HK1210462B

HK1210462B - Rsv antiviral compounds

Info

Publication number: HK1210462B
Application number: HK15111152.4A
Authority: HK
Inventors: Abdellah Tahri; Sandrine Marie Helene Vendeville; Tim Hugo Maria Jonckers; Pierre Jean-Marie Bernard Raboisson; Lili Hu; Samuël Dominique DEMIN; Ludwig Paul Cooymans
Original assignee: Janssen Sciences Ireland Uc
Priority date: 2012-10-16
Filing date: 2013-10-15
Publication date: 2018-07-06

Description

RSV antiviral compounds

Technical Field

The present invention relates to novel spiro compounds having antiviral activity, in particular, having inhibitory activity on the replication of the Respiratory Syncytial Virus (RSV). The invention further relates to such novel compounds, compositions comprising these compounds, and the preparation of these compounds for use in the treatment of respiratory syncytial virus infection.

Background

Human RSV or respiratory syncytial virus is a large RNA virus and, together with bovine respiratory syncytial virus, is a member of the pneumovirinae subfamily of the paramyxoviridae family (pneumoviridae). Human RSV is responsible for a range of respiratory diseases in people of all ages worldwide. It is the major cause of lower respiratory tract disease in infancy and childhood. More than half of all infants encounter RSV in the first year of their birth, and almost all infants encounter RSV in the first two years of their birth. Infections in young children can cause lung damage that persists for many years, and can cause chronic lung diseases later in life (chronic asthma, asthma). Older children and adults often suffer from (heavy) common colds upon RSV infection. In the later years, susceptibility has increased again, and RSV has implicated many outbreaks of pneumonia in the elderly, leading to significant mortality.

Infection with a virus from a given subgroup does not protect against subsequent infection with RSV isolated from the same subgroup in the next winter. Thus, although only two subtypes exist (a and B), re-infection with RSV is common.

Only three drugs are approved today for use against RSV infection. The first is ribavirin (a nucleoside analog), which provides an aerosol treatment for severe RSV infection in hospitalized children. Aerosol route of administration, toxicity (teratogenic risk), cost and highly variable efficacyThe forces limit its use. The other two kinds of medicines are used,(RSV-IG) and(palivizumab), polyclonal and monoclonal antibody immunostimulants, are all intended for use in a prophylactic manner. Both are expensive and require parenteral administration.

Other attempts to date to develop a safe and effective RSV vaccine have met with failure. Inactivated vaccines do not protect against disease and indeed in some cases disease that is enhanced during subsequent infection. Attempts have been made to attenuate live vaccines with limited success. Clearly, there is a need for an effective, non-toxic and easy to administer against RSV replication. It is particularly preferred to provide medicaments against RSV replication that can be administered orally.

Reference documents for structure-activity correlations for RSV inhibition of 5-substituted benzimidazole compounds are X.A. Wang et al, Bioorganic and Medicinal Chemistry Letters (Rapid Bioorganic and Medicinal Chemistry Letters) 17(2007) 4592-4598.

Compounds exhibiting anti-RSV activity are disclosed in WO 2012/080446, WO 2012/080447, WO 2012/080449, WO 2012/080450 and WO 2012/080451.

2-cyanopyrrolopyrimidines and spiro-substituted 2-cyanopyrrolopyrimidines useful as cathepsin K or S inhibitors in the treatment of various pain states are disclosed in WO-2004/069256 and WO-2004/076455, respectively. Tenon et al, Bioorganic & Medicinal Chemistry Letters 17, 6096-.

Potential problems that may be encountered with RSV antiviral agents are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.

It would be desirable to provide novel compounds having antiviral activity. It would be particularly desirable to provide novel medicaments having RSV replication inhibiting activity. In addition, it is desirable to find back compound structures that allow antiviral biological activity of an order of magnitude in the stronger range of the prior art, and preferably at the level of the surroundings of the most activity, more preferably even more active than the compounds disclosed in the art. It would also be desirable to find compounds with oral antiviral activity.

There is a need for additional RSV inhibitors that can overcome at least one of these disadvantages, or have one of the desired effects.

Summary of The Invention

To better address one or more of the above desires, in one aspect, the present invention presents antiviral compounds represented by formula (RI),

or any stereoisomeric form thereof, wherein:

het is a heterocycle of any one of the following formulae (a), (b), (c), (d):

each X is independently C or N; provided that at least two X are C;

R^1a、R^1b、R^1cor R^1dEach independently selected from the group consisting of: hHalogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy, N (R)⁶)₂、CO(R⁷)、CH₂NH₂、CH₂OH、CN、C(＝NOH)NH₂、C(＝NOCH₃)NH₂、C(＝NH)NH₂、CF₃And OCF₃；

When the attached X is N, R^1bOr R^1dIs absent;

each R²Is- (CR)⁸R⁹)_m-R¹⁰；

m is an integer from 0 to 6;

each R³Independently selected from the group consisting of: H. halogen, aryl, heteroaryl, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy and CO (R)⁷)；

Each R⁶Independently selected from the group consisting of: H. c₁-C₆Alkyl, COOCH₃And CONHSO₂CH₃；

Each R⁷Independently selected from the group consisting of: H. c₁-C₆Alkyl, OH, C₁-C₆Alkoxy, NH₂、NHSO₂N(C₁-C₆Alkyl radical)₂、NHSO₂NHCH₃、NHSO₂(C₁-C₆Alkyl), NHSO₂(C₃-C₇Cycloalkyl) and N (C)₁-C₆-alkyl groups)₂NR⁸R⁹And NR⁹R¹⁰；

R⁸And R⁹Each independently selected from the group consisting of: H. c₁-C₁₀Alkyl and C₃-C₇A cycloalkyl group; or R⁸And R⁹Together areForming a 4-to 6-membered saturated ring, which saturated ring may optionally comprise one or more heteroatoms selected from the group consisting of: n, S and O;

each R¹⁰Independently selected from the group consisting of: H. halogen, OH, CN, CF₂H、CF₃、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Cycloalkyl, C (═ O) NR⁸R⁹、C(＝O)OR⁸、SO₂R⁸、C(＝O)N(R⁸)SO₂R⁹、C(＝O)N(R⁸)SO₂N(R⁸R⁹)、NR⁸R⁹、NR⁸C(＝O)OR⁹、OC(＝O)R⁸O-benzyl, NR⁸SO₂R⁹、SO₂NR⁸R⁹、SO₂R⁸、OC(＝O)NR⁸R⁹、OC(＝O)NR⁸R¹²、N(R⁸)C(＝O)N(R⁸R⁹)、R¹¹、N(R⁸)C(＝O)OR¹²、OR¹¹、C(＝O)R¹¹And a 4 to 6 membered saturated ring containing one oxygen atom;

R¹¹is phenyl, pyridyl or pyrazolyl; each of them may be optionally substituted with one or more substituents each independently selected from the group consisting of: CF (compact flash)₃、CH₃、OCH₃、OCF₃And halogen;

R¹²is C₁-C₆Alkyl or C₃-C₇A cycloalkyl group; each substituted with one or more substituents each independently selected from the group consisting of: CF (compact flash)₃、CH₃、OCH₃、OCF₃And halogen;

each Z is independently C or N, provided that at least two Z are C;

q and V are each independentlyRepresents C-O, SO₂Or CR²⁰R²¹；

p and s independently represent an integer from 0 to 3, wherein the sum of p and s should be at least 2, and when p-0 or s-0, the carbon atom marked with ═ is directly attached to W;

R²⁰and R²¹Independently selected from the group consisting of: hydrogen, hydroxy, C₁-C₃Alkyl radical, C₃-C₇Cycloalkyl, CF₃、OCH₃、OCF₃And halogen;

R²²selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, CF₃、OCH₃、OCF₃And halogen;

w is selected from the group consisting of: SO, SO₂S, C, O and N, wherein this C or N may optionally be substituted by one or more R²³Substitution;

R²³selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkyl-R²⁴、SO₂R²⁴、SO₂N(R²⁴)₂Aryl, heteroaryl, C (═ O) OR²⁴、OR²⁴、C(＝O)R²⁴、C(＝O)N(R²⁴)₂、OC(＝O)N(R²⁴)₂、P(＝O)-(O-C₁-C₆-alkyl groups)₂、N(R²⁴)₂、NR²⁵C(＝O)OR²⁴、NR²⁵C(＝O)N(R²⁴)₂、NR²⁵SO₂R²⁴And 4-to 6-membered saturated rings containing one oxygen atom, wherein these C' s₁-C₆Alkyl radical, C₃-C₇Any of the cycloalkyl, aryl, or heteroaryl groups may be optionally substituted with one or more substituents selected from the group consisting of: halogen, halogen,OH、CN、OCH₃；

R²⁴Selected from the group consisting of: hydrogen, OH, halogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Cycloalkyl, aryl, heteroaryl, benzyl, and 4 to 6 membered saturated rings containing one oxygen atom, wherein these C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Any of cycloalkyl, aryl, heteroaryl, benzyl may be optionally substituted with one or more substituents selected from the group consisting of: halogen, CF₃、OH、CN、OCH₃、OC(＝O)CH₃And C substituted by at least one CN₁-C₃An alkyl group;

R²⁵selected from the group consisting of: hydrogen and C₁-C₃An alkyl group;

aryl represents phenyl or naphthyl;

heteroaryl represents a monocyclic 5-to 6-membered aromatic heterocyclic ring comprising one or more heteroatoms, each independently selected from the group consisting of: o, S and N; or a bicyclic 8-to 12-membered heteroaromatic ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N;

with the proviso that Het does not satisfy formula d (x)

Or a pharmaceutically acceptable addition salt or solvate thereof.

Preferably, R²³Selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl radical、C₃-C₇Cycloalkyl radical, C₁-C₆alkyl-R²⁴、SO₂R²⁴、SO₂N(R²⁴)₂Aryl, heteroaryl, C (═ O) OR²⁴、OR²⁴、C(＝O)R²⁴、C(＝O)N(R²⁴)₂、OC(＝O)N(R²⁴)₂And 4-to 6-membered saturated rings containing one oxygen atom, wherein these C' s₁-C₆Alkyl radical, C₃-C₇Any of the cycloalkyl, aryl, or heteroaryl groups may be optionally substituted with one or more substituents selected from the group consisting of: halogen, OH, CN, OCH₃；

R²⁴Selected from the group consisting of: hydrogen, OH, halogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Cycloalkyl, aryl, heteroaryl, benzyl, and 4 to 6 membered saturated rings containing one oxygen atom, wherein these C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Any of cycloalkyl, aryl, heteroaryl, benzyl may be optionally substituted with one or more substituents selected from the group consisting of: halogen, CF₃、OH、CN、OCH₃And OC (═ O) CH₃。

In a further aspect, the present invention relates to the aforementioned compounds for use in the treatment of RSV infections in warm-blooded animals, preferably humans. In yet another aspect, the invention features a method of treating a viral RSV infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined above. In yet another aspect, the invention resides in the use of a compound as defined above for the manufacture of a medicament for the treatment of RSV infections.

In a further aspect, the invention relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable excipient.

In yet another aspect, the present invention provides a process for the preparation of a compound as defined above.

Detailed description of the invention

Broadly, the present invention is based on the following judicious recognition: compounds of formula (RI) have substantial RSV inhibitory activity of interest.

The present invention will be further described with respect to particular embodiments and with reference to certain examples, but the invention is not limited thereto but only by the claims. When the term "comprising" is used in the description and claims of the present invention, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

Whenever the term "substituted" is used in the present invention, unless otherwise indicated or clear from the context, it is meant to indicate that one or more hydrogens (in particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen) on the atom or group indicated in the expression using "substituted" is replaced by a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound (i.e. a compound that is sufficiently robust to withstand separation from the reaction mixture to a useful degree of purity, and sufficiently robust to withstand formulation with a therapeutic agent).

As used herein, "C" as a group or moiety of a group₁-C₆Alkyl "defines a straight or branched chain saturated hydrocarbon group having from 1 to 6(1, 2, 3, 4, 5 or 6) carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the like.

"C" as a group or part of a group₁-C₁₀Alkyl "defines a straight or branched chain saturated hydrocarbon radical having from 1 to 10 carbon atoms, for exampleA group as defined in item (iv): c₁-C₆Alkyl and heptyl, octyl, nonyl, 2-methylhexyl, 2-methylheptyl, decyl, 2-methylnonyl, and the like.

"C" as a group or part of a group₁-C₄Alkoxy (C)₁-C₄alkyloxy) "or" C₁-C₄Alkoxy (C)₁-C₄alkoxy) "defines O-C₁-C₄Alkyl radical, wherein C₁-C₄Alkyl independently has the meaning given above.

"C" as a group or part of a group₁-C₆Alkoxy (C)₁-C₆alkyloxy) "or" C₁-C₆Alkoxy (C)₁-C₆alkoxy) "defines O-C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl independently has the meaning given above.

The term "C₃-C₇Cycloalkyl "alone or in combination, refers to a cyclic saturated hydrocarbon group having from 3 to 7 carbon atoms. Suitable C₃-C₇Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "- (CR) as used herein⁸R⁹)_m- "defines CR⁸R⁹M repetitions of subgroups, wherein each of these subgroups is defined independently.

Unless otherwise indicated or clear from the context, the terms "halogen" or "halogen" as a group or part of a group are generic to fluorine, chlorine, bromine, iodine.

The terms of the NRCOOR form are the same as N (R) COOR.

Preferred examples of 4-to 6-membered alicyclic rings which may optionally comprise one or more heteroatoms (the one or more heteroatoms being selected from the group consisting of N, S and O) are: cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, glycidylalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl, thiolanyl, piperazinyl, and pyrrolidinyl.

Heteroaryl represents a monocyclic 5-to 6-membered aromatic heterocyclic ring comprising one or more heteroatoms, each independently selected from the group consisting of: o, S and N; or a bicyclic 8-to 12-membered heteroaromatic ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N. Examples of such heteroaryl groups are furanyl, thiophenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, and benzimidazolyl.

It should be noted that the position of a group on any molecular moiety used in these definitions may be anywhere on such moiety, so long as it is chemically stable.

Unless otherwise indicated, the groups used in the definition of variables include all possible isomers. For example, pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

When any variable occurs more than one time in any constituent, each definition is independent.

Hereinbefore and hereinafter, the term "compounds of formula (RI)" or "these compounds of formula (RI)" is meant to include the tautomers and the stereoisomeric forms thereof, as well as the pharmaceutically acceptable addition salts and the solvates thereof.

The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" may be used interchangeably herein above or below.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible compounds consisting of the same atoms bonded by bonds in the same order but having different three-dimensional structures which are not interchangeable, which compounds of formula (RI) may possess.

It will be appreciated that some compounds of formula (RI) may contain one or more chiral centers and exist as stereochemically isomeric forms.

The present invention includes all stereoisomers of the compounds of formula (RI) and tautomers thereof, either as pure stereoisomers or as mixtures of two or more stereoisomers.

Enantiomers are stereoisomers that are non-overlapping mirror images of each other. A1: 1 mixture of enantiomers of a pair is a racemate or racemic mixture. Diastereomers (or diastereomers) are stereoisomers that are not enantiomers, i.e., they are unrelated mirror images. If the compound contains a double bond, these substituents may be in the E or Z configuration. The substituents on the divalent cyclic (partially) saturated groups may have either the cis- (cis-) or trans- (trans-) configuration, e.g., if the compound comprises a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Thus, the present invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof whenever chemically possible.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom may be designated by R or S. Resolved compounds with unknown absolute configuration can be designated (+) or (-), depending on the direction in which they rotate plane polarized light.

When a particular stereoisomer is identified, this means that said stereoisomer is substantially free of other isomers, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Thus, for example, when a compound of formula (RI) is designated as (R), this means that the compound is substantially free of the (S) isomer; for example, when a compound of formula (RI) is designated as E, this means that the compound is substantially free of Z isomer; for example, when a compound of formula (RI) is designated as cis, this means that the compound is substantially free of trans isomer.

Some compounds according to formula (RI) may also exist in their tautomeric form. Such forms, although not explicitly indicated in the above formulas, are also intended to be included within the scope of the present invention.

Unless otherwise mentioned or indicated, the chemical designation of a compound includes the mixture of all possible stereochemically isomeric forms which said compound may possess. The mixture may contain all diastereomers and/or the corresponding isomers having the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds of the present invention in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates of the invention may be obtained by the application of procedures known in the art. The diastereomeric racemates of formula (RI) can be obtained separately by conventional methods.

The absolute stereochemical configuration has not been experimentally determined for some compounds of formula (RI), their tautomers and stereoisomeric forms, and the pharmaceutically acceptable addition salts and solvates thereof, as well as for the intermediates used in their preparation. One of ordinary skill in the art can determine the absolute configuration of such compounds using methods known in the art, such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atoms occurring on the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

The compounds according to the invention therefore inherently include compounds having one or more isotopes of one or more elements and mixtures thereof, includingIncluding radioactive compounds, also known as radiolabeled compounds, in which one or more non-radioactive atoms have been replaced by one of its radioactive isotopes. The term "radiolabeled compound" refers to any compound according to formula (RI) that comprises at least one radioactive atom. For example, a compound may be labeled with a positron or with a gamma-emitting radioisotope. In the case of the radioligand binding technique,³h-atom or¹²⁵The I-atom is the atom of choice to be replaced. For imaging, the most commonly used positron-emitting (PET) radioisotopes are¹¹C、¹⁸F、¹⁵O and¹³n, all of which are accelerator generated and have half-lives of 20, 100, 2 and 10 minutes (min) respectively. Since the half-life of these radioisotopes is so short, it is only feasible to use them in situ in their production in systems with accelerators, thus limiting their use. The most widely used of these are¹⁸F、^99mTc、²⁰¹Tl and 123I. The handling of these radioisotopes, their generation, isolation and incorporation of one molecule is known to the skilled person.

In particular, the radioactive atom is selected from the group consisting of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular, the radioisotope is selected from the group consisting of³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷Br and⁸²br.

For therapeutic use, salts of compounds of formula (RI) are those in which the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

The pharmaceutically acceptable acid addition salts and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt and base addition salt forms which the compounds of formula (RI) are able to form. The pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, oxalic (i.e., oxalic), malonic, succinic (i.e., succinic), maleic, fumaric, malic (hydroxysuccinic), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids.

Conversely, the salt form may be converted to the free base form by treatment with a suitable base.

The compounds of formula (RI) containing an acidic proton can also be converted into their non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example: ammonium salts, alkali metal and alkaline earth metal salts (e.g., lithium, sodium, potassium, magnesium, calcium salts, and the like), salts with organic bases such as benzathine (benzathine), N-methyl-D-glucamine, hydrabamine (hydrabamine) salts, and salts with amino acids such as, for example, arginine, lysine, and the like.

The term solvate includes hydrates, as well as solvent addition forms, which the compounds of formula (RI) as well as their salts are able to form. Examples of such forms are, for example, hydrates, alcoholates and the like.

Certain embodiments are discussed in more detail below without detracting from the general scope of the invention.

These terms as well as others used in the specification are well understood by those of ordinary skill in the art.

Preferred features of the compounds of the invention are now enumerated.

The present invention relates to novel compounds of formula (RI),

or any stereoisomeric form thereof, wherein:

het is a heterocycle of any one of the following formulae (a), (b), (c), (d):

each X is independently C or N; provided that at least two X are C;

R^1a、R^1b、R^1cor R^1dEach independently selected from the group consisting of: H. halogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy, N (R)⁶)₂、CO(R⁷)、CH₂NH₂、CH₂OH、CN、C(＝NOH)NH₂、C(＝NOCH₃)NH₂、C(＝NH)NH₂、CF₃And OCF₃；

When the attached X is N, R^1bOr R^1dIs absent;

each R²Is- (CR)⁸R⁹)_m-R¹⁰；

m is an integer from 0 to 6;

each R³Independently of each otherSelected from the group consisting of: H. halogen, aryl, heteroaryl, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy and CO (R)⁷)；

R⁸And R⁹Each independently selected from the group consisting of: H. c₁-C₁₀Alkyl and C₃-C₇A cycloalkyl group; or R⁸And R⁹Together form a 4-to 6-membered saturated ring, which optionally comprises one or more heteroatoms selected from the group consisting of: n, S and O;

each Z is independently C or N, provided that at least two Z are C;

q and V each independently represent C-O, SO₂Or CR²⁰R²¹；

R²²selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, CF₃、OCH₃、OCF₃And halogen; r²²To a Z other than N;

R²³selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkyl-R²⁴、SO₂R²⁴、SO₂N(R²⁴)₂Aryl, heteroaryl, C (═ O) OR²⁴、OR²⁴、C(＝O)R²⁴、C(＝O)N(R²⁴)₂、OC(＝O)N(R²⁴)₂、P(＝O)-(O-C₁-C₆-alkyl groups)₂、N(R²⁴)₂、NR²⁵C(＝O)OR²⁴、NR²⁵C(＝O)N(R²⁴)₂NR²⁵SO₂R²⁴And 4-to 6-membered saturated rings containing one oxygen atom, wherein the C' s₁-C₆Alkyl radical, C₃-C₇Any of the cycloalkyl, aryl, or heteroaryl groups may be optionally substituted with one or more substituents selected from the group consisting of: halogen, OH, CN, OCH₃；

aryl represents phenyl or naphthyl;

with the proviso that Het does not satisfy formula d (x)

Or a pharmaceutically acceptable addition salt or solvate thereof.

In one embodiment, the present invention relates to compounds of formula (RI)

Or any stereoisomeric form thereof, wherein

Het is a heterocycle of any one of the following formulae (a), (b), (c), (d):

each X is independently C or N; provided that at least two X are C;

R^1a、R^1a、R^1cor R^1dEach independently selected from the group consisting of: H. halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CF₃And OCF₃；

When the attached X is N, R^1bOr R^1dIs absent;

each R2 is- (CR)⁸R⁹)_m-R¹⁰；

m is an integer from 2 to 6;

each R³Is H, halogen or C₁-C₆An alkyl group;

R⁸and R⁹Each independently selected from the group consisting of: h and C₁-C₁₀An alkyl group;

each R¹⁰Independently selected from the group consisting of: H. halogen, OH, CN, CF₂H、CF₃、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) NR⁸R⁹、C(＝O)OR⁸And SO₂R⁸；

Each Z is independently C or N, provided that at least two Z are C;

q and V each independently represent CR²⁰R²¹；

R²⁰and R²¹Is hydrogen;

R²²selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl, CF₃、OCH₃、OCF₃And halogen;

w is selected from the group consisting of: SO (SO)₂C, O and N, wherein this C or N may optionally be substituted by one or more R²³Substitution;

R²⁴Selected from the group consisting of: hydrogen, OH, halogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Cycloalkyl, aryl, heteroaryl, benzyl, and 4 to 6 membered saturated ring containing one oxygen atom, wherein such C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Any of cycloalkyl, aryl, heteroaryl, benzyl may be optionally substituted with one or more substituents selected from the group consisting of: halogen, CF₃、OH、CN、OCH₃、OC(＝O)CH₃And C substituted by at least one CN₁-C₃An alkyl group;

aryl represents phenyl or naphthyl;

heteroaryl is furyl, thiophenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, or benzimidazolyl;

or a pharmaceutically acceptable addition salt or solvate thereof.

Examples of compounds RI according to the present invention are represented by formulas Ia, Ib, Ic and Id, respectively.

In one embodiment, R^1dIndependently selected from the group consisting of: H. halogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy, N (R)⁶)₂、CO(R⁷)、CH₂NH₂、CH₂OH、C(＝NOH)NH₂、C(＝NOCH₃)NH₂、C(＝NH)NH₂、CF₃And OCF₃

Preferably, in any one of the embodiments defined herein, Het does not satisfy formula d (x)

Wherein R is²As defined herein in any one of the embodiments.

In an even more preferred embodiment, Het does not satisfy formula d (y)

Wherein R is^1dAnd R²As defined herein in any one of the embodiments.

In another embodiment, Het is represented by formula (a '), (b'), (c ') or (d'):

wherein at least one X is N. More preferably, for formulas (b ') and (d'), only one X is N.

R^1a、R^1b、R^1cOr R^1dIndependently selected from the group consisting of: h and halogen, more preferably consisting of chlorine, bromine and fluorine. Most preferably chlorine.

The compounds according to the invention have a radical R²I.e., - (CR)⁸R⁹)_m-R¹⁰And wherein m is an integer from 0 to 6, 1 to 4 or 3 or 4.

Preferably R⁸And R⁹Each independently selected from H or C₁-C₆An alkyl group. In one embodiment, R²Is C₁-C₆alkyl-R¹⁰. In a sub-embodiment, R²Is C₃-C₄alkyl-R¹⁰。

Each R¹⁰Independently selected from the group consisting of: H. halogen, OH, CN, CF₂H、CF₃、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (═ O) C₁-C₆Alkyl, C (═ O) C₃-C₇Cycloalkyl, C (═ O) NR⁸R⁹、C(＝O)OR⁸、SO₂R⁸、C(＝O)N(R⁸)SO₂R⁹、C(＝O)N(R⁸)SO₂N(R⁸R⁹)、NR⁸R⁹、NR⁸C(＝O)OR⁹、OC(＝O)R⁸O-benzyl, NR⁸SO₂R⁹、SO₂NR⁸R⁹、SO₂R⁸、OC(＝O)NR⁸R⁹、OC(＝O)NR⁸R¹²、N(R⁸)C(＝O)N(R⁸R⁹)、R¹¹、N(R⁸)C(＝O)OR¹²、OR¹¹、C(＝O)R¹¹And a 4 to 6 membered saturated ring containing one oxygen atom.

In a specific embodiment, R¹⁰Selected from the group consisting of: c₁-C₃Alkyl, H, OH, CN, F, CF₂H、CF₃、SO₂-C₁-C₃Alkyl, SO₂C₃-C₆A cycloalkyl group.

One particular embodiment of the invention relates to compounds of formula RII, RIII, RIV, RV, RVI or RVII;

or any stereoisomeric form thereof, wherein Het, X and R²³As defined in any one of the embodiments described.

In another embodiment of the compounds of formula RI, RII, RIII, RIV, RV or RVI, R²³Selected from the group consisting of: hydrogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₃alkyl-R²⁴、SO₂R²⁴、O-R²⁴Phenyl, pyridyl, pyrimidinyl, pyrazolyl, C (═ O) OR²⁴、C(＝O)R²⁴Wherein these C are₁-C₆Any of alkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl may be optionally substituted with one or more of the following substituents: OCH (OCH)₃Halogen, OH and CN.

General synthetic scheme

Compounds of formula RI, or their pharmaceutically acceptable salts, can be prepared according to the reaction schemes discussed herein below using synthetic methods known in the art of organic chemistry or modifications and derivations well known to those of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by conventional methods known in the art, such as those disclosed in standard reference books. Preferred methods include, but are not limited to, those described below.

During any of the synthetic sequences below, it is necessary and/or desirable to protect sensitive or reactive groups located on any of the molecules involved. This can be achieved by conventional protecting Groups, for example those described in t.w.greene (t.w. green) and p.g.m.wuts (p.g.m. wutz), Protective Groups in Organic Chemistry (protecting Groups in Organic Chemistry), John Wiley & Sons (John Wiley paternity), 1999, which are hereby incorporated by reference.

Unless otherwise indicated, the substituents in these schemes are as defined above. Isolation and purification of the product is accomplished by standard procedures known to those of ordinary skill in the art.

The following scheme is an exemplary process for preparing compounds of formula RI. In the following schemes, the numbers used (including numbers from I to XXVIII) are used to facilitate the assignment of the formulae in these schemes.

The compound of formula (Ia) can be synthesized, for example, using one of the methods shown in scheme 1. In general, coupling of fragment a or B to fragment C results in a derivative of formula (Ia).

Scheme 1 general Synthesis of Compounds of formula (Ia)

An example of suitable "coupling conditions" for reaction of fragment a with fragment C to form a compound of the type of formula (Ia) for method 1 is the Mitsunobu reaction. A suitable solvent for this type of reaction is THF (tetrahydrofuran).

Alternatively (but not limited to), a fragment B type compound (wherein LG is a leaving group, such as a halide, preferably chloro or sulfonate) may be reacted with a fragment C type compound by a base-mediated coupling reaction. (method 2) A possible base for influencing this reaction is, but not limited to, K₂CO₃、Cs₂CO₃Triethylamine and sodium hydride. Suitable solvents for this type of base-mediated coupling, but not limited to, are DMF (dimethylformamide) or THF (tetrahydrofuran).

Fragment a type compounds can be prepared substantially as depicted in scheme 2.

Scheme 2 general Synthesis of fragment A type Compounds

In general, compounds of fragment A type can be prepared by reaction with compounds such as, but not limited to, SOCl₂、PBr₃p-TsCl, MsCl to produce a fragment B type compound.

Scheme 3 general Synthesis of fragment B type Compounds

The fragment C type intermediate of formula (VI) can be prepared as depicted in scheme 4.

Scheme 4 general Synthesis of Compounds of fragment C (VI) type

The synthesis of spiro-2-oxo-indole derivatives and spiro-2-oxo-azaindole derivatives is shown in scheme 4. Intermediates of formula VI can be synthesized using the procedure described in scheme 4. Replacement of (U) of a nitropyridine or nitroaryl of formula I with tert-butyl ethyl malonate in a suitable solvent (e.g. THF or DMF) in the presence of a base (e.g. sodium cyanide or potassium carbonate) ((U) is a halide, preferably fluorine or an alkoxy, preferably methoxy) gives an intermediate of formula (II). Intermediate II is treated with an acid (e.g. trifluoroacetic acid or dry hydrochloric acid) to give intermediate III. The latter can be converted to intermediate V by condensation with a bis-halogen compound IV, preferably bromine, in the presence of a suitable base, such as potassium carbonate, sodium cyanide and the like, in a suitable solvent, such as DMF, THF or the like. The reduction of the nitro group of intermediate V, when it is done stoichiometrically, in the presence of ammonium chloride or tin chloride, in the presence of concentrated hydrochloric acid using iron, gives compound VI directly. Alternatively, the intermediate of formula III may first be reduced catalytically in the presence of a catalyst (e.g. palladium or platinum) using hydrogen in a suitable solvent (e.g. methanol) to give intermediate VII. The latter can be converted to intermediate VIII using hydrochloric acid or the like under acidic conditions in a suitable solvent (e.g., an alcohol such as isopropanol). The condensation of intermediate VIII with a bis-halogen compound IV, preferably chlorine or bromine, is carried out in the presence of a suitable inorganic base, such as potassium carbonate, sodium hydride or the like, in a suitable solvent, such as DMF, THF or the like, or using an organic base, such as sodium hexamethyldisilazide (NaHMDS) or an alkyllithium base, such as nBuLi, in a suitable solvent, such as THF or ether, to give intermediate VI.

Scheme 5 general Synthesis of Compounds of fragment C (VI) type

Alternatively, compounds of formula VI may be prepared (but are not limited to) by the general procedure shown in scheme 5.

Starting material IX can be purchased commercially or prepared using procedures known in the art. Acids X such as Weinreb amide can be activated using standard peptide coupling procedures (e.g., EDCI/HOBT, HATU, DCC, etc.). Once the acid, such as an ester or Weinreb amide, is activated, aniline IX can be added to convert it to intermediate XI.

Reaction of intermediate XI with PG (where PG is a protecting group, such as p-methoxybenzyl, benzyl, t-butoxycarbonyl, methanesulfonyl or toluenesulfonyl) in the presence of a suitable base (such as potassium carbonate, cesium carbonate or sodium hydride) in a suitable solvent (such as DMF or THF) gives intermediate XIII. Intermediate XIV is prepared according to the methods reported in Lee, s. (Lee, S.) and j.f.hartwig (j.f. hartwigh) (2001. j.org.chem. (journalof organic chemistry) 66 (10)): 3402 + 3415. The replacement of (U) ((U) is halogen, preferably bromine) in a solvent (e.g. 1, 4-dioxane) using palladium (II) acetate as catalyst in the presence of a base (e.g. potassium tert-butoxide) and a ligand (e.g. tricyclohexylphosphine) gives intermediate XIV. Removal of the Protecting group in intermediate XIV can be achieved using the methods described in Green (Green) and Wurts (Wutz), Protecting groups in Organic Synthesis3^rdEdition (protecting groups in organic synthesis, third Edition) to give intermediate VI.

Scheme 6 shows a process for the preparation of compounds of formula Ib, wherein R^1b、R²、R²²Q, V, W, X and Z are as defined above.

Referring to scheme 6, compounds of formula Ib can be synthesized by coupling 2-hydroxymethyleneimidazopyridine XV-a with spirooxo-indole or spirooxo-azaindole VI by methods known in the art (e.g., a mitsunobu reaction using, for example, diisopropyl azelate and triphenylphosphine) in a suitable solvent (e.g., DMF or THF). Alternatively, compounds of formula Ib can be prepared by displacement of (LG), wherein (LG) is a leaving group that is a halide, preferably chlorine XV-b, or a sulfonate, such as mesylate XV-c, in the presence of a base, such as sodium hydride, potassium carbonate or cesium carbonate, in a suitable solvent, such as DMF or THF.

Scheme 6

Preparation of Compounds XV-b and XV-c

Treatment of the alcohol XV-a with thionyl chloride provides 2-chloromethylimidazopyridine XV-b. Alternatively, the alcohol XV-a may be converted to intermediate XV-c by reaction with methanesulfonyl chloride in the presence of an organic base (e.g. triethylamine or diisopropylethylamine) in a suitable solvent (e.g. dichloromethane) (scheme 7).

Scheme 7

Compounds of formula XV-a are commercially available or can be obtained, but are not limited to, by the general procedure set forth in scheme 8 (wherein R is^1b、R²X is as defined above). Referring to scheme 8 below, haloheteroaryl XVI, wherein (U) is a halide, preferably fluorine, can be treated with a primary amine of formula XVII in the presence of a suitable base (e.g., potassium carbonate and the like) in a suitable solvent (e.g., ethanol or dichloromethane) at reaction temperatures ranging from room temperature to 100 ℃ to give compounds of formula XVIII. Using the conditions of the prior art (e.g. Pd/C, or other catalysts) in hydrogen or Fe/EtOH/CaCl₂Under the action of para-nitro groupHydrogenation can produce diamines of formula XIX. Alternatively, the conditions of the previous example (e.g. Pd/C or another catalyst) are used under hydrogen atmosphere or Fe/EtOH/CaCl₂Hydrogenation of the nitro group of compound XX then produces a diamine of formula XXI. In a suitable reducing agent (e.g. NaBH (OAc)₃Or Na (CN) BH₃) This is treated with an aldehyde of formula XXII in the presence of a solvent (e.g. dichloromethane, DMF or THF) at about room temperature to give a compound of formula XIX. Treatment of diamine XIX with glycolic acid or esters (like XXV) under strongly acidic conditions (e.g., aqueous hydrochloric acid) at elevated temperatures (e.g., reflux) can form imidazole rings to yield alcohols of formula XV-a.

Alternatively, diamine XIX may be condensed with a dialkoxyacetate of formula XXIV in the presence of acetic acid in a suitable solvent (e.g., methanol) to give the acetal XV-e. The acetal of compound XV-e may be removed with an acid (e.g., hydrochloric acid) to give an aldehyde of formula XV-f. In a suitable solvent (e.g., ethanol or THF), a suitable reducing agent (e.g., NaBH) can be used₄Or LiAlH₄) The resulting aldehyde of formula XV-f is reduced to an alcohol to produce the desired alcohol of formula XV-a. In addition, diamine XIX cyclizes with a dialkyl oxalate of formula XXIII in a suitable solvent (e.g., ethanol) at elevated temperature (with or without microwave heating) to produce an imidazole of formula XV-d. Alternatively, the compounds of formula XV-d can be prepared in a two-step synthesis starting from diamine XIX. First, diamine XIX may be reacted with alkyl trihaloacetimidate, preferably methyl 2, 2, 2-trichloroacetimidate, in an acidic medium, preferably in acetic acid, at a temperature ranging between 25 ℃ and 50 ℃ to yield a compound of formula XV-g. The compound of formula XV-g is then reacted with a metal carbonate, preferably sodium carbonate, in a suitable solvent, for example methanol, resulting in a compound of formula XV-d. Subsequently, in a suitable solvent (for example)E.g. ethanol or THF), using a suitable reducing agent (e.g. NaBH)₄Or LiAlH₄) The compound XV-d may be reduced to the desired alcohol of formula XV-a.

Scheme 8

An alternative route for preparing compounds of type XV-a is depicted in scheme 9. First, diamine XXI can be coupled to alkyl glycolic acid or esters (like XXV) under strongly acidic conditions (e.g., aqueous hydrochloric acid) at elevated temperatures (e.g., reflux) to yield alcohols of formula XXVI. This alcohol may be protected by PG, which is a protecting group such as, but not limited to, trityl, which results in compound XXVII. A suitable solvent for such a reaction may be, but is not limited to, dichloromethane. Treatment of compound XXVII with compound XXVIII (wherein LG is a leaving group such as halide, preferably bromide, or sulfonate) in the presence of a base such as sodium hydride, potassium carbonate, or cesium carbonate in a suitable solvent such as DMF or THF affords compound XV-h. Removal of PG in compound XV-h can be accomplished in the presence of an acid (e.g., hydrochloric acid) in the presence of a solvent (such as, but not limited to, dioxane) to yield compound XV-a.

Scheme 9

The compounds of formula Ic, or their pharmaceutically acceptable salts, can be prepared according to the reaction schemes discussed herein below. Unless otherwise indicated, the substituents in these schemes are as defined above. Isolation and purification of the product is accomplished by standard procedures known to those of ordinary skill in the art.

With reference to scheme 10, compounds of formula IcCompound (wherein R^1c、R²、R³、R²²Q, V, W and Z are as defined above) can be synthesized by methods known in the art (e.g., mitsunobu reaction using diisopropyl azedicarboxylate and triphenylphosphine) by coupling 2-hydroxymethyleneindole (XV-i) with (VI) in a suitable solvent (e.g., DMF or THF). Alternatively, a compound of formula Ic can be prepared by displacement of LG (a leaving group which is a halide, preferably chloro (XV-j)) or a sulfonate, such as methanesulfonate (XV-k)), in the presence of a base, such as sodium hydride, potassium carbonate or cesium carbonate, in a suitable solvent, such as DMF or THF.

Scheme 10

The starting material XXIX for use in the present invention is commercially available or may be synthesized by, but is not limited to, methods known in the art, such as Reisselt synthesis or Fisher synthesis, by reacting such indoles with R in the presence of a base, such as sodium hydride, potassium carbonate or cesium carbonate, in a suitable solvent, such as DMF or THF²Reaction of LG (where LG is a leaving group, e.g. halide, preferably bromide, or sulfonate) gives compound XXX (scheme 11). The conversion of the alkyl ester of compound XXX to the alcohol XV-i can be carried out using a metal hydride, such as lithium aluminium hydride or sodium borohydride, in a suitable solvent, such as THF, methanol or ethanol.

Scheme 11

Treatment of alcohol XV-i with thionyl chloride provides 2-chloromethylindole XV-j. Alternatively, the alcohol XV-i may be converted to intermediate XV-k by reaction with methanesulfonyl chloride in the presence of an organic base (e.g. triethylamine or diisopropylethylamine) in a suitable solvent (e.g. dichloromethane) (scheme 12).

Scheme 12

Scheme 13 shows a process for preparing compounds of formula (Id), wherein R^1d、R²、R³、R²²Q, V, W, X and Z are as defined above.

Scheme 13: general Synthesis of Compounds of formula (Id)

Compounds of formula Id can be synthesized by coupling 2-hydroxymethyleneazaindole XV-l with spirooxo-indole or spirooxo-azaindole VI in a suitable solvent such as DMF or THF by methods known in the art such as a mitsunobu reaction using, for example, diisopropyl azadicarboxylate (DIAD) and triphenylphosphine. Alternatively, compounds of formula Id can be prepared by displacement of LG (wherein LG is a leaving group that is a halide, preferably chloro XV-m, or sulfonate (e.g., mesylate XV-n)) in the presence of a base (such as, but not limited to, sodium hydride, potassium carbonate, or cesium carbonate) in a suitable solvent (e.g., DMF or THF).

Method 1

Method 2

Scheme 14: general Synthesis of XV-l type Compounds

Compound XV-l was prepared according to the method as depicted in scheme 14.

The starting material XXXI used in the present invention may be commercially available according to method 1 or may be synthesized by, but is not limited to, methods known in the art (e.g., lysatel synthesis or fischer synthesis). This compound is reacted with R in the presence of a base (e.g., sodium hydride, potassium carbonate or cesium carbonate) in a suitable solvent (e.g., DMF or THF)²Reaction of LG (where LG is a leaving group such as halide, preferably bromide, or sulfonate) gives compound XXXII. The conversion of the alkyl ester of compound XXXII to alcohol XV-l can be accomplished using a metal hydride (e.g., lithium aluminum hydride or sodium borohydride) in a suitable solvent (e.g., THF or methanol).

Alternatively, XV-l type compounds can also be synthesized as shown in scheme 14, method 2. Commercially available starting material XXXIII is protected by PG, where PG is a protecting group (such as, but not limited to, tosyl), which results in compound XXXIV. A suitable solvent for such reactions may be, but is not limited to, toluene. After metallation of compound XXXIV, it is treated with compound XXXV (wherein the halide is preferably chloro) in a suitable solvent such as, but not limited to, THF to yield compound XXXVI. Removal of PG in compound XXXVI can be carried out in the presence of a base (e.g., potassium carbonate or cesium carbonate) in a suitable solvent (e.g., THF and methanol) to obtain indole XXXVII. Indoles XXXVII with R in the presence of a base (e.g. sodium hydride, potassium carbonate or cesium carbonate) in a suitable solvent (e.g. DMF or THF)²Reaction of-LG (wherein LG is a leaving group, e.g. halide, preferably bromide, or sulfonate) gives compound XXXVIII. The conversion of the alkyl ester of compound XXXVIII to the alcohol XV-l can be carried out using a metal hydride (e.g., lithium aluminum hydride or sodium borohydride) in a suitable solvent (e.g., THF or ethanol).

Scheme 15: general Synthesis of XV-m and XV-n type Compounds

With reagents (like, but not limited to, SOCl)₂、PBr₃p-TsCl, MsCl) on alcohol XV-l provides 2-chloromethylindole XV-m or a compound like XV-n.

The compound of formula (RI) may be converted into the corresponding N-oxide form (following procedures known in the art for converting trivalent nitrogen into its N-oxide form). Generally the N-oxidation reaction can be carried out by reacting the starting material of formula (RI) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides (e.g., sodium peroxide, potassium peroxide); suitable organic peroxides may include peroxy acids such as, for example, peroxybenzoic acid or halogen-substituted peroxybenzoic acids (e.g., 3-chloroperoxybenzoic acid), peroxyalkanoic acids (e.g., peroxyacetic acid), alkyl hydroperoxides (e.g., t-butyl hydroperoxide). Suitable solvents are, for example, water, lower alcohols (e.g. ethanol and the like), hydrocarbons (e.g. toluene), ketones (e.g. 2-butanone), halogenated hydrocarbons (e.g. dichloromethane) and mixtures of such solvents.

All starting materials are commercially available or can be prepared by one of ordinary skill in the art.

Pure stereochemically isomeric forms of the compounds of formula (RI) may be obtained by the application of procedures known in the art. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., countercurrent distribution, liquid chromatography, and the like. Suitable physical separation methods which may advantageously be employed are, for example, selective crystallization and chromatography (e.g. column chromatography).

The compounds of formula (RI) as prepared in the above described processes are typically racemic mixtures of enantiomers which can be separated from each other following art-known resolution procedures. A racemic compound of formula (RI) which is sufficiently basic or acidic can be converted into the corresponding diastereomeric salt form by reaction with a suitable chiral acid or chiral base, respectively. The diastereomeric salt forms are subsequently separated, for example by selective or fractional crystallization, and the enantiomers are liberated therefrom by means of a base or an acid. An alternative way of separating the enantiomeric forms of the compounds of formula (RI) involves liquid chromatography, in particular using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These processes will advantageously employ enantiomerically pure starting materials.

In a further aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (RI) as defined herein or a compound of any embodiment of compounds of formula (RI) as defined herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context is an amount sufficient to prophylactically combat, stabilize or reduce a viral infection, and in particular an RSV viral infection, in an infected subject or a subject at risk of infection. In yet another aspect, the invention relates to a process for preparing a pharmaceutical composition as defined herein, which process comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (RI) as defined herein, or with a compound of any embodiment of compounds of formula (RI) as defined herein.

Thus, the compounds of the present invention, or any embodiments thereof, may be formulated into different dosage forms for administration purposes. As suitable compositions, it is possible to cite all compositions which are often used for systemic administration.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions are in unit dosage forms suitable, in particular, for administration orally, rectally, transdermally, or by parenteral injection. Oral administration is preferred. For example, in preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, and the like, in the case of oral liquid preparations (e.g., suspensions, syrups, elixirs, emulsions, and solutions); or solid carriers in the case of powders, pills, capsules and tablets, such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water in at least a major proportion, although other ingredients may be included to aid solubility, for example. For example, injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier may optionally include penetration enhancers and/or suitable wetting agents, optionally in combination with small proportions of suitable additives of any nature, which do not introduce significant deleterious effects on the skin.

The compounds of the invention may also be administered by such means by means of methods and formulations employed in the art of administration by inhalation or insufflation through the oral cavity. Thus, the compounds of the invention may generally be administered to the lungs in the form of a solution, suspension or dry powder (solution being preferred). Any system developed for delivering solutions, suspensions or dry powders via oral inhalation or insufflation is suitable for administration of the compounds of the present invention.

Accordingly, the present invention also provides a pharmaceutical composition suitable for administration by oral inhalation or insufflation comprising a compound of formula (RI) and a pharmaceutically acceptable carrier. Preferably, the compounds of the invention are administered as a spray or mist via inhalation of a solution.

It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, as well as divided multiple dosage forms thereof.

Compounds of formula (RI) exhibit antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those caused by orthomyxoviruses and paramyxoviruses, and in particular by human and bovine Respiratory Syncytial Virus (RSV). And a plurality of compounds of the invention are active against RSV mutant strains. In addition, many of the compounds of the present invention show good pharmacokinetic profiles and have attractive properties in terms of bioavailability (including acceptable half-life, AUC and peak values) and lack of adverse phenomena (e.g. not fast acting and insufficient tissue retention).

The compounds of the invention were tested for antiviral activity against RSV in vitro as described in the experimental part of the specification and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity of the compounds of the invention against RSV can be demonstrated in a test model using cotton rats, as described by Wyde et al in antiviral research (1998), 38, 31-42).

Due to their antiviral properties, in particular their anti-RSV properties, the compounds of formula (RI) or any embodiment thereof, their tautomers and stereoisomeric forms and pharmaceutically acceptable addition salts and solvates thereof, are useful in the treatment of individuals suffering from viral infections, in particular RSV infections, as well as for the prevention of these infections. In general the compounds of the invention are useful in the treatment of warm-blooded animals infected with viruses, in particular respiratory syncytial virus.

The compounds of the invention or any of its embodiments may therefore be used as medicaments. The use as a therapeutic agent or method comprises systemically administering to a virally infected subject or subject susceptible to viral infection an amount effective against a condition associated with the viral infection, particularly an RSV infection.

The invention also relates to the use of a compound of the invention, or any embodiment thereof, in the manufacture of a medicament for the treatment or prevention of a viral infection, in particular a RSV infection.

Furthermore the present invention relates to a method of treating a warm-blooded animal infected with, or at risk of infection with, a virus, particularly RSV, which comprises administering an anti-virally effective amount of a compound of formula (RI) as defined herein or a compound of any of the embodiments of a compound of formula (RI) as defined herein.

As is well known to those of ordinary skill in the art, the precise dose and frequency of administration depends on the particular compound of formula (RI) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, degree of disorder and general physical condition of the particular patient, as well as other drugs that the individual may take. Furthermore, it is clear that the effective daily amount may be reduced or increased depending on the response of the subject being treated and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.

A combination of another antiviral agent and a compound of formula (RI) may also be used as a medicament. The invention therefore also relates to a product comprising (a) a compound of formula (RI), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral therapy. The different drugs may be combined into a single formulation along with a pharmaceutically acceptable carrier. For example, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha to treat or prevent RSV infection.

The invention will be illustrated hereinafter with reference to the following non-limiting examples.

Experimental part

Synthesis of intermediates

Intermediate 1 b:2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indoline-3, 4 ' -pyran]Synthesis of (E) -2-ketones

Method 1

n-BuLi (108ml, 216mmol, 2M in THF) was added to a solution of oxindole 1a (CAS number: 59-48-3, 11g, 82.6mmol) in THF (1000ml) at-78 ℃. After complete addition, TMEDA (25g, 214.76mmol) was added, maintaining the internal temperature < -70 ℃. After 1h at-78 deg.C bis (2-bromomethyl) ether (CAS number: 5414-19-7, 57.5g, 247.8mmol) was added and the reaction was warmed to ambient temperature. After 48H the reaction is taken with H₂O was quenched and the mixture was quenched in EtOAc and H₂And distributing among the O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using CH₂Cl₂Gradient of 100: 0 to 97: 3 MeOHElution was performed to give 8% of 2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indoline-3, 4 ' -pyran]-2-one 1 b.

Method 2

Oxindole 1a (CAS number: 59-48-3, 40g, 264.659mmol) was added to a solution of LiHMDS (800ml, 800mmol) at-78 ℃. The mixture was stirred at-78 ℃ for 1 hour. Bis (2-bromomethyl) ether (CAS number: 5414-19-7, 61.378g, 264.659mmol) was then added, maintaining the internal temperature < -50 ℃. The reaction was warmed to ambient temperature. After 18 hours the reaction was taken with H₂O was quenched and the mixture was quenched in EtOAc and H₂And distributing among the O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 3: 1 petroleum ether to ethyl acetate to give 10.187g (17%) of 2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indoline-3, 4 ' -pyran]-2-one 1 b.

Intermediate 2 c:2-oxo spiro [ indoline-3, 4' -piperidine]Synthesis of tert-butyl (E) -1' -carboxylate

Step 1

Following method 2 for the synthesis of 2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indoline-3, 4 ' -pyran ] -2-one 1b, 1 ' -benzylspiro [ indoline-3, 4 ' -piperidine ] -2-one 2a was synthesized (59% (52g) yield) using N, N-bis (2-chloroethyl) benzylamine (CAS number: 55-51-6, 70g, 302mmol) instead of bis (2-bromomethyl) ether.

Step 2

A solution of 1 '-benzylspiro [ indolin-3, 4' -piperidin ] -2-one 2a (5g, 17.10mmol, 1eq.) in methanol (100ml) was hydrogenated for 15h at room temperature using 10% Pd/C (0.18g) as catalyst. The catalyst was filtered off and the solvent was evaporated under vacuum. The residue was then recrystallized from DIPE/acetonitrile to give 2.7g (78% yield) of spiro [ indolin-3, 4' -piperidin ] -2-one 2 b.

Step 3

To spiro [ indoline-3, 4' -piperidine at room temperature]-2-Ketone 2b (2.73g, 11.42mmol, 1eq.) in THF (100ml) Boc was added₂O (2.74g, 12.57mmol) and triethylamine (2.38mL, 17.135 mmol). the mixture was stirred at room temperature for 4h then the solvent was evaporated in vacuo and the residue was treated with a mixture of water and DCM the aqueous layer was extracted with DCM (3 ×) and the organic layers were combined, Na was used₂SO₄Drying, filtering and concentrating to give 2-oxospiro [ indoline-3, 4' -piperidine as a white foam]-1' -carboxylic acid tert-butyl ester 2c (4.02g, quantitative yield). 1HNMR (400MHz, DMSO-d6) ppm 1.44(s, 9H)1.56-1.73(m, 4H)3.55-3.79(m, 4H)6.86(dd, J ═ 7.70, 0.40Hz, 1H)6.95(td, J ═ 7.59, 1.10Hz, 1H)7.19(td, J ═ 7.70, 1.10Hz, 1H)7.43(dd, J ═ 6.80, 0.70Hz, 1H)10.41(br.s., 1H); m/z 303.05(M + H)⁺。

Intermediate 3f: 2 '-oxospiro [ azetidine-3, 3' -indoline]Synthesis of tert-butyl (E) -1-carboxylate

Step 1

To 2-bromoaniline (150g, 872mmol, 1eq.) and DMAP (138.5g, 1133mmol, 1.3eq.) in CH₂Cl₂(2500ml) A stirred solution was added N- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (CAS No.: 142253-55-2, 176g, 872mmol, 1eq) in one portion followed by stirring at room temperatureEDCI (217g, 1133mmol, 1.3eq.) was added in one portion. The resulting mixture was stirred at room temperature overnight. Then sequentially adding 10% citric acid aqueous solution, water and saturated Na₂CO₃Aqueous solution and brine, and Na₂SO₄Drying is carried out. After filtration, the solvent was removed under vacuum to give tert-butyl 3- ((2-bromophenyl) carbamoyl) azetidine-1-carboxylate 3b (328g, 85% yield).

Step 2

3- ((2-bromophenyl) carbamoyl) azetidine-1-carboxylic acid tert-butyl ester 3b (307g, 864mmol, 1eq.), 4-methoxybenzyl chloride (203g, 1296mmol, 1.5eq.) and K₂CO₃(358g, 2593mmol, 3eq.) in CH₃The mixture in CN (3000ml) was refluxed overnight. The solution was then filtered and the solid was treated with CH₃CN (1000ml) was washed. The filtrate was concentrated in vacuo and the crude product was triturated in petroleum ether/ethyl acetate (30: 1) to give tert-butyl 3- ((2-bromophenyl) (4-methoxybenzyl) carbamoyl) azetidine-1-carboxylate 3c (380g, 90% yield).

Step 3

In N₂Under the atmosphere, Pd (OAc)₂(2.25g, 10mmol, 0.025eq.) and PCy₃(2.8g, 10mmol, 0.025eq.) was added to a solution of tert-butyl 3- ((2-bromophenyl) (4-methoxybenzyl) carbamoyl) azetidine-1-carboxylate 3c (190g, 400mmol, 1eq.) and tert-BuONa (57.6g, 600mmol, 1.5eq.) in dioxane (960 ml). The reaction was carried out at 90 ℃ under N₂Stir under atmosphere overnight. The solution was then filtered and concentrated under vacuum. The residue was dissolved in CH₂Cl₂In (1), with NH₄Cl, brine and Na₂SO₄Drying is carried out. The solvent was removed under vacuum to give 158g (quantitative yield) of 1 ' - (4-methoxybenzyl) -2 ' -oxospiro [ azetidine-3, 3 ' -indoline]-1-carboxylic acid tert-butyl ester 3 d.

Step 4

CF is prepared by₃SO₃H (119ml, 1350mmol, 3eq.) addition to 1 ' - (4-methoxybenzyl) -2 ' -oxospiro [ azetidine-3, 3 ' -indoline]A mixture of tert-butyl 1-carboxylate 3d (178g, 450mmol, 1eq. crude) in TFA (750 ml). The mixture was stirred at 25 ℃ overnight. The solvent was then removed under vacuum and the residue (78.4g) was used directly in the next step.

Step 5

Spiro [ azetidine-3, 3' -indoline]-2' -Ketone 3e (78.4g, 450mmol, 1eq. crude) in CH₂Cl₂(1500ml) the solution was poured into K₂CO₃(186.6g, 1350mmol, 3eq.) in a mixture of ice water (1500 ml). The aqueous layer was separated and replaced with CH₂Cl₂(3 × 500mL) washing was performed. The aqueous layer was diluted in THF (1500ml) and added (Boc)₂O (98.2g, 450mmol, 1 eq.). The solution was stirred overnight. Then 500mL of ammonia in MeOH (7M) was added dropwise to the above solution. The organic solvent was evaporated under vacuum. Using CH for the aqueous solution₂Cl₂(800 ml. times.3), washed with brine and Na₂SO₄Dried, filtered and then concentrated under vacuum. The resulting residue was washed with tert-butyl methyl ether to give the pure product 2 '-oxospiro [ azetidine-3, 3' -indoline]Tert-butyl 1-carboxylate 3f (44g, 37% yield).

Intermediates 4c and 4 d:(3S) and (3R) -Hydroxyspiro [ cyclobutane-1, 3' -indoline]Synthesis of (E) -2' -ketones

Step 1

In a flask equipped with a condenser, a mixture of benzyl bromide (62.43g, 365.03mmol, 1eq.), 2- (bromomethyl) oxirane (50g, 365.03mmol, 1eq.), and HgCl₂(100mg) the resulting mixture was heated at 155 ℃ for 16 hours with stirring. Subjecting the product to a reactionSeparation was carried out by vacuum distillation through a 30cm Vigreux condenser (110-. The residue was purified by means of a silica gel column chromatography (eluent: dichloromethane) to give 65g of (((1, 3-dibromopropan-2-yl) oxy) methyl) benzene 4 a.

Step 2

Oxindole 1a (20g, 150.210mmol, 1eq.) was dissolved in THF (400ml) and HMPA (40 ml). The reaction mixture was cooled to-78 ℃, then n-BuLi (132.185ml, 330.462mmol, 2.2eq.) was added. The reaction mixture was stirred at-78 ℃ for 1 hour. Then (((1, 3-dibromopropan-2-yl) oxy) methyl) benzene 4a (46.27g, 150.210mmol, 1eq.) was added. The mixture was stirred successively at room temperature for 14 hours, quenched with water and extracted with dichloromethane. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate 10: 1). The product fractions were collected and the solvent was evaporated to give 15g of the desired product: 3- (benzyloxy) spiro [ cyclobutane-1, 3 '-indolin ] -2' -one 4 b.

Step 3

Reacting 3- (benzyloxy) spiro [ cyclobutane-1, 3' -indoline]A mixture of-2' -ketone 4b (15g, 53.699mmol, 1eq) and Pd/C (1.5g) in methanol (150ml) was hydrogenated under a pressure of 30psi for 15 h. The reaction mixture was filtered over a pad of celite, and the pad of celite was washed with CH₃OH washes several times. The combined filtrates were evaporated until dry. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate 3: 1) to give (3) -hydroxyspiro [ cyclobutane-1, 3' -indoline]-racemic mixture of 2' -ketones, its enantiomers 4c and 4d were separated by high performance liquid chromatography (HPLC conditions: column: SYNERGI 250. multidot. 5010. mu.m, flow rate: 80ml/min, mobile phase A: pure water (containing 0.075% TFA), mobile phase B: acetonitrile, gradient: 5% -30% (% B)). The desired fractions were collected and evaporated in vacuo to remove CH₃CN, combined with saturated NaHCO₃The solution makes it alkaline. By CH₂Cl₂The aqueous solution is extracted. Will be provided withThe organic layer was dried, filtered and the solvent was evaporated to give 4.59g of (3S) -hydroxyspiro [ cyclobutane-1, 3' -indoline]-2 '-one 4c and 0.89g of (3R) -hydroxyspiro [ cyclobutane-1, 3' -indoline]-2' -keto 4 d.

Intermediate 5 c:5-fluoro-2-oxospiro [ indoline-3, 4' -piperidine]Synthesis of tert-butyl (E) -1' -carboxylate

5-Fluoroindolin-2-one 5a (35g, 231.576mmol, 1eq.) was added to a solution of LiHMDS (700ml, 700mmol, 3eq.) at-78 ℃. The mixture was stirred at-78 ℃ for 1 hour, then tert-butyl bis (2-chloroethyl) carbamate 5b (56.075g, 231.576mmol, 1eq) was added, maintaining the internal temperature < -50 ℃. The reaction was then warmed to ambient temperature over 2 hours and refluxed overnight. Subjecting the mixture to hydrogenation with H₂O was quenched and the mixture was quenched in EtOAc and H₂And distributing among the O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, Na₂SO₄The resulting residue was purified by high performance liquid chromatography (HPLC conditions: column: Synergi-10 μm, 250 × 50mmI.D, flow rate: 80ml/min, mobile phase A: pure water (containing 0.1% TFA), mobile phase B: acetonitrile, gradient: 35% -65% (% B)) to give 5.003g (7% yield) of 5-fluoro-2-oxospiro [ indoline-3, 4' -piperidine ]]-1' -carboxylic acid tert-butyl ester 5 c.

Intermediate 6a: 5-fluoro-2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indoline-3, 4 ' -pyran]Synthesis of (E) -2-ketones

5-Fluoroindolin-2-one 5a (30g, 198.49mmol, 1.0eq.) was added to LiHMDS (1M in THF, 595.48ml, 595.48mmol, 3.0eq.) at-78 ℃. The mixture was stirred at-78 ℃ for 10 minutes and warmed to 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes, then bis (2-bromomethyl) ether (CAS number: 5414-19-7, 46.03g, 198.49mmol, 1.0eq.) was added. The mixture was stirred at room temperature overnight. Water (300ml) was added to the reaction mixture. The resulting precipitate was filtered off and washed with water to give 5-fluoro-2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indolin-3, 4 ' -pyran ] -2-one 6a (12g, 13% yield).

Intermediate 7b: 4-fluoro-2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indoline-3, 4 ' -pyran]Synthesis of (E) -2-ketones

4-Fluoroindolin-2-one 7a (9.5g, 62.856mmol, 1.0eq.) was added to LiHMDS (1M in THF, 188.568ml, 188.568mmol, 3.0eq.) at-78 ℃. The mixture was stirred at-78 ℃ for 10 minutes and warmed to 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes, then bis (2-bromomethyl) ether (14.577g, 62.856mmol, 1.0eq.) was added. The mixture was stirred at room temperature overnight. Water (300ml) was added to the reaction mixture. The resulting solid was filtered off and washed with water to give 4-fluoro-2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ indolin-3, 4 ' -pyran ] -2-one 7b (1.61g, 12% yield).

Intermediate 8 d:spiro [ cyclopentane-1, 3' -pyrrolo [2, 3-c ]]Pyridine compound]Synthesis of (E) -2 '(1' H) -one

Step 1

To a solution of tert-butyl ethyl malonate (160g, 850mmol) in THF (1600ml) was added NaH (80g, 2118mmol) portionwise at 0 ℃. The mixture was stirred at 15 ℃ for 1h, then 4-chloro-3-nitropyridine (112g, 706mmol) was added portionwise at 0 ℃. The mixture was stirred at 15 ℃ for 1 h. The reaction was quenched with water and 1N HCl was added until pH 5. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, dried and evaporated under vacuum to give 1- (tert-butyl) 3-ethyl 2- (3-nitropyridin-4-yl) malonate 8a (250g) which was used in the next step without further purification.

Step 2

To 1- (tert-butyl) 3-ethyl 2- (3-nitropyridin-4-yl) malonate 8a (crude, 250g, 706mmol) in CH₂Cl₂To a solution in (1500mL) was added TFA (250 mL). After stirring for 14h at 60 ℃, the mixture was evaporated. Then 10% NaHCO was added₃The aqueous solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, dried and evaporated in vacuo to give ethyl 2- (3-nitropyridin-4-yl) acetate 8b (180g), which was used in the next step without further purification.

Step 3

Ethyl 2- (3-nitropyridin-4-yl) acetate 8b (50g, 238mmol), 1, 4-dibromobutane (50g, 238mmol), K in DMF (500ml) was added₂CO₃(100g, 714mmol) and 4A molecular sieves (50g) were stirred at 80 ℃ for 14 h. Then 1N HCl is added and the mixture is taken up with CH₂Cl₂The extraction was performed twice. The organic layer was washed with 10% NaHCO₃The aqueous solution (2 ×), brine (2 ×) were washed, dried and evaporated in vacuo the residue was chromatographed over silica gel (eluent: CH)₂Cl₂Ethyl acetate 10/1) to give 8.4g (15% yield over 3 steps) of ethyl 1- (3-nitropyridin-4-yl) cyclopentane-1-carboxylate 8 c.

Step 4

Will be in CH₃OH (80ml), THF (80ml) and H₂Ethyl 1- (3-nitropyridin-4-yl) cyclopentane-1-carboxylate 8c (8.4g, 31.8mmol), Fe (7g, 127mmol) and NH in O (80ml)₄Cl (7g, 127mmol) was stirred and refluxed for 3h. The mixture was then filtered off and the solvent was evaporated under vacuum. Addition of 10% NaHCO₃And the mixture was extracted with ethyl acetate (3 ×), the combined organic layers were washed with brine, dried, and evaporated in vacuo, the residue was taken up in CH₃CN (2 ×) and the solid was collected and dried to give 4g (67% yield) of spiro [ cyclopentane-1, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-2 '(1' H) -one 8 d.

Intermediate 9c23, 5, 6-Tetrahydropiro [ pyran-4, 3' -pyrrolo [2, 3-c ]]-pyridine]Synthesis of (E) -2 '(1' H) -one

Step 1: synthesis of ethyl 2- (3-aminopyridin-4-yl) acetate (intermediate 9a)

A mixture of ethyl 2- (3-nitropyridin-4-yl) acetate 8b (65g, 309mmol, 90% purity, 1eq.) in methanol (1500ml) was hydrogenated at 20 ℃ C. (atmospheric pressure) over 10% Pd/C (6.5g) as catalyst for 16 h. Absorption of H₂After (3 eq.) the catalyst was filtered off and the filtrate was evaporated under vacuum to give 50g (yield: 90%) of ethyl 2- (3-aminopyridin-4-yl) acetate 9a, which was used in the next step without further purification.

Step 2: synthesis of 1, 3-dihydro-2H-pyrrolo [2, 3-c ] pyridin-2-one (intermediate 9b)

Ethyl 2- (3-aminopyridin-4-yl) acetate 9a (34g, 189mmol, 1eq.) was dissolved in 1.4N HCl (1000ml) and diisopropyl ether (1000 ml). The mixture was stirred at room temperature overnight. Separating the separated organic layer and using H₂And O, washing. The combined aqueous layers were washed with CH₂Cl₂Washed and evaporated to almost dryness. The resulting precipitate was filtered off and dried (vacuum, 60 ℃ C., 2 hours) to give 26g (yield: 94%) of 1, 3-dihydro-2H-pyrrolo [2, 3-c ] as a hydrochloride salt]Pyridin-2-one 9 b.

And step 3: synthesis of 2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3 ' -pyrrolo [2, 3-c ] -pyridin ] -2 ' (1 ' H) -one (intermediate 9c)

Reacting 1, 3-dihydro-2H-pyrrolo [2, 3-c ] at-78 DEG C]Pyridin-2-one 9b (12g, 70.34mmol, 1.05eq.) was added to a solution of 1M LiHMDS in THF (281ml, 281mmol, 4 eq.). The mixture was stirred at-78 ℃ for 10min and warmed to 0 ℃ naturally. After stirring for 0.5h at 0 ℃, 1-bromo-2- (2-bromoethoxy) ethane (15.54g, 66.99mmol, 1eq.) was added. The mixture was warmed to 20 ℃ and stirred at 20 ℃ for 0.5h, then refluxed overnight. After cooling to room temperature, the reaction mixture was successively quenched with 10% NH₄The Cl solution (300ml) was quenched and extracted with ethyl acetate (2 x 300 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and the solvent evaporated under vacuum. The residue was subjected to silica gel column chromatography (eluent: CH)₂Cl₂Methanol from 1: 0 to 20: 1) to give 1.735g (12% yield) of 2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-2 '(1' H) -one 9 c.

Intermediate 10c2 '-oxo-1', 2 '-dihydrospiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]Synthesis of tert-butyl (E) -1-carboxylate

Step 1: synthesis of 1-benzylspiro [ piperidine-4, 3 ' -pyrrolo [2, 3-c ] pyridin ] -2 ' (1 ' H) -one (intermediate 10a)

The hydrochloride salt 1, 3-dihydro-2H-pyrrolo [2, 3-c ] is reacted at-78 DEG C]Pyridin-2-one 9b (160g, 938mmol, 1eq.) was added to a solution of 1M LiHMDS in THF (3751ml, 3751mmol, 4 eq.). After warming to 0 ℃, N-benzyl-2-chloro-N- (2-chloroethyl) ethan-1-amine hydrochloride (218g, 938mmol, 1eq.) was added. The mixture was warmed to 20 ℃ and then refluxed overnight. After cooling to room temperature, the reaction mixture was successively quenched with 10% NH₄Cl solution (300ml) was quenched and washed withEthyl acetate (2 x 300ml) was extracted. The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and the solvent evaporated under vacuum. The residue was subjected to silica gel column chromatography (eluent: CH)₂Cl₂Methanol from 1: 0 to 10: 1) to give 70g (23% yield) of 1-benzylspiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-2 '(1' H) -one 10 a.

Step 2: synthesis of spiro [ piperidine-4, 3 ' -pyrrolo [2, 3-c ] pyridin ] -2 ' (1 ' H) -one (intermediate 10b)

1-Benzylspiro [ piperidine-4, 3' -pyrrolo [2, 3-C ] using 10% Pd/C (50g) as a catalyst]Pyridine compound]A mixture of-2 '(1' H) -ketone 10a (70g, 238.61mmol, 1eq.) in methanol (1000ml) was hydrogenated at 50 ℃ (50psi) for 15H. The catalyst was filtered off and the solvent was evaporated under vacuum. The residue is chromatographed on flash silica gel (eluent: CH)₂Cl₂Ethyl acetate from 1/0 to 0/1) to give 50g (93% yield) of spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-2 '(1' H) -one 10 b.

And step 3: synthesis of tert-butyl 2 '-oxo-1', 2 '-dihydrospiro [ piperidine-4, 3' -pyrrolo [2, 3-c ] -pyridine ] -1-carboxylate (intermediate 10 c).

Spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-2 '(1' H) -one 10b (50g, 246.05mmol, 1eq.) in MeOH (1000ml) was added Boc₂O (64.43g, 295.22mmol, 1.2 eq.). The mixture was stirred at room temperature overnight and then evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: dichloromethane: ethyl acetate from 1: 0 to 0: 1) to give 43.32g (58% yield) of 2-_{Oxo radical}-1 ', 2 ' -dihydrospiro [ piperidine-4, 3 ' -pyrrolo [2, 3-c ]]Pyridine compound]-1-carboxylic acid tert-butyl ester 10 c.

Intermediate 11c2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3' -pyrrolo [3, 2-c ]]Pyridine compound]Synthesis of (E) -2 '(1' H) -one

Step 1: synthesis of 3, 3, 7-tribromo-1, 3-dihydro-2H-pyrrolo [3, 2-c ] pyridin-2-one (intermediate 11a)

Br was added over a period of 20min at room temperature₂(26ml, 507mmol, 4eq.) was added dropwise to 1H-pyrrolo [3, 2-c ]]Pyridine (15g, 127mmol, 1eq.) in H₂O (500ml) and t-BuOH (500 ml). Addition of Br₂Thereafter, the pH of the mixture was about 1. Saturated NaHCO was added slowly and carefully over 30min₃Solution (800ml) and the pH of the mixture was adjusted to 6.5-7. The mixture was stirred for 1h and then filtered off. The resulting solid was further washed with water and co-evaporated with ethanol to give 28.5g (61% yield) of 3, 3, 7-tribromo-1, 3-dihydro-2H-pyrrolo [3, 2-c)]Pyridin-2-one 11 a.

Step 2: synthesis of 1, 3-dihydro-2H-pyrrolo [3, 2-c ] pyridin-2-one hydrobromide (intermediate 11b)

The reaction was carried out in three parallel reactors. 3, 3, 7-tribromo-1, 3-dihydro-2H-pyrrolo [3, 2-C) using Pd/C (14g) as a catalyst]A mixture of pyridin-2-one 11a (28.5g, 76.9mmol, 1eq.) in ethanol (2850ml) was hydrogenated at 30 deg.C (50psi) for 3 h. Absorption of H₂After (3 eq.) the catalyst was filtered off and the filtrate was evaporated in vacuo to give 14g (85% yield) of 1, 3-dihydro-2H-pyrrolo [3, 2-c)]Pyridin-2-one hydrobromide 11 b.

And step 3: synthesis of 2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3 ' -pyrrolo [3, 2-c ] -pyridin ] -2 ' (1 ' H) -one (intermediate 11c)

Reacting 1, 3-dihydro-2H-pyrrolo [3, 2-c ] at-78 DEG C]Pyridin-2-one hydrobromide 11b (11.7g, 54.4mmol, 1.04eq.) was added to a solution of 1M LiHMDS in THF (210ml, 210mmol, 4 eq.). The mixture was stirred at-78 ℃ for 10min and warmed to 0 ℃ naturally. After stirring at 0 ℃ for 0.5h, 1-bromo-2- (2-bromoethoxy) ethane (12.1g, 52.2 mmo) was addedl, 1 eq.). The mixture was warmed to 20 ℃ and then refluxed overnight. The mixture was then cooled to room temperature and saturated NH was used₄The Cl solution (200ml) was quenched, filtered over a pad of celite and the filtrate was extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and the solvent evaporated under vacuum. Dissolving the residue in CH₂Cl₂Methanol (5: 1) and purified by silica gel column chromatography (eluent: CH)₂Cl₂Methanol from 1: 0 to 10: 1) to give a residue, which was further purified with CH₃CN was washed to give 812mg (7% yield) of 2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3' -pyrrolo [3, 2-c ]]Pyridine compound]-2 '(1' H) -one 11 c.

Intermediate 12d2, 6-dimethyl-2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]Synthesis of (E) -2 '(1' H) -one

Step 1: synthesis of Oxydi (propane-2, 1-diyl) dimesylate (intermediate 12b)

Using methanesulfonyl chloride and triethylamine in isopropyl ether, 2' -oxydi (propan-1-ol) 12a (with LiAlH)₄Reduction of diethyl 2, 2' -oxydipropanate as described in Journal of the Chemical Society, PerkinTransactions 1: organic and Bio-Organic Chemistry (journal of the chemical society, Proc. 1: Organic and Bioorganic Chemistry) (1972-1999), (3), 245-50; 1975) to give oxybis (propane-2, 1-diyl) disulfonate 12 b. The obtainment of diethyl 2, 2' -oxydipropanate followed the report reported in Suramolecular Chemistry, 22 (11)&12) 827-837; the program in 2010: by mixing commercially available ethyl 2-hydroxypropionate and ethyl 2-bromopropionate in the presence of NaH in THF.

Step 2: synthesis of 1-bromo-24 (1-bromoprop-2-yl) oxy) propane (intermediate 12c)

To a solution of oxydi (prop-2, 1-diyl) dimethanesulfonate 12b in acetone was added LiBr and the reaction mixture was stirred at reflux until complete to give 1-bromo-2- ((1-bromoprop-2-yl) oxy) propane 12 c.

And step 3: synthesis of 2, 6-dimethyl-2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3 ' -pyrrolo [2, 3-c ] pyridin ] -2 ' (1 ' H) -one (intermediate 12d)

Synthesis of 2, 6-dimethyl-2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3 '-pyrrolo [2, 3-c ] pyridin ] -2' (1 'H) -one 12d following the protocol for the synthesis of 2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3' -pyrrolo [2, 3-c ] pyridin ] -2 '(1' H) -one 9c, 1-bromo-2- ((1-bromoprop-2-yl) oxy) propane 12c was used instead of 1-bromo-2- (2-bromoethoxy) ethane and NaH in DMF was used instead of LiHMDS.

Intermediate 13c2 ', 3', 5 ', 6' -Tetrahydropiro [ pyrrolo [2, 3-c ]]Pyridine-3, 4' -thiopyran]Synthesis of (E) -2(1H) -one 1 ', 1' -dioxide

Step 1: synthesis of bis (2-bromoethyl) sulfane (intermediate 13a)

At-15 ℃ in N₂Next, phosphorus tribromide (7.75g, 0.7eq.) was added to a solution of 2, 2' -thiodiethanol (5g, 40.9mmol) in dry THF. After stirring at-15 ℃ for 30 minutes, the reaction mixture was allowed to warm and stirred at room temperature for 12 hours. Then NaHCO at 0 deg.C₃aq. solution to dilute it. The organic layer was separated, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 10/1, v/v) to give 2.5g (22% yield) of bis (2-bromoethyl) sulfane 13 a.

Step 2: synthesis of 2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ pyrrolo [2, 3-c ] pyridine-3, 4 ' -thiopyran ] -2(1H) -one (intermediate 13b)

Synthesis of 2 ', 3', 5 ', 6' -tetrahydrospiro [ pyrrolo [2, 3-c ] pyridine-3, 4 '-thiopyran ] -2(1H) -one 13b following the protocol for the synthesis of 2, 3, 5, 6-tetrahydrospiro [ pyran-4, 3' -pyrrolo [2, 3-c ] pyridine ] -2 '(1' H) -one 9c, bis (2-bromoethyl) sulfane 13a was used instead of 1-bromo-2- (2-bromoethoxy) ethane and NaH (4eq.) in DMF at 0 ℃ was used instead of LiHMDS.

And step 3: synthesis of 2 ', 3 ', 5 ', 6 ' -tetrahydrospiro [ pyrrolo [2, 3-c ] pyridine-3, 4 ' -thiopyran ] -2(1H) -one (intermediate 13c)

2 ', 3', 5 ', 6' -tetrahydrospiro [ pyrrolo [2, 3-c ]]Pyridine-3, 4' -thiopyran]-2(1H) -one 13b in MeOH/H₂Oxidation of the solution in O with oxone to give 2 ', 3', 5 ', 6' -tetrahydrospiro [ pyrrolo [2, 3-c ]]Pyridine-3, 4' -thiopyran]-2(1H) -one 13 c.

Intermediate 14dSynthesis of 3- (methylsulfonyl) propan-1-amine hydrochloride

Step 1: synthesis of 3- (methylsulfonyl) propan-1-ol (intermediate 14a)

3- (methylthio) propan-1-ol (200g, 1900mmol, CAS 505-10-2) was dissolved in CH₂Cl₂(2000 mL). The mixture was cooled to 0 ℃ and then 85% m-CPBA (970g, 5700mmol, CAS 937-14-4) in water was added in portions, the temperature being maintained between 0 and 5 ℃. After addition, the mixture was allowed to warm to 25 ℃ and stirred for 15 h. The mixture was filtered through a pad of celite and the filtrate was purified by flash column (eluent: petroleum ether: ethyl acetate 3: 1 and then ethyl acetate: methanol 10: 1) to give intermediate 14a (75g, 29%).

Step 2: synthesis of 1-bromo-3- (methylsulfonyl) propane (intermediate 14b)

To intermediate 14a (75g, 543mmol) in CH at 0 deg.C₂Cl₂(750mL) phosphorus tribromide (53.6mL, 570mmol) was added dropwise, the temperature was maintained between 0 and 5 deg.C after addition, the mixture was allowed to warm to 25 deg.C and stirred for 15h, the mixture was poured into ice water, then the organic layer was separated, washed with brine (2 × 500mL), washed with Na₂SO₄Dried, filtered and evaporated in vacuo to yield the title compound 14b (77g, 71%).¹H NMR (400MHz, chloroform-d) ppm2.25-2.40(m, 2H)2.91(s, 3H)3.1-3.2(m, 2H)3.5-3.6(m, 2H).

And step 3: synthesis of N- (diphenylmethylene) -3- (methylsulfonyl) propan-amine (intermediate 14c)

To intermediate 14b (27g, 134mmol) in CH₃CN (60mL) solution Add benzophenone imine (27g, 148mmol) and DIEA (19.6g, 152 mmol.) the mixture is refluxed for 4h and then cooled to room temperature then the mixture is neutralized with 50% aqueous acetic acid at 25 deg.C Water (80mL) is added and the mixture is extracted with ethyl acetate (2 × 300 mL.) the combined organic layers are washed with brine, washed with Na₂SO₄Drying, filtering and evaporating under vacuum the residue is washed with petroleum ether (4 × 100 mL.) the mixture is treated with methyl tert-butyl ether the solid is collected and washed with petroleum ether the filtrate is dried under vacuum and the resulting residue is purified by column chromatography (eluent: CH: eluent: C/l)₂Cl₂Ethyl acetate from 1: 0 to 10: 1) to give the title compound 14c as a white solid (34g, 85%).

And 4, step 4: synthesis of 3- (methylsulfonyl) propan-1-amine hydrochloride (intermediate 14d)

To a solution of intermediate 14c (34g, 113mmol) in dioxane (600mL) was added a solution of 4N HCl/dioxane (120mL, 480mmol) dropwise at 0 ℃. After addition, the mixture was allowed to warm to 25 ℃ and stirred for 15 h. The mixture was filtered. The solid was collected and washed with dioxane to give the title product 14d as a yellow powder (11.5g, 50%).

Intermediate 15e5-chloro-2- (chloromethyl) -1- (3- (methylsulfonyl) propyl) -1H-benzo [ d]Synthesis of imidazole hydrochloride

Step 1: synthesis of 4-chloro-N- (3- (methylsulfonyl) propyl) -2-nitroaniline

A solution of 1-chloro-4-chloro-3-nitrobenzene (7.6g, 35mmol), 3- (methylsulfonyl) -propan-1-amine hydrochloride 14d (6g, 35mmol) and Diisopropylethylamine (DIEA) (13.5g, 105mmol) in ethanol (70mL) was refluxed for 14 h. The mixture was then cooled to 20 ℃ and the resulting precipitate was filtered and washed with ethanol. 11g (94%) of intermediate 15a are obtained as an orange powder.

Step 2: synthesis of 4-chloro-N1- (3- (methylsulfonyl) propyl) benzene-1, 2-diamine

Intermediate 15a (10g, 29.7mmol) in methanol (200mL), EtOAc (200mL) and THF (200mL) was hydrogenated at 20 deg.C (1atm) for 3h using Raney nickel (10g) as a catalyst. Absorption of H₂After (3eq), the catalyst was filtered off and the filtrate was evaporated. 10g (90%) of intermediate 15b were obtained as a black solid.

And step 3: synthesis of 5-chloro-2- (diethoxymethyl) -1- (3- (methylsulfonyl) propyl) -1H-benzo [ d ] imidazole

Intermediate 15b (10g, 29.7mmol) in 24 wt% KOEt (13.5g, 38.5mmol) in ethanol and dimethoxyacetic acid methyl ester (9.2g, 68.31mmol) were stirred and refluxed overnight the mixture was evaporated under vacuum then water (200mL) was added followed by acetic acid to neutralize the mixture was extracted with ethyl acetate (2 × 100mL) the combined organic layers were extracted with saturated NaHCO₃Washed with brine and Na₂SO₄Drying is carried out. The solvent was removed under vacuum to yield 12.3g (90%) of intermediate 15c as a dark oil.

And 4, step 4: synthesis of (5-chloro-1- (3- (methylsulfonyl) propyl) -1H-benzo [ d ] imidazol-2-yl) methanol

Intermediate 15c (12.3g, 29.3mmol) in THF (100mL) was stirred at 20 deg.C for 0.5h until completely dissolved. Concentrated HCl (21mL) and H were then added₂O (42 mL). The mixture was refluxed for 6h, and then cooled to-10 ℃. Addition of CH₃OH (50mL), followed by careful addition of NaBH₄(24g, 629 mmol.) the mixture was stirred at 10 ℃ for 0.5h and concentrated in vacuo, water (200mL) was added, the mixture was extracted with ethyl acetate (2 × 100mL), the combined organic layers were washed with brine and Na₂SO₄The resulting solid was washed with ethyl acetate (2 × 5mL) and dried under vacuum to yield 6.8g (60%) of intermediate 15d as an off-white solid.

¹H NMR(400MHz，DMSO-d₆)ppm 2.20(dq，J＝7.8，7.5Hz，2H)，2.98(s，3H)，3.16-3.24(m，2H)，4.42(t，J＝7.4Hz，2H)，4.73(d，J＝6.0Hz，2H)，5.73(t，J＝5.8Hz，1H)，7.42(dd，J＝8.7，1.9Hz，1H)，7.63(d，J＝8.5Hz，1H)，7.79-7.83(m，1H)。

Step 5

To a solution of alcohol 15d (363mg, 1.414mmol) in 30mL dichloromethane was added dropwise a solution of thionyl chloride (336mg, 2eq) in 10mL dichloromethane. The reaction mixture was stirred at 45 ℃ for 1 hour. It was then concentrated in vacuo to give the desired intermediate 15e as HCl salt (440mg, 99%), which was used as such in the next step.

Intermediate 16a(5-bromo-1- (3- (methylsulfonyl) propyl) -1H-benzo [ d]Synthesis of (E) -imidazol-2-yl) methanol

(5-bromo-1- (3- (methyl)Sulfonyl) propyl) -1H-benzo [ d]Synthesis of imidazol-2-yl) methanol 16a follows for the synthesis of (5-chloro-1- (3- (methylsulfonyl) propyl) -1H-benzo [ d]Imidazol-2-yl) methanol 15d, using 1-bromo-4-fluoro-3-nitrobenzene (7.6g, 35mmol) instead of 1-chloro-4-fluoro-3-nitrobenzene in the first step. 6.8g of the desired product 16a are obtained as an off-white solid.¹H NMR(400MHz，DMSO-d₆)ppm 2.20(dq，J＝7.8，7.5Hz，2H)，2.98(s，3H)，3.16-3.24(m，2H)，4.42(t，J＝7.4Hz，2H)，4.73(d，J＝6.0Hz，2H)，5.73(t，J＝5.8Hz，1H)，7.42(dd，J＝8.7，1.9Hz，1H)，7.63(d，J＝8.5Hz，1H)，7.79-7.83(m，1H)；m/z＝347&349(M + H) + Br pattern.

Intermediate 17bSynthesis of (5-chloro-1- (3- (methylsulfonyl) propyl) -1H-indol-2-yl) methanol

Step 1: synthesis of ethyl 5-chloro-1- (3- (methylsulfonyl) propyl) -1H-indole-2-carboxylate (intermediate 17a)

Ethyl 5-bromo-1H-indole-2-carboxylate (2.3g, 8.6mmol) was dissolved in DMF (50 mL). The mixture was stirred at room temperature and then a suspension of 60% sodium hydride in mineral oil (0.52g, 12.8mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then 1-bromo-3- (methylsulfonyl) propane 14b (2.6g, 12.8mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was poured into ice/water solution and extracted with ethyl acetate. The organic layer was washed with MgSO₄Dried and concentrated to give a crude brown oil. The crude product was purified by column chromatography using dichloromethane/methanol to give the title compound 5-chloro-1- (3- (methylsulfonyl) propyl) -1H-indole-2-carboxylic acid ethyl ester 17a (3.2g, 96%) as a white solid. 344(M + H) is given M/z⁺。

Step 2: synthesis of (5-chloro-1- (3- (methylsulfonyl) propyl) -1H-indol-2-yl) methanol (intermediate 17b)

To a solution of intermediate 17a (3.2g, 8.24mmol) in THF (100mL) was added lithium aluminum hydride (2M solution in THF, 5.2mL, 10.4mmol) at room temperature, the resulting mixture was stirred at room temperature overnight, the reaction mixture was quenched by the addition of ethyl acetate and ethanol, the resulting mixture was poured into ice/water solution and then filtered over celite, the aqueous layer was extracted with ethyl acetate (3 × 50mL), the combined organic extracts were washed with brine (100mL), MgSO₄It was dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane/methanol as eluent to give the desired product (5-chloro-1- (3- (methylsulfonyl) propyl) -1H-indol-2-yl) methanol 17b (2.5g, 88%) as a white solid. 302(M + H) M/z⁺。

Intermediate 18cSynthesis of 4- (5-chloro-2- (hydroxymethyl) -1H-indol-1-yl) -butyronitrile

Step 1: synthesis of ethyl 5-chloro-1- (3-cyanopropyl) -1H-indole-2-carboxylate (intermediate 18a)

Ethyl 5-chloroindole-2-carboxylate (33.55g, 150mmol) was dissolved in acetonitrile (600mL) and stirred at room temperature. Cesium carbonate (73.31g, 225mmol) was then added and stirring was continued for 30 minutes. 4-bromobutyronitrile (18.83mL, 180mmol) was added in small portions over one hour and stirring was continued at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane and washed with water. The organic layer was washed with MgSO₄It was dried, filtered and evaporated to give 43.5g (99% yield) of ethyl 5-chloro-1- (3-cyanopropyl) -1H-indole-2-carboxylate 18a, which was used as such in the next step. M/z 290(M + H)⁺。

Step 2: synthesis of 5-chloro-1- (3-cyanopropyl) -1H-indole-2-carboxylic acid (intermediate 18b)

Ethyl 5-chloro-1- (3-cyanopropyl) indole-2-carboxylate 18a (43.61g, 149.97mmol) was dissolved in 1, 4-dioxane (850mL) and stirred at room temperature. A solution of lithium hydroxide (10.78g, 450mmol) in distilled water (150mL) was then added. After stirring at room temperature overnight, the reaction mixture was evaporated until dryness. The residue was dissolved in 500mL of water and neutralized with aqueous 1N hydrochloric acid (450 mL). The white precipitate was filtered off and dried in vacuo to give 39.8g (quantitative yield) of 5-chloro-1- (3-cyanopropyl) -1H-indole-2-carboxylic acid 18 b. M/z 262(M + H)⁺。

And step 3: synthesis of 4- (5-chloro-2- (hydroxymethyl) -1H-indol-1-yl) butyronitrile (intermediate 18c)

5-chloro-1- (3-cyanopropyl) indole-2-carboxylic acid 18b (39.4g, 149.98mmol) and Huningbase (Hunigs base) (51.69mL, 300mmol) were dissolved in tetrahydrofuran (550mL) and stirred under nitrogen at-10 ℃. A solution of isobutyl chloroformate in tetrahydrofuran (50ml) was then added dropwise and stirring was continued for one hour at-10 ℃ and for one hour at ambient temperature. Sodium borohydride (17.02g, 450mmol) was then added portionwise at-10 ℃ and stirred for one hour, then distilled water (200mL) was carefully added to the reaction mixture and stirring continued for another hour at room temperature under nitrogen atmosphere. The mixture was neutralized with 10% citric acid in water and then extracted with ethyl acetate. The organic layer was washed with MgSO₄Dried, filtered and evaporated. The residue was purified on silica with a gradient of heptane/dichloromethane/methanol 50/50/0- > 0/100/0- > 0/99/1. The corresponding fractions were evaporated to yield 23.9g (64% yield) of 4- (5-chloro-2- (hydroxymethyl) -1H-indol-1-yl) butyronitrile 18c as a white powder. M/z 248(M + H)⁺。

Intermediate 19b(5-chloro-1- (4, 4, 4-trifluorobutyl) -1H-imidazo [4, 5-b)]Synthesis of pyridin-2-yl) methanol

Step 1: 6-chloro-N³- (4, 4, 4-trifluorobutyl) -pyridine-2, 3-diamine (intermediate 19a)

6-chloropyridine-2, 3-diamine (5g, 34.82mmol) was dissolved in dichloromethane (200mL), and acetic acid (20 drops) and 4, 4, 4-trifluorobutanal (4.38g, 34.8mmol) were added. The resulting mixture was stirred for 30 minutes, and then sodium triacetoxyborohydride (22.14g, 104.5mmol) was added. The reaction mixture was stirred at room temperature overnight and 50% Na was added dropwise₂CO₃The solution was allowed to stand until gas evolution ceased. The organic layer was separated over MgSO₄Dried, filtered and evaporated until dry. The residue was purified by column chromatography using heptane/EtOAc 7/3 to pure EtOAc. Recovery of intermediate 6-chloro-N as a white solid³- (4, 4, 4-trifluorobutyl) -pyridine-2, 3-diamine 19a, and dried in vacuo overnight (6.16g, 70%). 254(M + H)⁺。

Step 2: synthesis of (5-chloro-1- (4, 4, 4-trifluorobutyl) -1H-imidazo [4, 5-b ] pyridin-2-yl) methanol (intermediate 19b)

A mixture of intermediate 19a (5.68g, 22.46mmol) and 2-hydroxyacetic acid (4.27g, 56.2mmol) was stirred at 150 ℃ for 4 hours. The mixture was allowed to cool to room temperature and treated carefully with 3N hydrochloric acid. Making the mixture alkaline with ammonia water, and using CH₂Cl₂Extraction was performed (300 mL). The organic layer was washed with MgSO₄Dried and evaporated to dryness. The residue was purified by column chromatography on silica using CH₂Cl₂Purification to EtOAc gave 4.27g (65%) of (5-chloro-1- (4, 4, 4-trifluorobutyl) -1H-imidazo [4, 5-b) as a brown solid]Pyridin-2-yl) methanol 19 b. 294(M + H) with M/z⁺。¹HNMR (400MHz, chloroform-d) ppm 1.00(s, 2H), 1.12-1.23(m, 2H), 1.83-1.99(m, 2H), 2.12-2.31(m, 2H), 2.91(spt, J ═ 3.50Hz, 1H), 4.38-4.54(m, 2H), 5.38(s, 2H), 7.13(dd, J ═ 5.27, 0.50Hz, 1H), 7.27(d, J ═ 8.28Hz, 1H), 7.61(d, J ═ 8.53Hz, 1H), 8.36(d, J ═ 5.27Hz, 1H), 8.77(s, 1H).

Intermediate 20e(5-chloro-1- (4-fluorobutyl) -1H-pyrrolo [3, 2-b)]Synthesis of pyridin-2-yl) methanol

Step 1: synthesis of 2-bromo-6-chloropyridin-3-amine (intermediate 20a)

Bromine (24.86g, 155.57mmol) was added to a solution of 6-chloropyridin-3-amine (20.00g, 155.57mmol) and sodium acetate (25.52g, 311.14mmol) in acetic acid (383 ml). The reaction mixture was stirred at room temperature for 1 hour. The acetic acid was then evaporated. The residue was dissolved in EtOAc and taken up with saturated aqueous Na₂CO₃Water and brine. The organic layer was washed with MgSO₄Dried, filtered and evaporated to yield 32.20g of the desired product 20a (99.8%). M/z 206.96(M + H)⁺Cl + Br pattern.

Step 2: synthesis of 5-chloro-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid (intermediate 20b)

2-oxopropanoic acid (36.22g, 411.31mmol), palladium (II) acetate (7.74g, 34.15mmol) and Et₃N (69.11g, 682.94mmol) was added to a solution of 2-bromo-6-chloropyridin-3-amine 20a (32.20g, 155.21mmol) and TPP (35.83g, 136.59mmol) in dry DMF (300 ml). The reaction mixture was stirred at 100 ℃ overnight. The solvent was then evaporated, water was added and the aqueous layer was washed with EtOAc. The aqueous layer was acidified with concentrated HCl. The precipitate was filtered off and dried, yielding 25.21g of the desired product 20b (82.6%). M/z 197.1(M + H)⁺And Cl mode.

And step 3: synthesis of methyl 5-chloro-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate (intermediate 20c)

Reacting 5-chloro-1H-pyrrolo [3, 2-b)]Pyridine-2-carboxylic acid 20b (25.20g, 128.18mmol) was added to a refluxing mixture of sulfuric acid (20ml) and methanol (400 ml). The mixture was refluxed overnight. The mixture was then evaporated and cold NaHCO was added₃The solution was brought to basic pH. Filtering the precipitateTaken off and dried, yielding 16.15g of the desired product 20c (59.8%). M/z 211.17(M + H)⁺And Cl mode.

And 4, step 4: synthesis of methyl 5-chloro-1- (4-fluorobutyl) -1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate (intermediate 20d)

To 5-chloro-1H-pyrrolo [3, 2-b ]]A solution of pyridine-2-carboxylic acid methyl ester 20c (2.9g, 12.2mmol) in DMF (50mL) was added cesium carbonate (4g, 12.2mmol) and 1-bromo-4-fluorobutane (1.3mL, 12.2mmol) in that order. The resulting mixture was heated at 60 ℃ overnight. The reaction mixture was allowed to cool to room temperature, then poured into ice water and the product extracted 3 times with DCM. The combined organic layers were washed with Na₂SO₄Dried, filtered and evaporated to give the title product 20d as a pale yellow solid. The product was used as such in the next step. 313(M + H) M/z⁺And Cl mode.

And 5: synthesis of (5-chloro-1- (4-fluorobutyl) -1H-pyrrolo [3, 2-b ] pyridin-2-yl) methanol (intermediate 20e)

To 5-chloro-1- (4-fluorobutyl) -1H-pyrrolo [3, 2-b ] at-75 deg.C]A solution of 1M lithium aluminum hydride (11.96mL, 11.96mmol) in dry THF (100mL) was added to a solution of pyridine-2-carboxylic acid methyl ester 20d (3.82g, 10.8 mmol). The cooling bath was then removed and the reaction mixture was held at room temperature for 3 hours. Addition of EtOAc followed by saturated NH₄And (4) Cl solution. The mixture was stirred for 30 min. The organic layer was washed with Na₂SO₄Drying, filtering and evaporating to give a yellow oil which is purified by column chromatography to give the desired product (5-chloro-1- (4-fluorobutyl) -1H-pyrrolo [3, 2-b)]Pyridin-2-yl) methanol 20e (2.8g, 98%). 257(M + H) M/z⁺And Cl mode.

Intermediates 21b and 21c4- (5-chloro-2- (hydroxymethyl) -1H-benzo [ d]Imidazol-1-yl) butyronitrile (intermediate 21b) and 4- (6-chloro-2- (hydroxymethyl) -1H-benzo [ d]Synthesis of imidazol-1-yl) butyronitrile (intermediate 21c)

Step 1: synthesis of (5-chloro-1H-benzo [ d ] imidazol-2-yl) methanol (intermediate 21a)

A mixture of 4-chlorobenzene-1, 2-diamine (105g, 736mmol, 1eq.) and glycolic acid (112g, 2eq.) in xylene (1500 mL.) was stirred at 150 ℃ for 4 hours. The mixture was then cooled to 60 ℃ and treated with 3N HCl (480ml) and then basified to pH 7-8 by addition of aqueous ammonia. The mixture was filtered and the solid was collected with H₂O and methyl t-butyl ether were washed to give 123g (82% yield) of (5-chloro-1H-benzo [ d ]]Imidazol-2-yl) methanol 21 a.

Step 2: synthesis of 4- (5-chloro-2- (hydroxymethyl) -1H-benzo [ d ] imidazol-1-yl) butyronitrile (intermediate 21b) and 4- (6-chloro-2- (hydroxymethyl) -1H-benzo [ d ] imidazol-1-yl) butyronitrile (intermediate 21c)

Reacting (5-chloro-1H-benzo [ d ]]Imidazol-2-yl) methanol 21a (500mg, 2.738mmol, 1eq.), 4-bromobutyronitrile (466mg, 1.15eq.), cesium carbonate (1.338g, 1.5eq.), and potassium iodide (45mg, 0.1eq.) in acetonitrile (5mL) were refluxed overnight. The mixture was then cooled and filtered. The filtrate was evaporated in vacuo and the residue treated with ethyl acetate (30ml) and brine (20 ml). The separated organic layer was dried (Na)₂SO₄) Filtered and the solvent evaporated under vacuum. The residue is purified by column chromatography (eluent: CH)₂Cl₂Methanol from 1: 0 to 15: 1) to yield 732mg (54%) of a mixture comprising two regioisomers (regio-isomers) 21b and 21c (1/1 ratio). This mixture was further separated by SFC to provide the pure regioisomer 21 b.

Intermediate 22c3-aminospiro [ cyclobutane-1, 3' -indoline]Synthesis of (E) -2' -ketones

Step 1

To alcohol 4c or 4d (5g, 26.425mmol) in DCM was added Doss-martin periodinane (16.8g, 1.5eq) at 0 ℃. After 16h at room temperature, the reaction mixture was filtered off and NaHCO was added₃(50mL) of the saturated solution and NaS₂O₃Solution (50 mL). After stirring for 30min, the organic layer was separated and washed with Na₂SO₄Dried and concentrated in vacuo to provide the desired spiro [ cyclobutane-1, 3' -indoline as a racemic mixture]2', 3-dione 22a, which was used in the next step without further purification.

Step 2

Ketone 22a (2g, 10.68mmol), sodium carbonate (3.397g, 3eq) and hydroxylamine hydrochloride (1.485g, 2eq) in EtOH/H₂The mixture in O (1/1, 100mL) was heated at 100 ℃ for 1 h. The reaction mixture was then concentrated in vacuo and the resulting precipitate was filtered off, washed with water, and dried in a vacuum oven to give 3- (hydroxyimino) spiro [ cyclobutane-1, 3' -indoline]-2' -keto 22b (1.5g, 69% yield).

Step 3

Oxime 22b 7N NH in MeOH (50mL) over Raney Nickel (435mg, 1eq)₃Hydrogenation was carried out overnight. The solution was then filtered over celite (decalite) and concentrated in vacuo. The crude product was then purified in Et₂Trituration in O, and the resulting solid was filtered off and dried in an oven to give the aminospiro [ cyclobutane-1, 3' -indoline as a mixture of two isomers]-2' -keto 22c (1.3g, 85% yield).

Synthesis of the end product

Compound 11' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-indol-2-yl } methyl) -2 '-oxo-1', 2 '-dihydro-1H-spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]-pyridine]Synthesis of tert-butyl (E) -1-carboxylate

To { 5-chloro-1- [3- (methylsulfonyl) propyl group at room temperature]-1H-indol-2-yl } methanol 17b (4000mg, 13.25mmol), 2 '-oxo-1', 2 '-dihydro-1H-spiro [ piperidine-4, 3' -pyrrolo [2, 3-c)]Pyridine compound]-suspension of tert-butyl 1-carboxylate 10c (4423mg, 14.58mmol) and TPP (4172mg, 15.91mmol) in dry THF (92ml) DIAD (3.869ml, 19.88mmol) was added and the reaction mixture was stirred overnight. THF was evaporated and the crude product was purified by column chromatography. After evaporation of the relevant fractions, the residue was recrystallized from water. The crystals formed were filtered off and washed with some water and heptane to give the title product 1 as a beige powder (1231mg, Y ═ 15.8%).¹H NMR(400MHz，DMSO-d₆)ppm1.45(s，9H)1.80(t，J＝5.50Hz，4H)2.03-2.16(m，2H)3.01(s，3H)3.14-3.25(m，2H)3.60-3.83(m，4H)4.37(t，J＝7.48Hz，2H)5.20(s，2H)6.37(s，1H)7.16(dd，J＝8.69，2.09Hz，1H)7.53(d，J＝1.98Hz，1H)7.55(d，J＝8.80Hz，1H)7.69(d，J＝4.62Hz，1H)8.33(d，J＝4.84Hz，1H)8.39(s，1H)；m/z＝587.23(M+H)⁺+ Cl mode.

Compound 21' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-indol-2-yl } methyl) spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]Synthesis of (E) -2 '(1' H) -one

To the reaction product of 1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-indol-2-yl } methyl) 2 '-oxo-1', 2 '-dihydro-1H-spiro [ piperidine-4, 3' -pyrrolo [2, 3-c)]-pyridine]-1-Carboxylic acid tert-butyl ester 1(3.39g, 3.75mmol) in DCM (20ml) TFA (2.872ml, 37.53mmol) was added and the mixture was stirred at room temperature overnight. Then water was added and the reaction mixture was taken over Na₂CO₃Basification of the solution. The DCM was evaporated and the remaining aqueous suspension was stirred for 3 hours. The solid was filtered off, washed with water, and then purified by column chromatography to obtain a pink transparent oil. Will produceTrituration in ether gave the desired product 2 as a pink powder, which was dried in a vacuum oven (466mg, 23.7%);¹H NMR(400MHz，DMSO-d₆)ppm 1.62-1.88(m，4H)2.02-2.18(m，2H)2.93-3.07(m，5H)3.11-3.24(m，4H)4.38(t，J＝7.48Hz，2H)5.19(s，2H)6.33(s，1H)7.16(dd，J＝8.69，2.09Hz，1H)7.50-7.58(m，2H)7.64(d，J＝4.84Hz，1H)8.29-8.42(m，2H)；m/z＝487.27(M+H)⁺+ Cl mode.

Compound 31' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-indol-2-yl } methyl) -1- (methylsulfonyl) spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]Synthesis of (E) -2 '(1' H) -one

1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl) ester]-1H-indol-2-yl } methyl) spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-2 '(1' H) -one 2(500mg, 0.72mmol) was dissolved in DCM (5mL) and methanesulfonyl chloride (0.11mL, 1.44mmol) and Et were added₃N (0.30ml, 2.16 mmol). The mixture was stirred at room temperature for 30 minutes. Water was added and the reaction mixture was taken over Na₂HCO₃Basification of the solution. The product was extracted with DCM (2 times). The organic layer was washed with MgSO₄Dried, filtered and evaporated. The residue was purified by preparative column chromatography to give the desired product 3(172mg, Y42.4%).¹H NMR(400MHz，DMSO-d₆)ppm 1.88-2.16(m，6H)3.00(s，3H)3.01(s，3H)3.17-3.26(m，2H)3.41-3.51(m，2H)3.52-3.64(m，2H)4.38(t，J＝7.48Hz，2H)5.20(s，2H)6.38(s，1H)7.16(dd，J＝8.69，2.09Hz，1H)7.53(d，J＝1.98Hz，1H)7.56(d，J＝8.80Hz，1H)7.70(d，J＝4.84Hz，1H)8.36(d，J＝4.84Hz，1H)8.41(s，1H)；m/z＝565.03(M+H)⁺+ Cl mode.

Compound 41' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzimidazol-2-yl } methyl) -2 ' -oxo-1 ', 2 ' -dihydro-1H-spiro[ azetidine-3, 3' -indoles]Synthesis of tert-butyl (E) -1-carboxylate

Reacting 2 '-oxo-1', 2 '-dihydro-1H-spiro [ azetidine-3, 3' -indole]-1-Carboxylic acid tert-butyl ester 3f (1000mg, 3.65mmol) was dissolved in dry DMF (23ml) and 5-chloro-2- (chloromethyl) -1- [3- (methylsulfonyl) propyl]-1H-benzimidazole hydrochloride 15e (1304mg, 3.64mmol) and cesium carbonate (3563mg, 3.56 mmol). The reaction mixture was stirred at room temperature overnight. Ice water was added and the mixture was stirred overnight. The solid formed was filtered off and washed with water and a small amount of ether. After drying in a vacuum oven, the desired product 4 was obtained as a pink solid (1695mg, Y81.5%).¹H NMR(400MHz，DMSO-d₆)ppm 1.44(s，9H)2.10-2.21(m，2H)3.00(s，3H)3.19-3.25(m，2H)4.03-4.19(m，4H)4.47(t，J＝7.48Hz，2H)5.22(s，2H)7.13(td，J＝7.48，0.88Hz，1H)7.19(d，J＝7.70Hz，1H)7.27-7.34(m，2H)7.65-7.69(m，3H)；m/z＝559.21(M+H)⁺+ Cl mode.

Compound 51' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzimidazol-2-yl } methyl) spiro [ azetidine-3, 3' -indole]Synthesis of (E) -2 '(1' H) -one

To 1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl) at room temperature]-1H-benzimidazol-2-yl } methyl) -2 '-oxo-1', 2 '-dihydro-1H-spiro [ azetidine-3, 3' -indole]-1-carboxylic acid tert-butyl ester 4(1.5g, 2.63mmol) in DCM (20mL) was added TFA (1mL, 5 eq.). After 12h, more TFA (2mL) was added and the mixture was stirred for 24 h. The reaction was then passed over Na₂CO₃-the solution is neutralized. DCM was evaporated and the solid formed was filtered off and washed with water and ether to give a grey colourTFA salt of the desired product 5 as a powder (1.303g, Y86.5%).¹H NMR(400MHz，DMSO-d₆)ppm2.11-2.26(m，2H)3.01(s，3H)3.19-3.28(m，2H)4.16-4.35(m，4H)4.48(t，J＝7.48Hz，2H)5.22(s，2H)7.18-7.28(m，2H)7.32(dd，J＝8.80，1.98Hz，1H)7.36(td，J＝7.90，0.88Hz，1H)7.66(d，J＝1.98Hz，1H)7.69(d，J＝8.80Hz，1H)7.85(d，J＝6.82Hz，1H)9.27(br.s.，2H)；m/z＝459.18(M+H)⁺+ Cl mode.

Compound 61' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzimidazol-2-yl } methyl) -1- (2-hydroxy-2-methylpropanoyl) spiro [ azetidine-3, 3' -indole]Synthesis of (E) -2 '(1' H) -one

1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl) in dry DMF (4ml) was added at room temperature]-1H-benzimidazol-2-yl } methyl) spiro [ azetidine-3, 3' -indole]-2 '(1' H) -one 5(300mg, 0.50mmol), 2-hydroxy-2-methylpropionic acid (117mg, 1.12mmol) and Et₃N (0.482ml, 2.80mmol) was stirred vigorously while DECP (0.188ml, 1.12mmol) was added dropwise. Stirring was continued in a closed vessel at ambient temperature for 1 hour. Some ice was added followed by saturated sodium bicarbonate solution. The resulting suspension was stirred for 2 hours and the solid was filtered off and further purified by column chromatography eluting with a gradient of DCM and MeOH. All pure fractions were evaporated to give a pale yellow foam which was further triturated in ether and filtered off to give the title product 6(121mg, Y42.0%).¹H NMR(400MHz，DMSO-d₆)ppm 1.31(s，3H)1.33(s，3H)2.11-2.24(m，2H)3.00(s，3H)3.18-3.27(m，2H)4.02-4.20(m，2H)4.47(t，J＝7.37Hz，2H)4.55-4.75(m，2H)5.23(s，2H)5.25(s，1H)7.11-7.23(m，2H)7.27-7.35(m，2H)7.60-7.65(m，1H)7.65-7.71(m，2H)；m/z＝545.41(M+H)⁺+ Cl mode.

Compound 71' - ({ 5-chloro)-1- [3- (methylsulfonyl) propyl]-1H-benzimidazol-2-yl } methyl) -1- (pyridin-3-yl) spiro [ azetidine-3, 3' -indole]Synthesis of (E) -2 '(1' H) -one

1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl) ester]-1H-benzimidazol-2-yl } methyl) spiro [ azetidine-3, 3' -indole]A mixture of-2 '(1' H) -one 5(259mg, 0.43mmol) and 3-bromopyridine (0.084ml, 0.87mmol) in toluene (1.5ml) was degassed with nitrogen over 5 minutes. Then Pd is added₂(dba)₃(10mg, 0.01mmol), NaOtBu (52mg, 0.54mmol), and BINAP (20mg, 0.03 mmol). The mixture was degassed again and then heated in a μ -wave oven for 2 hours at 125 ℃. The reaction mixture was evaporated, taken up in water and extracted with DCM. Some insoluble material was filtered off. The two phases were separated and the organic layer was washed with Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was purified by preparative column chromatography to give the title product 7(35mg, Y ═ 15.0%).¹H NMR(400MHz，DMSO-d₆)ppm 2.09-2.21(m，2H)3.00(s，3H)3.19-3.27(m，2H)4.13-4.27(m，4H)4.47(t，J＝7.48Hz，2H)5.26(s，2H)6.99(ddd，J＝8.25，2.75，1.32Hz，1H)7.12-7.17(m，1H)7.20(d，J＝7.70Hz，1H)7.25(dd，J＝8.14，4.62Hz，1H)7.28-7.36(m，2H)7.64-7.71(m，3H)7.98(d，J＝2.64Hz，1H)8.02(dd，J＝4.62，1.32Hz，1H)；m/z＝536.07(M+H)⁺+ Cl mode.

Compound 81' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzimidazol-2-yl } methyl) -1- (2-hydroxy-2-methylpropyl) spiro [ azetidine-3, 3' -indole]Synthesis of (E) -2 '(1' H) -one

To the reaction product of 1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzimidazol-2-yl } -methyl) spiro [ azetidine-3, 3' -indole](ii) -2 '(1' H) -Ketone 5(150mg, 0.33mmol) in EtOH (20mL) and DMF (5mL) Et was added₃N (0.227ml, 1.63mmol) and 2, 2-dimethyloxacyclopropane (0.087ml, 0.98 mmol). The reaction mixture was heated at 60 ℃ for 40 hours. The heating was stopped and ice water was added. EtOH was evaporated. The solid formed was filtered and washed with water and ether to give a grey powder. After drying in a vacuum oven, the crude product was purified by column chromatography to give the title product 8 as a white solid (74mg, Y ═ 39.2%).¹H NMR(400MHz，DMSO-d₆)ppm 1.12(s，6H)2.06-2.17(m，2H)2.46(s，2H)2.99(s，3H)3.17-3.25(m，2H)3.54(q，J＝7.04Hz，4H)4.12(s，1H)4.45(t，J＝7.37Hz，2H)5.21(s，2H)7.10-7.17(m，2H)7.23-7.28(m，1H)7.30(dd，J＝8.58，1.98Hz，1H)7.64-7.68(m，2H)7.73-7.77(m，1H)；m/z＝531.09(M+H)⁺+ Cl mode.

Compound 91' - [ [ 5-chloro-1- (3-methylsulfonylpropyl) benzimidazol-2-yl]Methyl radical]-1- (2, 2, 2-trifluoroethyl) spiro [ azetidine-3, 3' -indoline]Synthesis of (E) -2' -ketones

1' - [ [ 5-chloro-1- (3-methylsulfonylpropyl) benzimidazol-2-yl]Methyl radical]Spiro- [ azetidine-3, 3' -indoline]A solution of (e) -2' -ketone 5(573mg, 1mmol), 2, 2, 2-trifluoroethyl 1, 1, 2, 2, 3, 3, 4, 4, 4-nonafluorobutane-1-sulfonate (382mg, 1mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.52mL, 3mmol) in dioxane (10mL) was stirred at 50 ℃ over the weekend. The reaction mixture was then allowed to cool to ambient temperature. The mixture was evaporated to dryness and the residue was crystallized from ethanol/acetonitrile 100/1. The off-white crystals were collected by filtration and dried in vacuo to give the title product 9(420mg, 77%).¹H NMR(360MHz，DMSO-d₆)ppm 2.13(m，J＝8.1Hz，2H)，3.00(s，3H)，3.22(m，J＝15.4Hz，2H)，3.42(q，J＝10.0Hz，2H)，3.64(d，J＝7.0Hz，2H)，3.75(d，J＝7.0Hz，2H)，4.46(t，J＝7.1Hz，2H)，5.22(s，2H)，7.07-7.22(m，2H)，7.31(d，J＝8.8Hz，1H)，7.27(d，J＝7.3Hz，1H)，7.62-7.79(m，3H)；m/z＝540.99(M+H)⁺+ Cl mode; melting point: 200.68 deg.C.

Compound 12(1R, 3R) -1' - ((5-chloro-1- (3- (methylsulfonyl) propyl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -3-hydroxyspiro [ cyclobutane-1, 3' -indoline]Synthesis of (E) -2' -ketones

(3R) -1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzimidazol-2-yl } methyl) -3-hydroxy spiro [ cyclobutane-1, 3' -indole]Synthesis of (E) -2 ' (1 ' H) -one 12 following the reaction conditions for the Synthesis of Compound 4, using (3R) -hydroxyspiro- [ cyclobutane-1, 3 ' -indoline]-2 ' -keto-4 d instead of 2 ' -oxo-1 ', 2 ' -dihydro-1H-spiro [ azetidine-3, 3 ' -indole]Tert-butyl 1-carboxylate 3f and a solid is obtained in light pink with a yield of 82%.¹H NMR(400MHz，DMSO-d₆)ppm 2.08-2.21(m，2H)2.27-2.38(m，2H)2.60-2.72(m，2H)2.99(s，3H)3.19-3.27(m，2H)4.46(t，J＝7.48Hz，2H)4.50-4.62(m，1H)5.20(s，2H)5.45(d，J＝6.82Hz，1H)7.05-7.14(m，2H)7.18-7.25(m，1H)7.30(dd，J＝8.80，1.98Hz，1H)7.45-7.55(m，1H)7.63-7.71(m，2H)；m/z＝474.05(M+H)+；MP＝209.84℃。

Compound 104(1R, 3R) -1' - ((5-chloro-1- (3- (methylsulfonyl) propyl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -2 '-oxospiro [ cyclobutane-1, 3' -indoline]Synthesis of methyl (E) -3-ylcarbamate

Reacting (3R) -1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl)]-1H-benzeneImidazol-2-yl } methyl) -3-hydroxyspiro [ cyclobutane-1, 3' -indole]A solution of-2 ' (1 ' H) -one 12(100mg, 0.205mmol), triethylamine (0.142mL, 1.023mmol) and N, N ' -disuccinimidyl carbonate (210mg, 0.82mmol) in DCM (1.5mL) was stirred at room temperature for 2H. A solution of 2M methylamine (1.54mL, 3.07mmol) was then added and the reaction mixture was then stirred for a further 30 minutes. It was then concentrated and the residue was purified by silica gel chromatography (using a gradient of MeOH in DCM (0 to 5%)) to give 110mg (99% yield) of 1' - ({ 5-chloro-1- [3- (methylsulfonyl) propyl) as a pale pink solid]-1H-benzimidazol-2-yl } methyl) -2 '-oxo-1', 2 '-dihydrospiro [ cyclobutane-1, 3' -indole]-3-ylcarbamic acid methyl ester 104. 1H NMR (400MHz, DMSO-d)₆)ppm 2.16(quin，J＝7.59Hz，2H)2.45-2.52(m，2H)2.59(d，J＝4.62Hz，3H)2.73-2.82(m，2H)3.00(s，3H)3.20-3.27(m，2H)4.47(t，J＝7.37Hz，2H)5.22(s，2H)5.25-5.35(m，1H)7.07-7.16(m，3H)7.22-7.28(m，1H)7.28-7.33(m，1H)7.48-7.54(m，1H)7.64-7.70(m，2H)；m/z＝531.15(M+H)+。

Compound 117N- [ (1' - { [ 5-chloro-1- (3-cyanopropyl) -1H-indol-2-yl)]Methyl } -2 '-oxo-1', 2 '-dihydro-1H-spiro [ azetidine-3, 3' -indole]-1-yl) sulfonyl]Synthesis of acetamide

4- { 5-chloro-2- [ (2 '-oxospiro [ azetidine-3, 3' -indole)]-1 '(2' H) -yl) methyl]A mixture of-1H-indol-1-yl } butyronitrile 59(588mg, 1.133mmol) and sulfamide (326mg, 3.4mmol) in dioxane (20mL) was heated in a microwave oven at 160 ℃ for 40 minutes. After cooling, the reaction mixture was concentrated in vacuo and the residue was recrystallized from methanol. This crude material (212mg, 0.438mmol) was then redissolved in DCM (30mL) and acetic anhydride (82. mu.L, 0.876mmol), N-methylmorpholine (96. mu.L, 0.876mmol) and DMAP (3.7mg, 0.03mmol) were added. After 3h at room temperature, two more equivalents of acetic anhydride and N-methylmorpholine were added, andthe reaction mixture was stirred overnight. Then quenched with MeOH (1mL) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (using a gradient of MeOH in DCM (0 to 5%)) to give 140mg (58% yield) of N- [ (1' - { [ 5-chloro-1- (3-cyanopropyl) -1H-indol-2-yl) as a white solid]Methyl } -2 '-oxo-1', 2 '-dihydro-1H-spiro [ azetidine-3, 3' -indole]-1-yl) sulfonyl]Acetamide 117. 1H NMR (400MHz, DMSO-d)₆)ppm1.93-2.04(m，1H)，2.16(s，3H)，2.58(t，J＝7.4Hz，2H)，4.25(d，J＝8.1Hz，2H)，4.27-4.35(m，2H)，4.40(d，J＝8.4Hz，2H)，5.12(s，2H)，6.38(s，1H)，7.08(d，J＝7.9Hz，1H)，7.11-7.21(m，2H)，7.26-7.35(m，1H)，7.48-7.55(m，2H)，7.58(d，J＝7.0Hz，1H)，10.84-10.85(m，0H)，11.75(br.s.，2H)；m/z＝524(M-H)^-；MP＝182.85℃。

Compound 115(1' - { [ 5-chloro-1- (3-cyanopropyl) -1H-benzimidazol-2-yl]Methyl } -2 '-oxo-1', 2 '-dihydro-1H-spiro [ piperidine-4, 3' -pyrrolo [2, 3-c)]Pyridine compound]Synthesis of diethyl (1-yl) phosphonate

Mixing 4- (5-chloro-2- ((2 '-oxo spiro [ piperidine-4, 3' -pyrrolo [2, 3-c))]Pyridine compound]-1 '(2' H) -yl) methyl) -1H-benzo [ d]A mixture of imidazol-1-yl) butyronitrile hydrochloride 84(500mg, 0.985mmol), diethoxy cyanophosphonate (0.448mL, 3eq) and triethylamine (0.411mL, 3eq) in DMF (10mL) was stirred at room temperature for 2 hours. The mixture was then extracted with DCM and washed with water. The organics were then washed with MgSO₄Dried, concentrated in vacuo and purified by silica gel chromatography (using a gradient: MeOH (0 to 10%) in DCM), followed by preparative HPLC (stationary phase: RPVydac Denali C18-10 μm, 200g, 5cm, mobile phase: 0.25% NH)₄HCO₃Solution in water, CH₃CN) to give 320mg (56% yield) (1' - { [ 5-chloro-1- (3-cyanopropyl) -1H-benzimidazol-2-yl)]Methyl } -2'-oxo-1', 2 '-dihydro-1H-spiro [ piperidine-4, 3' -pyrrolo [2, 3-c ]]Pyridine compound]-1-yl) phosphonic acid diethyl ester 115. 571(M + H) M/z⁺。

Intermediates 148 and 1494- (2- (((1r, 3r) -3-amino-2 '-oxospiro [ cyclobutane-1, 3' -indoline)]-1' -yl) methyl) -5-chloro-1H-benzo [ d]Imidazol-1-yl butyronitrile and 4- (2- (((1s, 3s) -3-amino-2 '-oxospiro [ cyclobutane-1, 3' -indoline)]-1' -yl) methyl) -5-chloro-1H-benzo [ d]Synthesis of imidazol-1-yl) butyronitrile

To a solution of amine 22c (194mg, 1.035mmol) in dry DMF (10mL) was added sodium hydride (79mg, 2eq) at room temperature. After 30 minutes, 4- (5-chloro-2- (chloromethyl) -1H-benzo [ d ] was added]Imidazol-1-yl) butyronitrile hydrochloric acid (332mg, 1eq) and the reaction mixture was stirred at room temperature for 2h then the crude product was filtered off and the filtrate was concentrated under vacuum the crude product obtained was further passed through a preparative SFC (stationary phase: Chiralcel Diacel OJ 20 × 250mm, mobile phase: CO: flow: Secrete₂Having 0.2% iPrNH₂iPrOH) to give pure isomers 148(85mg, 19% yield) and 149(158mg, 35% yield).

For a 148:¹H NMR(400MHz，DMSO-d₆)ppm 1.91-2.10(m，2H)2.13-2.27(m，2H)2.55-2.71(m，4H)3.78(quin，J＝8.03Hz，1H)4.38(t，J＝7.59Hz，2H)5.20(s，2H)7.08(td，J＝8.10，1.54Hz，2H)7.20(td，J＝7.70，1.32Hz，1H)7.29(dd，J＝8.58，1.98Hz，1H)7.53-7.70(m，3H)；m/z＝420[M+H]⁺. For 149:¹H NMR(400MHz，DMSO-d₆)ppm1.80-2.20(m，4H)2.20-2.34(m，2H)2.36-2.47(m，2H)2.59(t，J＝7.48Hz，2H)3.77-3.95(m，1H)4.36(t，J＝7.50Hz，2H)5.21(s，2H)7.00-7.14(m，2H)7.16-7.25(m，1H)7.29(dd，J＝8.58，1.98Hz，1H)7.55(d，J＝6.82Hz，1H)7.64(d，J＝8.80Hz，1H)7.66(d，J＝1.76Hz，1H)。

compounds 143 and 1441- ((1s, 3s) -1' - ((5-chloro-1- (3-cyanopropyl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -2 '-oxospiro [ cyclobutane-1, 3' -indoline]-3-yl) -3-isopropylurea and 1- ((1r, 3r) -1' - ((5-chloro-1- (3-cyanopropyl) -1H-benzo [ d)]Imidazol-2-yl) methyl) -2 '-oxospiro [ cyclobutane-1, 3' -indoline]Synthesis of (E) -3-isopropyl urea (E) -3-yl urea.

4- (2- (3-amino-2 '-oxo spiro [ cyclobutane-1, 3' -indoline)]-1' -yl) methyl) -5-chloro-1H-benzo [ d]A mixture of imidazol-1-yl) butyronitrile (racemic mixture, 500mg, 1.191mmol), isopropyl 2-isocyanate (0.14mL, 1.2eq) and DIPEA (3.175mL, 2eq) was stirred at room temperature for 1 h. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC (stationary phase: RP Vydac Denali C18-10 μm, 200g, 5cm, mobile phase: 0.25% NH in water₄HCO₃Solution of CH₃CN) to give a pure mixture of enantiomers which were subsequently purified by preparative SFC (stationary phase: chiralpak Diacel AD 30 × 250mm, mobile phase: CO 2₂Having 0.2% iPrNH₂MeOH) to yield 240mg (40% yield) of 143 and 122mg (20% yield) of 144.

The compounds in the following table were synthesized according to the protocol described above and methods known to the chemist of ordinary skill in the art.

Antiviral activity

Black 96-well clear bottom microtiter plates (Corning, Amsterdam, Netherlands) were filled with serial 4-fold dilutions of compounds in a final volume of 50. mu.l of medium (phenol red-free RPMI medium, 10% FBS, 0.04% gentamicin (50mg/ml) and 0.5% DMSO) using a custom-made robotic system repeated twice, then 100. mu.l of Hela cell suspension (5 × 10) in medium (Belgium) was filled with a multimanifold dispenser (Thermo Scientific), Erembodegem (Elmenbodegem, Belgium)⁴Cells/ml) was added to each well followed by 50 μ Ι rgrsv224(MOI ═ 0.02) virus in culture medium. The rgRSV224 virus is an engineered virus comprising an additional GFP gene (Hallak et al, 2000) and is derived from NIH (Beehive)Sesda, MD (Maryland, USA) is licensed. Media, virus-infected and mock-infected controls were included in each test. Cells were incubated at 5% CO₂Incubations were carried out at 37 ℃ in atmosphere. Three days after virus exposure, virus replication was quantified by measuring GFP expression in cells by MSM laser microscopy (Tibotec (tibottac), belsse, belgium). EC (EC)₅₀Is defined as the concentration at which 50% inhibition of GFP expression occurs. In parallel, the compounds were incubated for three days in a set of white 96-well microtiter plates (Corning) and the cytotoxicity of the compounds in the hela cells was determined by measuring the ATP content of the cells using the ATPlite kit (PerkinElmer (platinum elemer), Zaventem (zafterm), belgium) according to the manufacturer's instructions. CC (challenge collapsar)₅₀Is defined as the concentration at which 50% cytotoxicity occurs. SI calculation as CC₅₀/EC₅₀。

Reference to the literature

Hallak (Hiragak) LK，Spillmann D，Collins (corins) PL，Peeples (pierce) Pers) MEGlycosaminoglycan replication for respiratory syncytial virus infection J.Virol. ("J.Virol") 740, 10508-.

Claims

1. A compound of formula (RI),

or any stereoisomeric form thereof, wherein:

het is a heterocycle of any one of the following formulae (b) and (d):

each X is independently C or N; provided that at least two X are C;

R^1bor R^1dEach independently selected from H and halo, and when Het is of sub-formula (b), at least one R^1bThe substituents are halogen;

when the attached X is N, R^1bOr R^1dIs absent;

each R²Is- (CR)⁸R⁹)_m-R¹⁰；

m is an integer from 0 to 6;

each R³Independently selected from H and CO (R)⁷)；

Each R⁷Is NH₂；

R⁸And R⁹Each independently selected from H and C₁-C₁₀An alkyl group;

each R¹⁰Independently selected from H, halogen, OH, CN, CF₂H、CF₃、C₁-C₆Alkyl and SO₂R⁸；

Each Z is independently C or N, provided that at least two Z are C;

q and V each independently represent CR²⁰R²¹；

p and s independently represent an integer from 0 to 3, wherein the sum of p and s is at least 2, and the carbon atom marked with ×, when p = 0 or s = 0, is directly attached to W;

R²⁰and R²¹Is hydrogen;

R²²is hydrogen;

w is selected from SO, SO₂S, C, O and N, wherein the C or N may optionally be substituted with one or more R²³Substitution;

R²³selected from hydrogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆alkyl-R²⁴、SO₂R²⁴、SO₂N(R²⁴)₂Aryl, heteroaryl, C (= O) OR²⁴、OR²⁴、C(=O)R²⁴、OC(=O)N(R²⁴)₂、P(=O)-(O-C₁-C₆-alkyl groups)₂、NR²⁵C(=O)OR²⁴、NR²⁵C(=O)N(R²⁴)₂Wherein said C is₁-C₆Any of alkyl, aryl or heteroaryl groups may be optionally substituted with one or more substituents selected from halogen or OH;

R²⁴selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (= O) C₁-C₆Alkyl, aryl, heteroaryl, benzyl, and one 4-to 6-membered saturated ring containing one oxygen atom, wherein said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, C (= O) C₁-C₆Any of alkyl, aryl, heteroaryl, benzyl may optionally be substituted with one or more substituents selected from halogen, CF₃、OH、CN、OCH₃Or OC (= O) CH₃Substituted with the substituent(s);

R²⁵selected from hydrogen and C₁-C₃An alkyl group;

aryl represents phenyl;

heteroaryl represents a monocyclic 5-to 6-membered aromatic heterocyclic ring comprising one or more heteroatoms each independently selected from O, S and N; or a bicyclic 8-to 12-membered heteroaromatic ring containing one or more heteroatoms each independently selected from O, S and N;

or a pharmaceutically acceptable addition salt thereof.

2. A compound according to formula (RI) as claimed in claim 1, wherein Het is represented by formula (a) or (c):

R^1aor R^1cEach independently selected from H and halo, and when Het is of sub-formula (a), at least one R^1aThe substituents are halogen;

and R is²And R³Is as defined in claim 1.

3. A compound according to formula (RI) as claimed in claim 1, wherein Het is represented by formula (b ') or (d'):

wherein at least one X is N;

and R is^1b、R^1dAnd R²Is as defined in claim 1.

4. A compound according to formula (RI) as claimed in claim 2, wherein Het is represented by formula (a ') or (c'):

and R is^1a、R^1cAnd R²Is as defined in claim 2.

5. The compound of claim 3, wherein for formulas (b ') and (d'), one X is N.

6. The compound of claim 1 or 2, wherein R^1a、R^1b、R^1cOr R^1dEach independently selected from chlorine, bromine and fluorine.

7. The compound of claim 6, wherein R^1a、R^1b、R^1cOr R^1dEach of which is chlorine.

8. The compound of claim 1In which R is²Is- (CR)⁸R⁹)_m-R¹⁰And wherein m is an integer from 1 to 4 and R⁸And R⁹Each independently selected from H or C₁-C₆An alkyl group.

9. The compound of claim 1, wherein R²Is C₁-C₆alkyl-R¹⁰。

10. The compound according to claim 1, wherein the compound has the formula RII, RIII, RIV, RV, RVI or RVII;

or any stereoisomeric form thereof, wherein Het, X and R²³Is as defined in claim 1.

11. The compound as claimed in claim 1, wherein the compound is

Or a pharmaceutically acceptable addition salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 11.

13. Use of a compound as claimed in any one of claims 1 to 11, or a pharmaceutical composition as claimed in claim 12, in the manufacture of a medicament for the treatment of respiratory syncytial virus infection.