),4.79-4.55(m,4H),4.18(d,J＝14.4Hz,1H),3.42-3.48(m,5H),3.09-3.25(m,4H),3.00-2.90(m,1H),2.02-2.67(m,1H)。LCMS:[M]⁺＝621.9。

diastereomer 2:¹H NMR(400MHz,DMSO-d₆):δ11.30(s,1H),9.48(s,2H),9.21(s,1H),7.90(d,J＝9.1Hz,1H),7.83(s,1H),7.73(s,1H),7.37(d,J＝8.6Hz,1H),7.15(d,J＝9.1Hz,2H),7.07(d,J＝2.0Hz,1H),7.05(d,J＝2.0Hz,1H),5.19-5.08(m,2H),4.73-4.64(m,2H),4.56-4.44(m,2H),4.08(d,J＝13.6Hz,1H),3.27-3.07(m,3H),3.00-2.92(m,2H),2.85-2.77(m,2H),2.76-2.71(m,2H),2.67-2.39(m,2H)。LCMS:[M]⁺＝621.9。

1- (azetidin-3-ylmethyl) -3- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piper-ine) Oxazin-2-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1H-imidazole-3-ylium chloride salt Acid salts

Diastereomer 1:¹H NMR(400MHz,DMSO-d₆):δ10.55(s,1H),9.26(s,1H),7.77-7.72(m,3H),7.32-7.30(m,2H),7.06-7.02(m,2H),4.72-4.68(m,1H),4.60-4.49(m,3H),4.33-4.28(m,3H),4.17-4.08(m,4H),3.67-3.65(m,1H),3.48-3.31(m,5H),3.20-3.13(m,4H),3.10-2.85(m,2H),2.49-2.54(m,1H)。LCMS:[M]⁺＝633.1。

diastereomer 2:¹H NMR(400MHz,DMSO-d₆):δ9.37(s,1H),7.83(d,J＝8.8Hz,1H),7.70-7.65(m,2H),7.53(d,J＝1.6Hz,1H),7.38(d,J＝8.8Hz,1H),7.29(d,J＝9.2Hz,1H),7.18-78.15(m,1H),5.16-4.89(m,4H),4.62(d,J＝7.2Hz,2H),4.29-4.19(m,6H),4.09-3.53(m,8H),3.42-3.39(m,1H),3.17-3.07(m,3H)。LCMS:[M]⁺＝633.1。

3- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) -1-methyl-1H-imidazole-3-chloronium hydrochloride

Diastereomer 1:¹H NMR(400MHz,CD₃OD):δ9.06(s,1H),7.81-7.78(d,J＝12Hz,1H),7.59-7.48(m,3H),7.34-7.32(d,J＝8Hz,1H),7.19-7.11(m,2H),4.85-4.91(m,5H),4.24-4.20(d,J＝16Hz,1H),3.96(s,3H),3.68-3.41(m,6H),3.20-3.07(m,3H),2.80(s,1H)。LCMS:[M]⁺＝578.1。

diastereomer 1:¹H NMR(400MHz,CD₃OD):δ9.00(s,1H),7.76-7.74(d,J＝8Hz,1H),7.67(s,1H),7.54(s,1H),7.34-7.26(m,2H),7.06-7.03(m,2H),5.10-5.08(m,2H),4.61-4.52(m,3H),4.14-4.11(d,J＝12Hz,1H),3.47-3.38(m,6H),3.17-3.29(m,4H),2.93-2.88(m,2H),2.54-2.49(m,1H)。LCMS:[M]⁺＝578.1。

n- ((6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrakis Hydrogen-1H-pyrido [3,4-b]Indol-1-yl) methyl) azetidin-3-amine hydrochloride

Diastereomer 1:¹H NMR(400MHz,CD₃OD):δ7.78(d,J＝9.2Hz,1H),7.43(d,J＝2.0Hz,1H),7.32-7.28(m,2H),6.84(dd,J＝8.4,2.0Hz,1H),5.34(brs,1H),4.56-4.53(m,1H),4.46-4.45(m,1H),4.40-4.32(m,4H),4.04-4.0(m,1H),3.57-3.36(m,9H),3.25-3.21(m,2H),3.07-3.00(m,1H),2.78-2.74(m,1H)。LCMS:[M+1]⁺＝568.1。

diastereomer 2:¹H NMR(400MHz,CD₃OD):δ7.77(d,J＝9.2Hz,1H),7.35(s,1H),7.26(d,J＝8.4,Hz,1H),7.09-7.04(m,2H),5.29(brs,1H),4.65-4.17(m,8H),3.53-3.39(m,5H),3.27-3.17(m,4H),3.02-2.94(m,2H),2.57-2.53(m,1H).LCMS:[M+1]⁺＝568.1。

(6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl)) s) Pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methylamines

Diastereomer 1:¹H NMR(400MHz,CD₃OD):δ7.76(d,J＝8.8Hz,,1H),7.42(s,1H),7.31(d,J＝8.8Hz,1H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),5.04-4.93(m,2H),4.28-4.24(m,2H),3.88-3.83(m,1H),3.63-3.13(m,8H),3.03-2.86(m,3H)。LCMS:[M+1]⁺＝513.0。

diastereomer 2:¹H NMR(400MHz,CD₃OD):δ7.76(d,J＝9.2Hz,1H),7.32(s,1H),7.25(d,J＝8.8Hz,1H),7.07-7.02(m,2H),5.25(d,J＝9.2Hz,1H),4.43-4.12(m,1H),4.17-4.02(m,2H),3.53(d,J＝12.8Hz,1H),3.45-3.35(m,3H),3.26-3.13(m,5H),2.94-2.83(m,2H),2.51(d,J＝15.2Hz,1H)。LCMS:[M+1]⁺＝513.0。

n- (2-aminoethyl) -6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) - 2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ]]Indole-1-carboxamide dihydrochloride

Diastereomer 1:¹h NMR (300MHz, methanol-d₄)δ7.82(d,J＝9.1Hz,1H),7.45(d,J＝2.0Hz,1H),7.37(d,J＝8.6Hz,1H),7.21(d,J＝9.2Hz,1H),7.11(dd,J＝8.7,2.0Hz,1H),5.33(s,1H),4.27(d,J＝14.9Hz,1H),3.84(s,1H),3.77–3.59(m,2H),3.58–3.34(m,5H),3.26(dd,J＝14.0,5.2Hz,2H),3.17(d,J＝6.9Hz,2H),3.07–2.61(m,4H)。LCMS:[M+H⁺]＝570.2。

Diastereomer 2:¹h NMR (300MHz, methanol-d₄)δ7.87(d,J＝9.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.44–7.34(m,1H),7.24(d,J＝9.2Hz,1H),7.15(dd,J＝8.7,2.0Hz,1H),5.53(s,1H),4.27(d,J＝15.0Hz,1H),3.90(d,J＝13.3Hz,1H),3.81–3.56(m,4H),3.56–3.37(m,3H),3.32–3.12(m,6H),3.05(d,J＝21.4Hz,2H)。LCMS:[M+H⁺]＝570.0。

6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -N-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-1-carboxamide hydrochloride

¹H NMR (300MHz, methanol-d₄)δ7.87(dd,J＝9.1,4.0Hz,1H),7.46(dd,J＝7.0,2.0Hz,1H),7.40–7.32(m,1H),7.23(d,J＝9.2Hz,1H),7.12(ddd,J＝8.6,4.8,2.0Hz,1H),5.43(s,1H),4.30(d,J＝15.1Hz,1H),3.83(d,J＝13.1Hz,1H),3.74–3.35(m,5H),3.32–3.11(m,4H),2.97(s,2H),2.87(d,J＝3.7Hz,3H)。LCMS:[M+H⁺]＝541.1。

6-chloro-2- ((1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indole-1-carboxamide hydrochloride (10)

¹H NMR (300MHz, methanol-d 4) δ 7.78(d, J ═ 9.1Hz,1H),7.39(dd, J ═ 2.1,0.6Hz,1H),7.31(dd, J ═ 8.6,0.6Hz,1H),7.11(d, J ═ 9.1Hz,1H),7.05(dd, J ═ 8.6,2.1Hz,1H),5.12(s,1H),4.50(s,1H),4.30(d, J ═ 14.4Hz,1H),3.83(d, J ═ 13.1Hz,1H), 3.55-3.36 (m,4H), 3.29-3.15 (m,2H),3.05(d, J ═ 7.0, 1H),2.98(s, 2H), 2.15 (s,1H), 2.15 (d, 1H). LCMS: [ M + H⁺]＝527.1。

(1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indol-2-yl) (1- (5-chloro-6-) (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methanone dihydrochloride

¹H NMR (500MHz, methanol-d)₄)δ7.92(d,J＝9.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.32(dd,J＝8.9,3.6Hz,2H),7.09(dd,J＝8.6,2.0Hz,1H),6.15(d,J＝4.2Hz,1H),6.04–5.90(m,1H),4.56–4.41(m,1H),4.29(d,J＝15.3Hz,1H),4.00–3.83(m,1H),3.61(d,J＝13.3Hz,1H),3.53(td,J＝12.7,11.8,3.7Hz,1H),3.49–3.36(m,4H),3.28–3.17(m,1H),3.08–2.97(m,1H),2.80(dd,J＝15.6,3.7Hz,1H)。LCMS；[M+H]⁺＝527.1。

1- ((6-chloro-2- (1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazine-2-carbonyl) -2,3,4, 9-tetrahydro- 1H-pyrido [3,4-b]Indol-1-yl) methyl) guanidine dihydrochloride

¹H NMR (500MHz, methanol-d)₄)δ7.94(d,J＝9.0Hz,1H),7.47(d,J＝2.0Hz,1H),7.34(dd,J＝10.2,8.8Hz,2H),7.10(dd,J＝8.6,2.0Hz,1H),6.14(d,J＝4.4Hz,1H),5.95(dd,J＝8.5,4.4Hz,1H),4.47(dd,J＝14.4,5.0Hz,1H),4.38–4.25(m,1H),3.86(ddd,J＝15.4,12.7,3.2Hz,1H),3.76(dd,J＝14.2,4.6Hz,1H),3.72–3.61(m,2H),3.59–3.48(m,2H),3.37(dd,J＝13.3,4.6Hz,1H),3.27(td,J＝12.7,3.8Hz,1H),3.06–2.94(m,1H),2.88–2.80(m,1H)。LCMS:[M+H]⁺＝569.2。

(1- ((azetidin-3-ylamino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)]Indole- 2-yl) (1- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) piperazin-2-yl) methanone trihydrochloride

¹H NMR (500MHz, methanol-d)₄)δ7.92(d,J＝9.0Hz,1H),7.47(d,J＝2.0Hz,1H),7.34(dd,J＝8.9,5.1Hz,2H),7.12(dd,J＝8.6,2.0Hz,1H),6.18(d,J＝4.3Hz,1H),6.02(s,1H),4.59–4.41(m,2H),4.40–4.25(m,5H),4.08(t,J＝14.1Hz,1H),3.66(d,J＝13.2Hz,1H),3.62–3.52(m,1H),3.51–3.42(m,4H),3.35(td,J＝3.2,1.6Hz,2H),2.82(dd,J＝15.6,3.8Hz,1H)。LCMS:[M+H]⁺＝582.1。

General scheme 35

The compound 2- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4,9- tetrahydro-1H-pyrido [3,4-b]Synthesis of indol-1-yl) methyl) amino) acetamide Triformate

Mixing N- (2- (1- (aminomethyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ]]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine (300mg, 0.66mmol), 2-chloroacetamide (60mg, 0.66mmol), K₂CO₃(230mg, 1.65mmol) and NaI (100mg, 0.66mmol) in MeCN (2mL)/H₂The mixture in O (0.5mL) was stirred at 30 ℃ for 3 days. The mixture was filtered and the filtrate was purified by preparative high performance liquid chromatography to give 2- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b) as a white solid]Indol-1-yl) methyl) amino) acetamide (17.00mg, yield: 5%).¹H NMR(400MHz,DMSO-d₆):δ10.98(s,1H),8.37(brs,3H),7.62(d,J＝8.8Hz,1H),7.39～7.27(m,4H),7.08(brs,1H),6.99(dd,J＝8.4Hz,2.0Hz,1H),6.81(d,J＝8.8Hz,1H),3.78～3.50(m,4H),3.08(s,3H),2.89～2.70(m,6H),2.45～2.41(m,1H)。LCMS:[M+H]⁺＝515.2。

The key intermediate 3- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -1,2, 3-oxathiazolidine 2,2-dioxides Representative Synthesis of (A): a mixture of 2-chloro-6- (trifluoromethyl) pyridine (1.82g, 10mmol) and 2-aminoethan-1-ol (3mL, 50mmol) was heated to 120 ℃ for 8 h. The mixture was cooled to room temperature and diluted with ethyl acetate (60mL), washed with saturated ammonium chloride solution (30mL) and brine (20mL), then Na₂SO₄Drying and concentration gave 2- ((6- (trifluoromethyl) pyridin-2-yl) amino) ethan-1-ol (1.85g, 90% yield) as a pale yellow oil which was carried on to the next step without further purification.¹H NMR (500MHz, chloroform-d) δ 7.55-7.41 (m,1H),6.89(d, J ═ 7.1Hz,1H),6.57(d, J ═ 8.5Hz,1H),5.52(t, J ═ 5.8Hz,1H),4.37(s,1H), 3.82-3.73 (m,2H),3.49(td, J ═ 5.6,4.2Hz, 2H).

A mixture of 2- ((6- (trifluoromethyl) pyridin-2-yl) amino) ethan-1-ol (2.06g, 10mmol) and NCS (1.40g, 10.05mmol) in 20mL acetonitrile was heated to 65 ℃ overnight. The mixture was concentrated and the residue was triturated with hexane/ethyl acetate (v: v ═ 3:1) to remove solids. The filtrate was concentrated and purified by flash chromatography on silica gel using hexane and ethyl acetate to give 2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethan-1-ol (2.0g, 85%) as a pale yellow oil.¹H NMR (500MHz, chloroform-d) δ 7.43(d, J ═ 8.9Hz,1H),6.53(d, J ═ 8.9Hz,1H),5.47(t, J ═ 5.7Hz,1H),3.89(s,1H), 3.83-3.69 (m,2H), 3.51-3.32 (m, 2H).

To a solution of thionyl chloride (2.5mmol, 181 μ L) in anhydrous DCM (6mL) at 0 ℃ was added dropwise a solution of 2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethan-1-ol (481mg, 2mmol) in 4mL anhydrous DCM. The reaction mixture was stirred at 0 ℃ for 10min, then pyridine (0.483mL, 6mmol) was added. After stirring at room temperature for 1h, the reaction mixture was quenched with water and extracted three times with DCM. The combined organic phases were washed with brine, washed with Na₂SO₄Dried, concentrated and purified by flash chromatography on silica gel using hexane and ethyl acetate to give 3- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -1,2, 3-oxathiazolidin 2-oxide (415mg, 72%).¹H NMR (500MHz, chloroform-d) δ 7.80(d, J ═ 8.7Hz,1H),6.94(d, J ═ 8.7Hz,1H),5.16(ddd, J ═ 10.5,8.9,6.4Hz,1H),4.88(ddd, J ═ 1H), and9.1,7.2,2.3Hz,1H),4.05(ddd,J＝8.9,6.4,2.3Hz,1H),3.78(ddd,J＝10.5,9.1,7.2Hz,1H)。

3- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -1,2, 3-oxathiazolidine 2, 2-dioxide: to 3- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -1,2, 3-oxathiazolidine 2-oxide (52mg, 0.18mmol) in CH at 0 deg.C₃To a solution of CN (2mL) and water (2mL) were added ruthenium chloride (1.86mg, 0.009mmol) and sodium periodate (58mg, 0.27 mmol). The reaction mixture was stirred at 0 ℃ for 30 min. Diluted with ethyl acetate (10mL) and water (10mL) and extracted three times with ethyl acetate. The combined organic phases were washed with brine, washed with Na₂SO₄Dried and concentrated. The crude product was used in the next step without further purification.¹H NMR (500MHz, chloroform-d) δ 7.87(d, J ═ 8.8Hz,1H),7.50(d, J ═ 8.8Hz,1H),4.84(t, J ═ 6.5Hz,2H),4.40(t, J ═ 6.5Hz, 2H).

Key intermediate 6-chloro-1- (chloromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole hydrochloride substituted Epitopic Synthesis: to a mixture of 2- (5-chloro-1H-indol-3-yl) ethane-1-amine hydrochloride (925mg, 4mmol) and a 50 wt% solution of 2-chloroacetaldehyde (0.56mL, 4.4mmol) was added a 4N HCl (4mmol) solution. The reaction mixture was heated to 100 ℃ for 12 h. After cooling to room temperature and filtration of the brown solid, the filtrate is washed with water and diethyl ether and dried on a high vacuum pump to give 6-chloro-1- (chloromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as a brown solid]Indole hydrochloride (905mg, 77% yield).¹H NMR(500MHz,DMSO-d₆)δ11.68(s,1H),10.42(s,1H),9.63(s,1H),7.58(d,J＝2.0Hz,1H),7.41(d,J＝8.6Hz,1H),7.14(dd,J＝8.6,2.1Hz,1H),5.12(dd,J＝6.8,3.0Hz,1H),4.56–4.46(m,1H),4.34(ddd,J＝12.3,7.0,1.5Hz,1H),3.60(dt,J＝12.5,4.9Hz,1H),3.39–3.30(m,1H),3.12–2.76(m,2H)。

6-chloro-1- (chloromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indoles: reacting 6-chloro-1- (chloromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole hydrochloride basified with 2n naoh solution, extracted three times with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give a light brown solid pure enough for further reactionShould be used.¹H NMR (500MHz, chloroform-d) δ 8.17(s,1H),7.48(d, J ═ 2.0Hz,1H),7.27(d, J ═ 8.0Hz,1H),7.15(dd, J ═ 8.6,2.0Hz,1H),4.38(td, J ═ 6.3,3.1Hz,1H),3.83(d, J ═ 6.2Hz,2H),3.30(dt, J ═ 12.7,5.3Hz,1H),3.13(ddd, J ═ 12.5,6.9,5.3Hz,1H), 2.84-2.67 (m, 2H).

Key intermediate 1- (azidomethyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Representative of indoles Synthesis of

2-azido-1, 1-diethoxyethane

Adding NaN₃A mixture of (2.5g, 0.038mol, 1.5 equiv.), KI (0.5g, 0.0030mol, 0.1 equiv.), and 2-bromo-1, 1-diethoxyethane (5.0g, 0.026mol, 1.0 equiv.) was stirred at 90 ℃ for 48 h. The reaction was then poured into H₂O (100mL), extracted with EtOAc (50 mL. times.3). The combined organic phases were washed with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2-azido-1, 1-diethoxyethane (2.4g, yield: 58.1%) as a colorless oil.¹H NMR(400MHz,CDCl₃):δ4.60(t,J＝5.3Hz,1H),3.77-3.55(m,4H),3.25-3.24(d,J＝5.2Hz,2H),1.24(t,6H)。

1- (azidomethyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indoles

2-azido-1, 1-diethoxyethane (1.9g, 0.012mol, 1.5 equiv.), 2- (5-chloro-1H-indol-3-yl) ethane-1-amine hydrochloride (1.8g, 0.008mol, 1.0 equiv.) and TFA (1.8g, 0.016mol, 2.0 equiv.) in butanol (40mL)/H₂The mixture in O (3mL) was stirred in a sealed tube at 100 ℃ for 16 h. The reaction mixture was then cooled to room temperature and purified by reverse phase high performance liquid chromatography to give 1- (azido)Methyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole (1.3 g). Further chiral SFC separation provided two respective enantiomers: p1(437.5mg, yield: 14.1%) and P2(446.7mg, yield: 14.3%) were each a brown solid.

P1:¹H NMR(400MHz,DMSO-d₆):δ10.96(s,1H),7.42(s,1H),7.31(d,J＝8.4Hz,1H),7.02(dd,J＝8.4Hz,2.4Hz,1H),4.17(s,1H),3.66-3.54(m,2H),3.12-3.07(m,1H),2.94-2.90(m,1H),2.59-2.55(m,3H)。LCMS:[M+1]⁺＝262.0。

P2:¹H NMR(400MHz,DMSO-d₆):δ10.96(s,1H),7.42(s,1H),7.31(d,J＝8.4Hz,1H),7.04-7.02(m,1H),4.17(s,1H),3.66-3.53(m,2H),3.12-3.07(m,1H),2.93-2.90(m,1H),2.59-2.55(m,3H)。LCMS:[M+1]⁺＝262.0。

Key intermediate 1- ((1H-imidazol-1-yl) methyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole Representative Synthesis of indole

A solution of imidazole (0.68g, 10mmol) in DMF (4mL) was added dropwise over 10min to a stirred, cold suspension of NaH (60% suspension in mineral oil) in DMF (3 mL). When the vigorous evolution of hydrogen subsided, the mixture was stirred for 20min on a water bath at 50 ℃ to complete the salt formation. Mixing the mixture in ice-H₂The O bath was again cooled and a solution of 2-bromo-1, 1-diethoxyethane (1.5mL, 10mmol) in DMF (1mL) was added dropwise over 10 min. Stirring was then continued at 135 ℃ for 75 min. The mixture was cooled and filtered to remove NaBr. DMF was removed on a rotary evaporator to give 1- (2, 2-diethoxyethyl) -1H-imidazole (1.81g, 98%) which was used in the next step without further purification.¹H NMR (300MHz, methanol-d₄)δ7.66(t,J＝1.2Hz,1H),7.16(t,J＝1.3Hz,1H),6.96(t,J＝1.2Hz,1H),4.69(t,J＝5.2Hz,1H),4.12(d,J＝5.2Hz,2H),3.74(dq,J＝9.4,7.0Hz,2H),3.50(dq,J＝9.4,7.0Hz,2H),1.17(t,J＝7.0Hz,6H)。

To a mixture of 1- (2, 2-diethoxyethyl) -1H-imidazole (1.06g, 5.7mmol) and 5-chlorotryptamine hydrochloride (1.2g, 5.2mmol) was added 2N HCl (3.9mL, 7.8mmol) and H₂O (1.3 mL). The mixture was stirred at reflux for 16 h. The mixture was then cooled to 0 ℃ for 2H and filtered to give the desired product 1- ((1H-imidazol-1-yl) methyl) -6-chloro-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] as a white solid]Indole (1.02g, 55% yield).¹H NMR(300MHz,DMSO-d₆)δ11.97(s,1H),10.60(m,2H),9.31(s,1H),7.93(s,1H),7.75(s,1H),7.61(s,1H),7.46(d,J＝8.6Hz,1H),7.17(d,J＝8.8Hz,1H),5.48–5.15(m,2H),5.02(dd,J＝14.7,9.5Hz,1H),3.28(t,J＝11.7Hz,2H),2.98(q,J＝6.4,5.3Hz,2H)。

Process for the key intermediate tert-butyl 4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -2-formylpiperazine-1-carboxylate Representative Synthesis

To a solution of tert-butyl 2- (hydroxymethyl) piperazine-1-carboxylate (6.0g, 27.8mmol, 1.2 equivalents) in NMP (10mL) was added 3, 6-dichloro-2- (trifluoromethyl) pyridine (5.0g, 23.2mmol, 1.0 equivalents) and DIPEA (8.9g, 69.5mmol, 3.0 equivalents). The mixture was stirred at 140 ℃ for 2 days. The mixture was directly purified by reverse phase high performance liquid chromatography to give tert-butyl 4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -2- (hydroxymethyl) piperazine-1-carboxylate (2.2g, yield: 25.1%) as a pale yellow solid. LCMS (liquid Crystal Module) [ M +1 ]]⁺＝395.9。

To a solution of compound 4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (2.4g, 6.1mmol, 1.0 eq) in DCM (30mL) was added Dess-martin periodinane (3.9g, 9.1mmol, 1.5 eq). The mixture was stirred at room temperature for 2 h. The mixture was directly purified by silica gel column chromatography (PE: EA ═ 10:1) to give tert-butyl 4- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -2-formylpiperazine-1-carboxylate (1.6g, yield: 65.1%) as a white solid. LCMS: [ M+1]⁺＝394.0。

General scheme 36

N- (2- (1- ((azetidin-3-ylamino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b)] Representative Synthesis of indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine: to 6-chloro-1- (chloromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]To a solution of indole (0.1mmol) and 2, 6-lutidine (0.12mmol) in 0.5mL acetonitrile was added the freshly prepared 3- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -1,2, 3-oxathiazolidine 2, 2-dioxide (0.15 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then added to a solution of tert-butyl 3-aminoazetidine-1-carboxylate (2mmol) in acetonitrile (0.1mL) at 80 ℃ and stirred for 1h at 80 ℃. After LCMS showed disappearance of starting material, the solvent was removed under reduced pressure. The residue obtained is redissolved in 1mL of 1N HCl solution and heated to 100 ℃ for 30 min. After cooling to room temperature, the mixture was basified with 2N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TCL plate (DCM/MeOH 9:1, Rf ═ 0.6) to give 3- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ])]Indol-1-yl) methyl) amino) azetidine-1-carboxylic acid tert-butyl ester (14.2mg, 23% yield).

To 3- (((6-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) methyl) amino) azetidine-1-carboxylic acid tert-butyl ester (14mg) in dioxane (1mL) was added 4N HCl in dioxane (34. mu.L, 5 equivalents). The resulting solution was stirred at room temperature for 3h and concentrated. The residue was purified by reverse phase high performance liquid chromatography to give N- (2- (1- ((azetidin-3-ylamino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3,4-b ] as an off-white solid]Indol-2-yl) ethyl) -5-chloro-6- (trifluoromethyl) pyridin-2-amine (8.2 mg).¹H NMR(400MHz,CD₃OD):δ7.65-7.54(m,1H),7.50-7.37(m,1H),7.31-7.22(m,1H),7.12-7.00(m,1H),6.83-6.71(m,1H),4.67-4.41(m,1H),4.28-4.04(m,2H),3.75-3.53(m,5H),3.37-3.31(m,2H),3.30-3.08(m,2H),2.91-2.80(m,3H),2.71-2.52(m,1H)。LCMS:[M+1]⁺＝512.9。

(2- (1- (((azetidin-3-ylmethyl) amino) methyl) -6-chloro-1, 3,4, 9-tetrahydro-2H-pyrido [3, 4-b]indol-2-yl) ethyl) (5-chloro-6- (trifluoromethyl) pyridin-2-yl) sulfamic acid

¹H NMR(400MHz,CD₃OD):δ7.61-7.59(m,2H),7.45-7.41(m,1H),7.23-7.19(m,1H),6.84(d,J＝8.8Hz,1H),5.16(brs,1H),4.37-4.33(m,1H),4.20-3.94(m,8H),3.74-3.64(m,4H),3.56-3.37(m,4H),3.30-3.10(m,1H)。LCMS:[M+1]⁺＝527.0。

General scheme 37

N-benzoyl-4-azepinone (1-Benzoylazepan-4-one)To a mixture of azepan-4-one hydrochloride (4.35g, 29.1mmol) and benzoyl chloride (4.1mL, 35.6mmol) was added Et₃N (9.9mL, 71.2 mmol). The mixture was stirred for 16h, and DCM (50mL) was added. The mixture was washed with water and Na₂SO₄Dried and evaporated. The residue was purified by silica gel column chromatography to give N-benzoyl-4-azepinone (4.81g, 76%).

(9-chloro-1, 2,4, 5-tetrahydroazepino [4, 5-b)]Indol-3 (6H) -yl) (phenyl) methanonesN-benzoyl-4-azepinone (4.81g, 22mmol), 4-chlorophenylhydrazine hydrochloride (3.96g, 22mmol) and CH₃CO₂A stirred solution of H (0.5mL) in EtOH (50mL) was refluxed for 30min, then the solvent was removed under reduced pressure. Addition of HCO₂H (40mL) and the mixture was heated to reflux temperature for 30 min. The mixture was concentrated and washed with aqueous NaOH (2N). Subjecting the obtained solution toDCM was extracted three times and the combined organic layers were taken over Na₂SO₄Dried, filtered, and evaporated in vacuo to give the crude product. The mixture was purified by flash chromatography on silica gel to give (9-chloro-1, 2,4, 5-tetrahydroazepino [4, 5-b)]Indol-3 (6H) -yl) (phenyl) methanone (1.05g, 15%).¹H NMR(300MHz,CDCl₃)δ8.50–8.10(m,1H),7.48–7.35(m,14H),7.17–7.01(m,2H),3.99(t,J＝5.5Hz,2H),3.65(t,J＝5.6Hz,2H),3.15–2.75(m,4H)。

9-chloro-1, 2,3,4,5, 6-hexahydroazepino [4,5-b]IndolesThe (9-chloro-1, 2,4, 5-tetrahydroazepine [4,5-b ] is synthesized]A mixture of indol-3 (6H) -yl) (phenyl) methanone (0.2g, 0.6mmol), KOH (1.4g, 25.0mmol) and MeOH (10mL) was heated to reflux temperature. When the starting material disappeared, the reaction was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The crude product was used directly in the next step without further purification.¹H NMR(300MHz,CDCl₃)δ7.77(s,1H),7.43(d,J＝2.0Hz,1H),7.24–7.15(m,1H),7.07(dd,J＝8.5,2.0Hz,1H),3.17–3.02(m,5H),2.98–2.93(m,2H),2.90–2.85(m,2H)。

2- (9-chloro-1, 2,4, 5-tetrahydroazepino [4, 5-b)]Indol-3 (6H) -yl-1- (3, 4-dichlorophenyl) ethyl Alcohol(s)

¹HNMR(300MHz,CDCl₃)δ7.79(s,1H),7.53(d,J＝1.8Hz,1H),7.44–7.37(m,2H),7.25–7.01(m,3H),4.72(dd,J＝10.5,3.3Hz,1H),3.17–2.76(m,10H),2.49(dd,J＝12.6,10.5Hz,1H)。LCMS[M+H⁺]409.0。

2- (9-chloro-1, 2,4, 5-tetrahydroazepino [4, 5-b)]Indol-3 (6H) -yl-N- (5-chloro-6-methylpyridine- 2-yl) acetamides

¹HNMR(300MHz,CDCl₃)δ9.67(s,1H),8.09(d,J＝8.7Hz,1H),7.88(s,1H),7.64(d,J＝8.7Hz,1H),7.40(d,J＝1.8Hz,1H),7.22–7.13(m,1H),7.11–7.03(m,1H),3.45(s,2H),3.14–2.96(m,6H),2.95–2.83(m,2H),2.52(s,3H)。LCMS[M+H⁺]403.1。

5-chloro-N- (2- (9-chloro-1, 2,4, 5-tetrahydroazepino [4, 5-b)]Indol-3 (6H) -yl) ethyl) -6-methyl Pyridin-2-amines

¹HNMR(300MHz,CDCl₃)δ7.74(s,1H),7.40(d,J＝2.1Hz,1H),7.34(d,J＝8.7Hz,1H),7.19–7.13(m,1H),7.09–7.03(m,1H),6.22(d,J＝8.7Hz,1H),5.13(s,1H),3.40–3.34(m,2H),3.10–2.84(m,10H),2.45(s,3H)。LCMS[M+H⁺]389.1。

General scheme 38

6-chloro-2, 3,4, 9-tetrahydro-1H-carbazol-1-one4-Chlorophenylhydrazine hydrochloride (5.37g, 30mmol) was added portionwise to a stirred solution of cyclohexane-1, 2-dione (3.36g, 30mmol) in EtOH (30mL) at room temperature. The reaction mixture turned bright orange within 5 minutes. The reaction was stirred at room temperature for 16h, then the heterogeneous reaction mixture was filtered and the solid was collected. The filtrate was concentrated and combined with the solid. Concentrated HCl (3mL) and CH were then added₃CO₂H (12mL), and the reaction mixture was heated at 120 ℃ for 20 min. The mixture was cooled slightly and ice was added. The resulting precipitate was collected by filtration to give a crude product. The crude product was purified by silica gel column chromatography, followed by recrystallization (CH)₂Cl₂Hexane) further purified to obtainTo pure 6-chloro-2, 3,4, 9-tetrahydro-1H-carbazol-1-one (1.60g, 7.3mmol, 24% yield).¹HNMR(300MHz,CDCl₃)δ9.12(s,1H),7.67–7.58(m,1H),7.39–7.34(m,1H),7.33–7.28(m,1H),2.97(t,J＝6.0Hz,2H),2.76–2.60(m,2H),2.37–2.19(m,2H)。LCMS[M+H⁺]220.1。

7-chloro-2, 3,4, 5-tetrahydroazepino [3,4-b]Indol-1 (10H) -onesA stirred mixture of 6-chloro-2, 3,4, 9-tetrahydro-1H-carbazol-1-one (0.66g, 3mmol) in polyphosphoric acid (15g) was heated to 60 ℃ and treated with NaN₃(0.25g, 3.9mmol) for 20 min. After heating at the same temperature overnight, the mixture was poured into ice water. The product is treated with CH₂Cl₂Extracting; the extract was washed with water and MgSO₄Dried and concentrated. Crude product 7-chloro-2, 3,4, 5-tetrahydroazepino [3,4-b]Indol-1 (10H) -one can be used directly in the next step.¹HNMR(300MHz,CDCl₃)δ9.15(s,1H),7.33–7.24(m,1H),7.20–7.13(m,1H),7.10–7.03(m,1H),6.10(s,1H),3.60–3.45(m,2H),2.33–2.12(m,2H)。LCMS[M+H⁺]235.1。

7-chloro-1, 2,3,4,5, 10-hexahydroazepino [3,4-b]Indoles7-chloro-2, 3,4, 5-tetrahydroazepino [3,4-b ]]Indol-1 (10H) -one (47mg, 0.2mmol) and BH₃A stirred mixture of THF (0.6mL, 0.6mmol) was heated to reflux for 24 h. After completion of the reaction, the solvent was removed under reduced pressure. MeOH was then added and the mixture was concentrated again. The crude product was purified by silica gel column chromatography to give pure 7-chloro-1, 2,3,4,5, 10-hexahydroazepino [3,4-b]Indole (14.8mg, 0.067mmol, 34% yield).¹HNMR(300MHz,CDCl₃)δ7.78(s,1H),7.51–7.41(m,1H),7.21–7.15(m,1H),7.10–7.02(m,1H),4.03(s,2H),3.28–3.15(m,2H),2.97–2.76(m,2H),1.96–1.79(m,2H)。LCMS[M+H⁺]221.1。

2- (7-chloro-4, 5-dihydroazepino [3, 4-b)]Indol-2 (1H,3H,10H) -yl) -1- (3, 4-dichlorophenyl) Ethanol

¹HNMR(300MHz,CDCl₃)δ7.76(s,1H),7.45(t,J＝2.4Hz,2H),7.45(t,J＝2.4Hz,1H),7.27(d,J＝8.4Hz,1H),7.20(d,J＝8.7Hz,1H),7.13(dd,J＝8.1,2.1Hz1H),7.08(dd,J＝8.7,2.1Hz,1H),4.66(dd,J＝10.2,3.6Hz,1H),4.02(d,J＝2.7Hz,1H),3.31–3.21(m,2H),2.90–2.78(m,3H),2.39–2.31(m,1H),2.39–2.31(m,1H),1.94–1.70(m,4H)。LCMS:[M+H⁺]409.0。

2- (7-chloro-4, 5-dihydroazepino [3, 4-b)]Indol-2 (1H,3H,10H) -yl-N- (5-chloro-6-methylpyridine Pyridin-2-yl) acetamide

¹HNMR(300MHz,CDCl₃)δ9.59(s,1H),8.11(s,1H),8.02(d,J＝8.7Hz,1H),7.63(d,J＝8.7Hz,1H),7.46(d,J＝1.8Hz,1H),7.21–7.11(m,1H),7.11–7.01(m,1H),4.01(s,2H),3.37–3.26(m,2H),3.23(s,2H),2.96–2.81(m,2H),2.52(s,3H),1.92–1.76(m,2H)。

5-chloro-N- (2- (7-chloro-4, 5-dihydroazepino [3, 4-b)]Indol-2 (1H,3H,10H) -yl) ethyl) -6- Methylpyridin-2-amines

¹H NMR(300MHz,CDCl₃)δ7.94(s,1H),7.45(d,J＝1.8Hz,1H),7.31(d,J＝8.7Hz,1H),7.21–7.15(m,1H),7.09–7.03(m,1H),6.18(d,J＝8.7Hz,1H),3.97(s,2H),3.83–3.59(m,2H),3.31–3.18(m,4H),2.92–2.63(m,4H),2.44(s,3H)。LCMS:[M+H⁺]389.1。

General scheme 39

5-chloro-2, 3-dimethyl-1H-indole4-Chlorophenylhydrazine hydrochloride (1.79g, 10mmol) and ethyl methyl ketone (0.89mL, 10mmol) were added to acetic acid (8mL) and the reaction mixture was heated to reflux temperature. The reaction was then cooled to room temperature and poured into ice water. The crude product was extracted with water and Na₂SO₄Dried and concentrated in vacuo to afford the product as a brown solid. The residue was further purified by silica gel column chromatography to give 5-chloro-2, 3-dimethyl-1H-indole (0.77g, 4.3mmol, 43% yield).¹HNMR(300MHz,CDCl₃)δ7.65(s,1H),7.44(d,J＝1.9Hz,1H),7.14(dd,J＝8.5,0.6Hz,1H),7.06(dd,J＝8.5,2.0Hz,1H),2.35(s,3H),2.19(s,3H)。

5-chloro-2, 3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester5-chloro-2, 3-dimethyl-1H-indole (0.77g, 4.3mmol) was dissolved in THF, followed by the addition of DMAP (52.5mg, 0.43mmol) and (Boc)₂And O. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated and purified by silica gel column chromatography using hexane/EtOAc ═ 9:1 to give 5-chloro-2, 3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (1.16g, 4.1mmol, 97% yield).

2, 3-bis (bromomethyl) -5-chloro-1H-indole-1-carboxylic acid tert-butyl ester5-chloro-2, 3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (0.56g, 2mmol), NBS (0.71g, 4mmol) and benzoyl peroxide (10mg) in dry CCl₄The solution in (1) was refluxed for 2 h. The suspension was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 2, 3-bis (bromomethyl) -5-chloro-1H-indole-1-carboxylic acid tert-butyl ester (0.53g, 1.2mmol, 60% yield).¹HNMR(300MHz,CDCl₃)δ8.11(d,J＝9.0Hz,1H),7.64–7.56(m,1H),7.33(dd,J＝9.0,2.1Hz,1H),5.00(s,2H),4.64(s,2H),1.73(s,9H)ppm。

7-chloro-2- (2- (3, 4-dichlorophenyl) -2-hydroxyethyl) -2, 3-dihydropyrrolo [3,4-b]Indole-4 (1H) -carbaryl Tert-butyl ester2, 3-bis (bromomethyl) -5-chloro-1H-indole-1-carboxylic acid tert-butyl ester (85.5mg, 0.2mmol), 2-amino-1- (3, 4-dichlorophenyl) ethane-1-ol (41.2mg, 0.2mmol) and K₂CO₃A mixture (0.11g, 0.8mmol) in THF was heated to reflux for 10 h. The mixture was then concentrated. The crude product was purified by silica gel column chromatography to give 7-chloro-2- (2- (3, 4-dichlorophenyl) -2-hydroxyethyl) -2, 3-dihydropyrrolo [3,4-b]Indole-4 (1H) -carboxylic acid tert-butyl ester (33.7mg, 0.07mmol, 35% yield).¹HNMR(300MHz,CDCl₃)δ8.08(d,J＝8.7Hz,1H),7.55(d,J＝1.8Hz,1H),7.43(d,J＝8.4Hz,1H),7.31(d,J＝2.1Hz,1H),7.27–7.20(m,2H),5.22–4.88(m,1H),4.72(dd,J＝9.6,3.3Hz,1H),4.28–4.18(m,2H),4.06–3.88(m,2H),3.16–3.03(m,1H),2.98–2.84(m,1H),1.62(s,9H)ppm。LCMS:[M+H⁺]481.1。

2- (7-Chloropyrrolo [3,4-b ]]Indol-2 (1H,3H,4H) -yl) -1- (3, 4-dichlorophenyl) ethanolMixing 7-chloro-2- (2- (3, 4-dichlorophenyl) -2-hydroxyethyl) -2, 3-dihydropyrrolo [3,4-b]Indole-4 (1H) -carboxylic acid tert-butyl ester (52.5mg, 0.12mmol), TFA (1mL) and CH₂Cl₂(1mL) of the mixture was stirred at room temperature until the starting material disappeared. The mixture was then concentrated and treated with aqueous NaOH (2N) and CH₂Cl₂And (4) extracting. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2- (7-chloropyrrolo [3, 4-b)]Indol-2 (1H,3H,4H) -yl) -1- (3, 4-dichlorophenyl) ethanol (1.2mg, 16% yield).¹HNMR(300MHz,CDCl₃)δ8.00(s,1H),7.56(d,J＝2.1Hz,1H),7.44(d,J＝8.4Hz,1H),7.40(d,J＝2.1Hz,1H),7.30–7.27(m,1H),7.26–7.23(m,1H),7.11(dd,J＝8.7,2.1Hz,1H),4.74(dd,J＝9.6,3.3Hz,1H),4.34–3.83(m,5H),3.11(dd,J＝12.3,3.6Hz,1H),2.90(dd,J＝12.3,9.9Hz,1H)ppm。LCMS:[M+H⁺]381.0。

7-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) -2-oxoethyl) -2, 3-dihydropyrrole And [3,4-b ]]Indole-4 (1H) -carboxylic acid tert-butyl ester

2, 3-bis (bromomethyl)Yl) -5-chloro-1H-indole-1-carboxylic acid tert-butyl ester (52.5mg, 0.12mmol), 2-amino-N- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) acetamide (30.9mg, 0.12mmol) and K₂CO₃A mixture (66.2mg, 0.48mmol) in THF was heated to reflux for 10 h. The mixture was then concentrated and the crude product was purified via silica gel column chromatography to give 7-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) -2-oxoethyl) -2, 3-dihydropyrrolo [3,4-b]Indole-4 (1H) -carboxylic acid tert-butyl ester (3.3mg, 0.006mmol, 5% yield).¹HNMR(300MHz,CDCl₃)δ9.74(s,1H),8.48(d,J＝8.9Hz,1H),8.08(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.33(d,J＝2.1Hz,1H),7.23(d,J＝2.2Hz,1H),4.37(t,J＝3.5Hz,2H),4.16(t,J＝3.5Hz,2H),3.72(s,2H),1.64(s,9H)。LCMS:[M+H⁺]529.1。

N- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -2- (7-chloropyrrolo [3, 4-b)]Indole-2 (1H,3H,4H) - Yl) acetamideReacting 7-chloro-2- (2- ((5-chloro-6- (trifluoromethyl) pyridin-2-yl) amino) -2-oxoethyl) -2, 3-dihydropyrrolo [3,4-b]Indole-4 (1H) -carboxylic acid tert-butyl ester (3.3mg, 0.006mmol), TFA (2mL) and CH₂Cl₂(2mL) the mixture was stirred at room temperature for 1.5 h. The mixture was then concentrated and neutralized with aqueous NaOH (2N) and CH₂Cl₂And (4) extracting. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N- (5-chloro-6- (trifluoromethyl) pyridin-2-yl) -2- (7-chloropyrrolo [3, 4-b)]Indol-2 (1H,3H,4H) -yl) acetamide (1.4mg, 0.003mmol, 54% yield).¹HNMR(300MHz,CDCl₃)δ9.78(s,1H),8.47(d,J＝8.9Hz,1H),8.06(s,1H),7.85(d,J＝8.9Hz,1H),7.39(d,J＝2.0Hz,1H),7.30–7.27(m,1H),7.13(dd,J＝8.7,2.1Hz,1H),4.22(d,J＝4.6Hz,4H),3.75(s,2H)。LCMS:[M+H⁺]429.0。

General scheme 40

1- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-dimethylmethylamineReacting 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl (3.05g, 20mmol), 40% aqueous dimethylamine (3.8mL, 30mmol), and CH₃CO₂The mixture of H is stirred at 0 ℃ and then a 36% aqueous formaldehyde solution is added dropwise. The mixture was allowed to warm to room temperature. After stirring overnight, TLC showed no starting material present. 10% aqueous NaOH (60mL) was added and the mixture was stirred at room temperature for an additional 2 h. It was then extracted with DCM, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 1- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-dimethylmethylamine (1.22g, 36% yield).

5-chloro-3- (2-nitroethyl) -1H-pyrrolo [2,3-b]Pyridine compound1- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-dimethylmethylamine (1.45g, 6.9mmol) was dissolved in a mixed solvent of methanol (10mL) and nitromethane (10 mL). The solution was cooled to 0 ℃. Addition of Me₂SO₄(0.78mL, 8.3mmol) followed by the slow addition of sodium methoxide (0.53g, 9.8mmol) over 15 min. The ice bath was removed and the mixture was stirred overnight. The reaction mixture was washed with EtOAc (20mL) and saturated NH₄Aqueous Cl (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated in vacuo. The crude product 5-chloro-3- (2-nitroethyl) -1H-pyrrolo [2,3-b]The pyridine was used directly in the next step without further purification.

2- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethanaminesReacting 5-chloro-3- (2-nitroethyl) -1H-pyrrolo [2,3-b]Pyridine was dissolved in methanol (100mL) and aqueous HCl (2M, 100 mL). Zinc powder (5.885g, 90mmol) was added portionwise over 15 min. The suspension was then heated at reflux temperature for 3 h. After cooling to room temperature, the reaction mixture was filtered and the solid filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. A cooled aqueous NaOH solution (15% w/w, 20mL) was added and the resulting aqueous solution was extracted with DCM. The organic extracts were combined and MgSO₄Drying and concentrating to obtain crude product 2- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethylamine, which was used directly in the next step. LCMS: [ M + H⁺]196.1。

3-chloro-6, 7,8, 9-tetrahydro-5H-pyrrolo [2,3-b:5,4-c']Dipyridine2- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethylamine (44.3mg, 0.23mmol) was dissolved in EtOH (0.3 mL). HCl (58 μ L, 4M in dioxane) was added followed by HCHO solution (37%). The reaction was stirred at 150 ℃ for 2 days. The reaction mixture was then concentrated. The crude product was purified by silica gel column chromatography to give 3-chloro-6, 7,8, 9-tetrahydro-5H-pyrrolo [2,3-b:5,4-c']Bipyridine (22.3mg, 47% yield).¹HNMR(300MHz,CD₃OD)δ8.04(d,J＝2.3Hz,1H),7.81(d,J＝2.2Hz,1H),3.99(d,J＝1.6Hz,2H),3.13(t,J＝5.8Hz,2H),2.78–2.55(m,2H)。LCMS:[M+H⁺]208.1。

2- (3-chloro-5H-pyrrolo [2,3-b:5,4-c']Bipyridine-7 (6H,8H,9H) -yl) -1- (3, 4-dichlorobenzene Yl) ethanol

¹HNMR(300MHz,CDCl₃)δ9.26(s,1H),8.24–8.12(m,1H),7.81–7.73(m,1H),7.56–7.46(m,1H),7.46–7.36(m,1H),7.25–7.11(m,1H),4.87–4.68(m,1H),4.08–3.68(m,3H),3.21–2.89(m,2H),2.88–2.78(m,3H),2.68–2.57(m,1H)ppm。LCMS:[M+H⁺]396.0。

2- (3-chloro-5H-pyrrolo [2,3-b:5,4-c']Bipyridin-7 (6H,8H,9H) -yl) -N- (5-chloro-6- (trifluoro-phenyl) phosphonium chloride Methyl) pyridin-2-yl) acetamide

¹HNMR(300MHz,CDCl₃)δ9.77(s,1H),9.27(s,1H),8.48(dd,J＝8.9,0.6Hz,1H),8.20(s,1H),7.98–7.84(m,1H),7.81(d,J＝2.0Hz,1H),3.97(s,2H),3.48(s,2H),3.07(t,J＝5.7Hz,2H),2.88(t,J＝5.8Hz,2H)。LCMS:[M+H⁺]444.0。

5-chloro-N- (2- (3-chloro-5H-pyrrolo)[2,3-b:5,4-c']Bipyridin-7 (6H,8H,9H) -yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹HNMR(300MHz,CDCl₃)δ8.79(s,1H),8.14(s,1H),7.74(d,J＝2.1Hz,1H),7.51–7.40(m,1H),6.50(d,J＝8.9Hz,1H),5.34(s,1H),3.76(s,2H),3.53(q,J＝5.6Hz,2H),2.90(dt,J＝14.5,5.8Hz,4H),2.77(t,J＝5.7Hz,2H)。LCMS:[M+H⁺]430.0。

General scheme 41

(Z) -3- (2- (5-chloro-6-methylpyridin-3-yl) hydrazono) piperidin-2-one

Step 1: a round-bottom flask was charged with 18mL of water, ethyl 2-oxopiperidine-3-carboxylate (1.37g, 8mmol) and solid KOH (1.88g, 33.6 mmol). The mixture was stirred at room temperature for 30min and quenched by dropwise addition of concentrated HCl (3.2mL, 38.4 mmol). NaCl (5.8g) was then added to the solution and taken up in 85:15 CHCl₃The resulting saturated mixture was extracted with a solution of/i-PrOH (5X 20 mL). The combined organics were passed over Na₂SO₄Dried and concentrated in vacuo to give 2-oxopiperidine-3-carboxylic acid.

Step 2: 5-chloro-6-methylpyridin-3-amine (0.285g, 2mmol) was dissolved in concentrated HCl (0.67mL, 8mmol) and the mixture was cooled to-10 ℃ and NaNO was added dropwise₂(0.151g, 2.2mmol) in water (5mL) to form the diazonium salt 5-chloro-6-methylpyridine-3-diazonium chloride.

And step 3: 2-Oxopiperidine-3-carboxylic acid (0.342g, 2mmol) was dissolved in water and cooled in an ice bath. The cooled solution is then added directly to the reaction mixture of the diazonium salt 5-chloro-6-methylpyridine-3-diazonium chloride prepared in step 2. The reaction mixture was stirred at 0 ℃ overnight to form the hydrazone. The reaction was neutralized with 2N aqueous NaOH, concentrated, and the crude product was purified by silica gel column chromatography to give (Z) -3- (2- (5-chloro-6-methylpyridin-3-yl) hydrazono) piperidin-2-one (0.284g, 57% yield).

3-chloro-2-methyl-8, 9-dihydro-5H-pyrrolo [3,2-b:5,4-c']Bipyridin-6 (7H) -ones(Z) -3- (2- (5-chloro-6-methylpyridin-3-yl) hydrazono) piperidin-2-one (0.284g, 1.13mmol) and HCO₂H (4mL) was added to the pressurized tubular reactor and the reaction was heated at 145 ℃ for 8H (or until the signal for the starting material disappeared). The reaction was then concentrated and neutralized with aqueous NaOH (2N). The crude product was purified by silica gel column chromatography to give pure 3-chloro-2-methyl-8, 9-dihydro-5H-pyrrolo [3,2-b:5,4-c']Bipyridin-6 (7H) -one (87mg, 33% yield).

3-chloro-2-methyl-6, 7,8, 9-tetrahydro-5H-pyrrolo [3,2-b:5,4-c']DipyridineMixing 3-chloro-2-methyl-8, 9-dihydro-5H-pyrrolo [3,2-b:5,4-c']Bipyridin-6 (7H) -one (44.7mg, 0.19mmol) and BH₃A stirred mixture of THF (0.57mL, 0.57mmol) in 2mL THF was heated to reflux. After completion of the reaction, the solvent was removed under reduced pressure. MeOH was then added, and the mixture was concentrated again. The crude product was purified by silica gel column chromatography to give 3-chloro-2-methyl-6, 7,8, 9-tetrahydro-5H-pyrrolo [3,2-b:5,4-c']Bipyridine (13.7mg, 33% yield).

5-chloro-N- (2- (3-chloro-2-methyl-8, 9-dihydro-5H-pyrrolo [3,2-b:5,4-c']Dipyridine-7 (6H) - Yl) ethyl) -6- (trifluoromethyl) pyridin-2-amine

¹HNMR(300MHz,CDCl₃)δ7.75(s,1H),7.58(s,2H),7.48(s,1H),7.45(s,1H),3.91–3.86(m,2H),3.77(s,2H),3.73(d,J＝6.0Hz,2H),2.95(s,2H),2.91(d,J＝7.2Hz,2H),2.72(s,3H)。LCMS:[M+H⁺]444.2。

Biological detection scheme

Bacterial strains representing pathogenic species of clinical interest (so-called ESKAPE pathogens) were selected for MIC studies using compounds a and B. The results are shown in Table A. These species are from the following families or genera: enterococcus (Enterococcus), Staphylococcus (Staphylococcus), Klebsiella (Klebsiella), Acinetobacter (Acinetobacter), Pseudomonas (Pseudomonas) and Enterobacteriaceae (Enterobacteriaceae). Specifically, Enterococcus faecium (Enterococcus faecalis) HM-204 and HM-460, Staphylococcus aureus (Staphylococcus aureus) strains NRS384 and COL, Klebsiella pneumoniae (Klebsiella pneumoniae) strains NR-48976 and NR-48977, Acinetobacter baumannii (Acinetobacter baumannii) strains NR-17783 and NR-19299, Pseudomonas aeruginosa (Pseudomonas aeruginosa) strains NR-48982, and Salmonella enterica (Salmonella enterica) strains NR-22067 and NR-22068 are available from BEI Resources. Escherichia coli (Escherichia coli) strain ATCC 25922 and Staphylococcus aureus (S.aureus) strain ATCC 25923(MSSA) and ATCC BAA-44(MRSA) were purchased from American Type Culture Collection (ATCC).

General procedure for Minimum Inhibitory Concentration (MIC) determination. The Minimum Inhibitory Concentration (MIC) of Antimicrobial compounds A, B and C was determined by the broth microdilution method (broth microdilution method) as detailed in the handbook of Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute), Cocker and Clinical and Laboratory Standards Institute, Methods for Dilution of Antimicrobial Succinity Tests for bacterial that Grow Aerobically. All antimicrobial compounds were purchased from Sigma-Aldrich. The growth medium used for all MIC experiments (except those of enterococcus faecium) was Mueller Hinton Broth (MHB) purchased from HIMEDIA by VWR (accession No.: 95039-356). For experiments with enterococcus faecium, the growth and susceptibility medium was BD Bacto, purchased from VWR^TMBrain Heart Infusion (BHI) Broth (accession No.: 90003-. A USA Scientific CytoOne 96-well Clear Tissue Culture assay plate (96-well Clear Tissue Culture assays) (accession No.: CC7682-7596) was used for all MIC and MRC experiments. MIC test plates were prepared by diluting the antibiotics to be tested to a 2-fold series of test plates. A total of 8 concentrations of each compound were testedIn triplicate. Compounds were prepared in 180 μ L in MHB or BHI and 2% DMSO at twice the expected final concentration.

Bacterial inocula were prepared by selecting 5-7 colonies from agar plates for one day culture in BHI of the bacterial species to be detected. It grows at 37 ℃ for 2-4 h. In the mid-log phase of growth (OD)₆₀₀0.15-0.4), the day-to-day culture is diluted to OD in a suitable detection medium (MHB or BHI)₆₀₀0.002. 100 μ L of this inoculum was added to each experimental well of a 96 well assay plate, allowing for an additional dilution of the bacterial culture by two fold, the initial OD in the assay plate₆₀₀At 0.001, final volume of 200 μ L, expected compound concentration is 1% DMSO. The MIC assay plate was then incubated at 37 ℃ for 18h with shaking.

MIC was determined according to the definition in the clinical and laboratory standards association manual. After overnight growth, the plates were read visually and the absorbance at 600nm was read using a BioTek Epoch2 Microplate spectrometer (BioTek). The MIC is understood as the concentration of antibiotic at which no bacterial growth is visible to the naked eye, or the concentration at which the absorbance at 600nm does not exceed 0.1 (the approximate absorbance of the blank).

Table a. Minimum Inhibitory Concentrations (MIC) of compound a and compound B against a group of pathogenic bacteria.

Determination of the MIC of the antibiotic to MRSA and MSSA in the Presence of Compound C. Methicillin-resistant staphylococcus aureus (MRSA) strain ATCC BAA-44 and methicillin-resistant staphylococcus aureus (MSSA) strain ATCC 25923 were used to determine MIC values for various antibacterial compounds in the presence of 5 μ g/mL of compound C. The experiment was performed analogously to the CLSI MIC assay described previously; except that 10. mu.g/mL of Compound C was first added to the detection Medium (MHB) prior to establishment and inoculation. Such asThe test antibiotic was then diluted into the test plate as described previously. The final concentration of compound C after inoculation with BAA-44 was 5. mu.g/mL. MIC values were determined by the method described above.

Minimum re-sensitivity concentration (MRC) determination. The antibiotic MIC breakpoint value (breakthrough), at which staphylococcus aureus is considered susceptible, was determined from the CLSI manual supplement. MHB was supplemented with antibiotics at concentrations two-fold greater than CLSI sensitive MIC values. Two-fold serial dilutions of compound C were prepared in antibiotic supplemented medium in 96-well microplates. By dilution to OD₆₀₀0.002 MRSA was inoculated with these bacteria and cultured with shaking at 37 ℃ for 18h, and then the results were interpreted. The concentration Of1 in the antibiotic supplemented medium was considered the minimum re-sensitization concentration (MRC) at which no growth was observed.

Minimum Inhibitory Concentrations (MIC) of antibiotic against MRSA strains BAA-44 and NRS-384, respectively, in the absence and presence of 5mg/L of Compound C.

Table C Minimum Inhibitory Concentration (MIC) and minimum re-sensitization concentration (MRC) of compound C in various MRSA strains.

The foregoing discussion of the invention has been presented for purposes of illustration and description. The foregoing is not intended to limit the invention to the form or forms disclosed herein. Although the description of the invention has included description of one or more embodiments and certain variations and modifications, other variations and modifications are within the scope of the invention, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. The invention is intended to obtain rights which include alternative embodiments to the extent permitted, including alternate, interchangeable and/or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and/or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter. All references cited herein are incorporated by reference in their entirety.