HK1244786B - Indole and azaindoles derivatives and their use in neurodegenerative diseases - Google Patents

Description

Indole and azaindole derivatives and their use in treating neurodegenerative diseases

Related applications

This patent application claims priority to U.S. Provisional Patent Application No. 62/091,855, filed December 15, 2014, and U.S. Provisional Patent Application No. 62/117,128, filed February 17, 2015, both of which are hereby incorporated by reference in their entirety.

Technical Field

The present invention relates to indole compounds that are useful as P2X7 antagonists. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using the compositions to treat various diseases.

Background of the Invention

The P2X7 receptor is a ligand-gated ion channel receptor that belongs to the Purinergic receptor family. The receptor is expressed on many cell types associated with the immune and nervous systems. In the nervous system, P2X7 is expressed on microglia, oligodendrocytes, and astrocytes. Transient activation of the P2X7 receptor channel with its endogenous ligand, ATP, leads to several downstream events, including the processing and release of the proinflammatory cytokine IL1-β from monocytes and macrophages. P2X7 activation also plays an important role in regulating glutamate release and uptake in astrocytes.

The P2X7 receptor is an ion channel-type receptor activated by ATP that can regulate neurotransmission in the central nervous system (CNS) by activating presynaptic and/or postsynaptic P2X7 receptors on central and peripheral neurons and glia (Deuchars SA et al., J. Neurosci. 21: 7143-7152, (2001), Kanjhan R et al., J. Comp. Neurol. 407: 11-32 (1997), Le KT et al., Neuroscience 83: 177-190 (1998)). Activation of the P2X7 receptor on cells of the immune system (macrophages, mast cells, and lymphocytes) leads to the release of interleukin-1β (IL-1β), giant cell formation, degranulation, and shedding of L-selectin. After intraperitoneal injection of lipopolysaccharide (LPS), ATP can increase the local release and processing of IL-1 in rats through a P2X7 receptor-mediated mechanism (Griffiths et al., J. Immunology Vol. 154, pages 2821-2828 (1995); Solle et al., J. Biol. Chemistry, Vol. 276, pages 125-132, (2001)).

Antagonism of the P2X7 receptor is considered an attractive therapeutic approach for the treatment of multiple sclerosis and Alzheimer's disease because of its important role in suppressing CNS inflammation and supporting neuroprotection.

Summary of the Invention

It has been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective P2X7 antagonists. The compounds are represented by the general formula I:

or a pharmaceutically acceptable salt thereof, wherein X, Y, R ¹ and R ² have the meanings defined and described in the Examples herein.

The compounds of the present invention and pharmaceutically acceptable compositions thereof can be used to treat various diseases, disorders or symptoms associated with P2X7 activity, including those described herein.

Detailed Description of Certain Embodiments

1. General Definition of the Compounds of the Invention

In certain embodiments, the present invention provides P2X7 antagonists. In some embodiments, such compounds include those represented by the formula described herein, or a pharmaceutically acceptable salt thereof, wherein the variables are defined and described.

2. Compounds and Definitions

The compounds of the present invention include those summarized above and further described by the classes, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th edition). In addition, general principles of organic chemistry are described in "Organic Chemistry" (Thomas Sorrell, University Science Books, Sausalito: 1999) and "March's Advanced Organic Chemistry" (5th edition, eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001), the entire contents of which are incorporated herein by reference.

As used herein, the term "aliphatic" or "aliphatic group" refers to a substituted or unsubstituted straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, with a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in some embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, a "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic _C3 - _C7 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, with a single point of attachment to the rest of the molecule. Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

The term "lower alkyl" refers to a C _1-4 straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

The term "lower haloalkyl" refers to a C _1-4 straight or branched chain alkyl group containing one or more halogen atoms.

The term "heteroatom" refers to one or more oxygen, sulfur, nitrogen, or phosphorus (including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR ⁺ (as in N-substituted pyrrolidinyl)).

As used herein, the term "unsaturated" refers to a moiety having one or more units of unsaturation.

As used herein, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated linear or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, alkynylene chains, which are linear or branched as defined herein.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -( _CH2 ) _n- , where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups. The term "alkynylene" refers to a divalent alkynyl group. Substituted alkynylene chains are groups containing at least one triple bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "halogen" refers to F, Cl, Br or I.

The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "arylhydroxy" or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, and the like, which optionally include one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms "heteroaryl" and "heteroaryl-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroarhydroxy", refer to radicals having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; 6, 10, or 14 pi electrons shared in the cyclic array; and 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups formed by the fusion of a heteroaromatic ring with one or more aromatic, cycloaliphatic, or heterocyclic rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the term "heteroaryl ring" or "heteroaromatic group," any of which includes rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted.

As used herein, the terms "heterocycle,""heterocyclyl,""heterocyclicgroup," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen," when used with respect to a ring atom of a heterocycle, includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺ NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that forms a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclic group," and "heterocyclic moiety" are used interchangeably herein and also include groups in which a heterocyclic ring is fused to one or more aromatic, heteroaromatic, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclic ring. A heterocyclic group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

As described herein, certain compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogen atoms of the designated moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogen atoms explicitly or implicitly indicated in the structure (e.g., at least ) and at least . Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the specified group, the substituents at each position may be the same or different. Combinations of substituents envisioned by the present invention are preferably those that result in stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not undergo substantial alteration when subjected to conditions that allow their manufacture, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atoms of the “optionally substituted” group are independently deuterium; halogen; –(CH ₂ ) _0-4 R°; –(CH 2 ) _0-4 OR°; –O(CH ₂ ) _0-4 R°, –O–(CH _{2 ) 0-4} C(O)OR°; –(CH ₂ ) _0-4 CH(OR°) ₂ ; –(CH ₂ ) _{0-4 SR} °; –(CH ₂ ) _0-4 PH, which may be substituted by R°; –(CH ₂ ) _0-4 O(CH ₂ ) _0-1 PH, which may be substituted by R°; –CH═CHPH, which may be substituted by R°; –(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl, which may be substituted by R°; –NO ₂ ; –CN; –N ₃ ; –(CH ₂ ) _0–4 N(R°) ₂ ;–(CH ₂ ) _0–4 N(R°)C(O)R°;–N(R°)C(S)R°;–(CH ₂ ) _0–4 N(R°)C(O)NR° ₂ ;-N(R°)C(S)NR° ₂ ;–(CH ₂ ) _0–4 N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR° ₂ ; –N(R°)N(R°)C(O)OR°; –(CH ₂ ) _0–4 C(O)R°; –C(S)R°; –(CH ₂ ) _0–4 C(O)OR°; –(CH ₂ ) _0–4 C(O)SR°;-(CH ₂ ) _0–4 C(O)OSiR° ₃ ;–(CH ₂ ) _0–4 OC(O)R°;–OC(O)(CH ₂ ) _0–4 SR°, SC(S)SR°;–(CH ₂ ) _0–4 SC(O)R°;–(CH ₂ ) _0–4 C(O)NR° ₂ ;–C(S)NR° ₂ ;–C(S)SR°;–SC(S)SR°,-(CH ₂ ) _0–4 OC(O)NR° ₂ ;-C(O)N(OR°)R°;–C(O)C(O)R°;–C(O)CH ₂ C(O)R°;–C(NOR°)R°;-(CH ₂ ) _0–4 SSR°;–(CH ₂ ) _0–4 S(O) ₂ R°;–(CH ₂ ) _0–4 S(O) ₂ OR°；–(CH ₂ ) _0–4 OS(O) ₂ R°；–S(O) ₂ NR° ₂ ；–(CH ₂ ) _0–4 S(O)R°；–N(R°)S(O) ₂ NR° ₂ ；–N(R°)S(O) ₂ R°；–N(OR°)R°；–C(NH)NR° ₂ ；–P(O) ₂ R°；–P(O)R° ₂ ；–OP(O)R° ₂ ；–OP(O)(OR°) ₂ ；SiR° ₃ ；–(C _1–4 linear or branched alkylene)O–N(R°) ₂ ； or (C _1–4 linear or branched alkylene)C(O)O–N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, C _1-6 membered aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -NH(CH ₂ ) _0-1 Ph, -CH ₂ -(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent occurrences of R° together with the atoms intervening therebetween form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by two independently occurring R° together with the intervening atoms) are independently deuterium, halogen, –(CH ₂ ) _0–2 R ^● , –(haloR ^● ), –(CH ₂ ) _0–2 OH, –(CH ₂ ) _0–2 OR ^● , –(CH ₂ ) _0–2 CH(OR ^● ) ₂ , –O(haloR ^● ), –CN, –N ₃ , –(CH ₂ ) _0–2 C(O)R ^● , –(CH ₂ ) _0–2 C(O)OH, –(CH ₂ ) _0–2 C(O)OR ^● , –(CH ₂ ) _0–2 SR ^● , –(CH ₂ ) _0–2 SH, –(CH ₂ ) _0–2 NH ₂ , –(CH ₂ ) _0–2 NHR ^● , –(CH ₂ ) _0-2 NR ^● ₂ , –NO ₂ , –SiR ^● ₃ , –OSiR ^● ₃ , –C(O)SR ^● , –(C _1-4 straight or branched alkylene)C(O)OR ^● , or –SSR ^● , wherein each R ^● is unsubstituted or, when preceded by “halo”, substituted only with one or more halogens, and is independently selected from C _1-4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR ^* ₂ , ═NNHC(O)R ^* , ═NNHC(O)OR ^* , ═NNHS(O) ₂ R ^* , ═NR ^* , ═NOR ^* , —O(C(R ^* ₂ )) _2-3 O—, or —S(C(R ^* ₂ )) _2-3 S—, wherein each independent occurrence of R ^* is selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bound to an ortho-substitutable carbon of an "optionally substituted" group include: -O(CR ^* ₂ ) _2-3 O-, wherein each independently occurring R ^* is selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogen, –R ^● , –(haloR ^● ), –OH, –OR ^● , –O(haloR ^● ), –CN, –C(O)OH, –C(O)OR ^● , –NH ₂ , –NHR ^● , –NR ^● ₂ , or –NO ₂ , wherein each R ^● is unsubstituted or, when preceded by “halo”, substituted only with one or more halogens, and is independently a C _1-4 aliphatic group, –CH ₂ PH, –O(CH ₂ ) _{0– 1} Ph, or a 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include, or wherein each is independently hydrogen, a _C1-6 aliphatic group which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, two independently occurring substituents together with their intervening atoms form an unsubstituted 3-12 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group are independently halogen, –R ^● , –(haloR ^● ), –OH, –OR ^● , –O(haloR ^● ), –CN, –C(O)OH, –C(O)OR ^● , –NH ₂ , –NHR ^● , –NR ^● ₂ , or –NO ₂ , wherein each R ^● is unsubstituted or, when preceded by “halo”, is substituted only with one or more halogens, and is independently a C _1-4 aliphatic group, –CH ₂ Ph, –O(CH ₂ ) _{0– 1} PH, or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In certain embodiments, the terms "optionally substituted," "optionally substituted alkyl," "optionally substituted alkenyl," "optionally substituted alkynyl," "optionally substituted carbocycle," "optionally substituted aryl," "optionally substituted heteroaryl," "optionally substituted heterocycle," and any other optionally substituted groups used herein refer to unsubstituted or substituted groups wherein one, two, three or more hydrogen atoms are independently replaced by typical substituents, including but not limited to:

-F, -Cl, -Br, -I, deuterium,

-OH, protected hydroxy, alkoxy, oxo, thiooxo,

-NO ₂ , -CN, CF ₃ , N ₃ ,

-NH ₂ , protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclyl, -dialkylamino, -diarylamino, -diheteroarylamino,

-O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl,

-C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl,

-CONH ₂ , -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl,

-OCO ₂ -alkyl, -OCO ₂ -alkenyl, -OCO ₂ -alkynyl, -OCO 2 -carbocyclyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocyclyl, -OCONH ₂ , -OCONH-alkyl, -OCONH-alkenyl, -OCONH- _alkynyl , -OCONH-carbocyclyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl,

-NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHCO ₂ -alkyl, -NHCO ₂ -alkenyl, -NHCO ₂ -alkynyl, -NHCO ₂ -carbocyclyl, -NHCO 2 -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocyclyl, -NHC(O)NH ₂ , -NHC(O)NH- _alkyl , -NHC(O)NH-alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH-carbocyclyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH ₂ , -NHC(S)NH-alkyl, -NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, -NHC(S)NH-carbocyclyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclyl, -NHC(NH)NH ₂ , -NHC(NH)NH-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyclyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)NH-heterocyclyl,

-C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-carbocyclyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclyl,

-S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl-SO ₂ NH ₂ , -SO ₂ NH-alkyl, -SO ₂ NH-alkenyl, -SO 2 NH-alkynyl, -SO ₂ NH-carbocyclyl, -SO ₂ NH-aryl, -SO ₂ NH-heteroaryl, -SO ₂ NH-heterocyclyl _,

-NHSO ₂ -alkyl, -NHSO ₂ -alkenyl, -NHSO ₂ -alkynyl, -NHSO ₂ -carbocyclyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocyclyl,

-CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ ,

-mono-, di-, or tri-alkylsilyl groups,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclyl, -heterocyclyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl, or methylthiomethyl.

As used herein, the term "pharmaceutically acceptable salt" is intended to refer to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, or other problems or complications, and that are commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Science 5, 1977, 66, 1-19, the contents of which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases, as well as organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, gluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include suitable non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure (e.g., enantiomers, diastereomers, tautomers, and geometric (or conformational) isomers); for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, individual stereochemical isomers as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

In addition, unless otherwise indicated, structures described herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures include replacement of hydrogen by deuterium or tritium, or replacement of carbon by a ¹³ C- or ¹⁴ C-enriched carbon, and such compounds are within the scope of the present invention. In some embodiments, a group includes one or more deuterium atoms.

Compounds of Formula I are also intended to include isotopically labeled forms thereof. Isotopically labeled forms of compounds of Formula I differ from the compounds described herein only in that one or more atoms of the compound are replaced by one or more atoms having an atomic mass or mass number different from that of the atoms typically found in nature. Examples of isotopes that are readily commercially available and can be incorporated into compounds of Formula I by known methods include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ^2H , ^3H , ^13C , ^14C , ^15N , ^18O , 17O, 31P, ^32P , ^35S , ^18F , and ^36CI , ^respectively . Compounds of Formula I, prodrugs thereof, or pharmaceutically acceptable salts thereof containing one or more of ^the aforementioned isotopes and/or isotopes of other atoms are to be understood as part of the present invention. Isotopically labeled compounds of Formula I can be used in a variety of advantageous ways. For example, isotopically labeled compounds of Formula 1 incorporating radioactive isotopes such as ³ H or ¹⁴ C can be used in drug and/or substrate tissue distribution assays. These two radioactive isotopes, tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred due to their ease of preparation and good detectability. Since heavier isotopes such as deuterium ( ² H) have greater metabolic stability, incorporating such isotopically labeled compounds into compounds of Formula I can be therapeutically beneficial. Higher metabolic stability directly leads to increased in vivo half-life or reduced dosage, which in most cases represents a preferred embodiment of the present invention. Isotopically labeled compounds of Formula I can generally be prepared by following the steps disclosed in the synthetic schemes and related descriptions in the Examples and Preparations sections of this text, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants. The compounds of the present invention can be substituted with ¹⁸ F for use as PET imaging agents.

To control the oxidative metabolism of a compound through the primary kinetic isotope effect, deuterium ( ² H) can be incorporated into the compound. The primary kinetic isotope effect is a change in the rate of a chemical reaction due to the substitution of an isotopic nucleus, which is caused by a change in the ground state energy required to form a covalent bond after the isotope substitution. Substitution of a heavier isotope generally results in a decrease in the ground state energy of the chemical bond, thereby causing a decrease in the rate of the rate-limiting bond cleavage reaction. If bond cleavage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be significantly altered. This is explained as follows: If deuterium is bonded to a non-substitutable position on a carbon atom, the rate difference _km /k _d is generally 2-7. If this rate difference is successfully applied to a compound of Formula I that is easily oxidized, the in vivo properties of the compound can be significantly altered, thereby improving its pharmacokinetic properties.

When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining favorable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are susceptible to oxidative metabolism. Existing in vitro liver microsome assays provide valuable information about this type of oxidative metabolic process, which allows for the rational design of deuterated compounds of Formula I to enhance stability due to their resistance to oxidative metabolism. Consequently, the pharmacokinetic properties of compounds of Formula I are significantly improved, as quantitatively demonstrated by an extension of in vivo half-life (t/2), the concentration with the best efficacy ( _Cmax ), the area under the dose-response curve (AUC), and F, as well as by reduced clearance, dosage, and material cost.

The following description serves to illustrate the above: A series of analogs of a compound of formula I having multiple sites susceptible to oxidative metabolism, such as benzylic hydrogen atoms and nitrogen-bonded hydrogen atoms, were prepared. Various combinations of these hydrogen atoms were replaced with deuterium atoms, thereby replacing some, most, or all of the hydrogen atoms. Determination of the half-life advantageously and accurately determined the degree of improved resistance to oxidative metabolism. This method confirmed that this type of deuterium-hydrogen substitution could increase the half-life of the parent compound by up to 100%.

Deuterium-hydrogen substitution in compounds of Formula I can also be used to advantageously alter the metabolite profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite is produced by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that a deuterated analogue will significantly reduce or eliminate the production of the undesirable metabolite, even if that particular oxidation reaction is not the rate-determining step. For more information on deuterium-hydrogen substitution in the prior art, see, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foste R, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33 (10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16 (4), 683-688, 1993.

As used herein, the term "modulator" is defined as a compound that binds to and/or inhibits a target with measurable affinity. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately less than 50 μM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately less than 5 μM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately between 1 μM and 5 μM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately less than 1 μM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately between 500 nM and 1000 nM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately less than 500 nM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately between 100 nM and 500 nM. In certain embodiments, the IC ₅₀ and/or binding constant of a modulator is approximately less than 100 nM. In certain embodiments, the _IC50 and/or binding constant of a modulator is between about 10 nM and 100 nM. In certain embodiments, the _IC50 and/or binding constant of a modulator is less than about 10 nM.

As used herein, the terms "measurable affinity" and "measurably inhibit" refer to a measurable change in P2X7 activity between a sample containing a compound or composition of the invention and P2X7 and an equivalent sample containing P2X7 but not a compound or composition of the invention.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" means possessing stability sufficient to allow manufacture and to maintain the integrity of the compound for a sufficient period of time to be useful for the various purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment.

3. Description of Example Compounds

One aspect of the present invention provides a compound represented by formula I,

or a pharmaceutically acceptable salt, wherein:

X is CR or N;

Y is Cl or CF ₃ ;

R ¹ is a C _1-6 aliphatic group, a C _5-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 7-10 membered fused bicyclic saturated ring, partially unsaturated ring, aromatic ring or heteroaromatic ring; each of the above groups is optionally substituted by 1-5 ^RA ; or R ¹ is -SO ₂ R, -SOR, -C(O)R, -CO ₂ R or -C(O)N(R) ₂ ; each of the above groups is optionally substituted by 1-5 ^RA ;

R ² is a C _1-6 aliphatic group, a C _5-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 7-10 membered fused bicyclic saturated ring, partially unsaturated ring, aromatic ring or heteroaromatic ring; each of ^{the above groups is optionally substituted by 1-5 RA; or R 2 is} -SO ₂ R, -SOR, -C(O)R, -CO ₂ R or -C(O)N(R) ₂ ;

each ^RA is independently -R, halogen, -haloalkyl, -hydroxyalkyl, -OR, -SR, -CN, -NO2, _-SO2R , _-SOR , -C(O)R, _-CO2R , -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , _-NRSO2R , or -N(R) ₂ ;

each R is independently hydrogen, a _C1-6 aliphatic group, a _C3-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, each of which is optionally substituted; or

Two R groups on the same atom together with the atoms to which they are attached form a C _3-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of the above groups is optionally substituted.

In some embodiments, R ¹ is a C _1-6 aliphatic group optionally substituted with 1-5 ^RA . In some embodiments, R ¹ is a C _1-6 alkyl group. In some embodiments, R ¹ is a C _1-6 alkenyl group. In some embodiments, R ¹ is a C _1-6 alkynyl group.

In some embodiments, ^R is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, straight or branched pentyl, or straight or branched hexyl, each of which is optionally substituted with 1-5 ^RA . In some embodiments, ^R is ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, tert-butenyl, straight or branched pentenyl, or straight or branched hexenyl, each of which is optionally substituted with 1-5 ^RA . In some embodiments, R is ^ethynyl , n-propynyl, isopropynyl, n-butynyl, sec-butynyl, tert-butynyl, straight or branched pentynyl, or straight or branched hexynyl, each of which is optionally substituted with 1-5 ^RA .

In some embodiments, R ¹ is C _5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered fused bicyclic saturated ring, partially unsaturated ring, aromatic ring, or heteroaromatic ring; each of the above groups is optionally substituted by 1-5 ^RA .

In some embodiments, R ¹ is a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 instances of ^RA .

In some embodiments, ^R is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl , cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, dihydroindolinyl, indolizinyl, indolyl, 3H-indolyl, isoindoline, isoindolene, isobenzofuranyl, isochromanyl, isoindazolyl, isoindoline, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1, 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, benzoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, 2-azaspiro[3.3]heptane, or xanthenyl; each of which is optionally substituted with 1-5 instances of ^RA .

In some embodiments, R ¹ is pyrrolidinyl, tetrahydrofuranyl, azetidinyl, or 2-azaspiro[3.3]heptane, xanthenyl; each of which is optionally substituted with 1-5 ^RA .

In some embodiments, R ¹ is -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, or -C(O)N(R) ₂ ; each of which is optionally substituted with 1-5 instances of ^RA .

In some embodiments, R ¹ is -C(O)R, -CO ₂ R, or -C(O)N(R) ₂ ; each of which is optionally substituted with 1-5 instances of ^RA .

In some embodiments, R ¹ is

In some embodiments, R ² is a C _1-6 aliphatic group optionally substituted with 1-5 ^RA . In some embodiments, R ² is a C _1-6 alkyl group. In some embodiments, R ² is a C _1-6 alkenyl group. In some embodiments, R ² is a C _1-6 alkynyl group.

In some embodiments, R ² is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, linear or branched pentyl, or linear or branched hexyl, each of which is optionally substituted with 1-5 instances of ^RA .

In some embodiments, ^R2 is _C5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered fused bicyclic saturated, partially unsaturated, aromatic, or heteroaromatic ring; each of the above groups is optionally substituted by 1-5 ^RA .

In some embodiments, R ² is a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of the above groups is optionally substituted with 1-5 ^RA .

In some embodiments, ^R2 is _-SO2R , -SOR, -C(O)R, _-CO2R , or -C(O)N(R) ₂ .

In some embodiments, ^R2 is

In some embodiments, R ¹ , R ² , and ^RA are each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by formula II:

or a pharmaceutically acceptable salt thereof, wherein R ¹ and ^RA are each as defined above and further described by example, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by formula III:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by formula IV:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by Formula V:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by Formula VI:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by Formula VII:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by formula VIII:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides compounds represented by Formula IX:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by the general formula X:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by the general formula XI:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by Formula XII:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides a compound represented by Formula XIII:

or a pharmaceutically acceptable salt thereof, wherein R ² is each as defined above and further described by embodiment, class, subclass, and herein, alone or in combination.

In some embodiments, the present invention provides compounds given in Table 1:

Table 1

In some embodiments, the present invention provides a compound selected from the compounds described above or a pharmaceutically acceptable salt thereof.

Various structural representations may show heteroatoms without groups, radicals, charges, or counterions attached thereto. One of ordinary skill in the art will understand that such representations mean that the heteroatoms are attached to hydrogen (eg, should be understood as).

In certain embodiments, the compounds of the present invention are synthesized according to the following schemes. More specific examples of compounds prepared using the schemes are provided in the following examples.

4. Use, preparation and administration

Pharmaceutically acceptable compositions

According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is effective to measurably modulate P2X7 in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is effective to measurably modulate P2X7 in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of the composition.

As used herein, the term "patient" or "subject" refers to an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol, and lanolin.

"Pharmaceutically acceptable derivative" refers to any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or a metabolite or residue having inhibitory activity.

The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or by implantation into a container. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention include aqueous or oily suspensions. These suspensions are prepared using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions made with nontoxic parenteral acceptable diluents or solvents (e.g., solutions in 1,3-butanediol). Acceptable vehicles and solvents used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are typically used as solvents or suspending media.

For this reason, any available gentle fixed oil comprises synthetic mono- or di-glyceride. Fatty acids such as oleic acid and glyceride derivatives thereof can be used to prepare injection, as natural pharmaceutically acceptable oils, for example olive oil or castor oil, especially their polyoxyethylated oils. These oil solutions or suspensions also contain long-chain alcohol diluents or dispersants, for example carboxymethyl cellulose or similar dispersants, which are usually used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensoids. Other conventional surfactants, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, are usually used in the preparation of pharmaceutically acceptable solids, liquids, or other dosage forms also can be used for the purpose of preparation.

The pharmaceutically acceptable compositions of the present invention are administered orally in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions, or solutions. For oral tablets, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an oral aqueous suspension is desired, the active ingredient is combined with an emulsifier and a suspending agent. Optionally, certain sweeteners, flavorings, or coloring agents may be added, if desired.

Alternatively, the pharmaceutically acceptable compositions of the present invention are administered in the form of suppositories for rectal administration. These are prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum and release the drug. Such materials include cocoa butter, beeswax, and propylene glycol.

The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas and organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each area or organ.

Topical application to the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

For topical application, a pharmaceutically acceptable composition is prepared in a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Exemplary carriers for topical application of the compounds of the present invention include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene olefins, polyoxypropylene olefin compounds, emulsifying wax and water. Alternatively, a pharmaceutically acceptable composition is prepared in a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, CETE aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutically acceptable compositions of the present invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives and absorption enhancers to enhance bioavailability, and can also use fluorocarbons and/or other conventional solubilizing agents or dispersants.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

The compounds of the present invention are optionally combined with carrier materials to produce a single dosage form of the composition, the amount of which will depend on the host being treated, the specific mode of administration. Preferably, the compositions provided should be formulated into a dosage between 0.01-100 mg/kg body weight/compound, which can be administered daily to patients receiving these compositions.

It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, dietary status, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

Uses of compounds and pharmaceutically acceptable compositions

In certain embodiments, the present invention provides a method for positively antagonizing P2X7 in a patient or biological sample, comprising administering to the patient a compound of the present invention or contacting the biological sample with a compound of the present invention.

In certain embodiments, the present invention relates to the use of the compounds of the present invention and/or physiologically acceptable salts thereof in antagonizing P2X7. The compounds are characterized by having a high affinity for P2X7, ensuring reliable P2X7 binding, preferably antagonizing P2X7. In certain embodiments, the substance has monospecificity to ensure unique and direct recognition of a single P2X7 target. In the context of the present invention, the term "recognition" - without limitation - relates to any type of interaction between a specific compound and a target, in particular covalent or non-covalent binding or association, such as covalent bonds, hydrophilic/hydrophobic interactions, van der Waals forces, ion pairs, hydrogen bonds, ligand-receptor interactions, etc. Such associations may also include the presence of other molecules (e.g., peptides, proteins, or nucleotide sequences). The receptor/ligand interactions of the present invention are characterized by high affinity, high selectivity, and minimal or no cross-reactivity with other target molecules, thereby eliminating unhealthy and harmful effects on the treated subject.

In certain embodiments, the present invention relates to a method for antagonizing P2X7 using at least one compound of formula I and/or a physiologically acceptable salt of the present invention under conditions of antagonizing the P2X7 receptor. In certain embodiments, the system is a cell system. In other embodiments, the system is an in vitro translation system, and the translation system is based on protein synthesis and does not require living cells. A cell system is defined as any subject as long as the subject contains cells. Therefore, the cell system can be selected from a single cell, a cell culture medium, a tissue, an organ, and an animal. In certain embodiments, the method for antagonizing P2X7 is performed in vitro. The teachings of the above description on the compound of formula I (including any preferred embodiment thereof) are effective and applicable, and are not limited to the compound of formula I and its salt in the method for antagonizing P2X7. In certain embodiments, the method for antagonizing P2X7 is performed in vitro. The teachings of the above description on the compound of formula I (including any preferred embodiment thereof) are effective and applicable, and are not limited to the compound of formula I and its salt in the method for antagonizing P2X7.

In certain embodiments, the compounds according to the present invention exhibit advantageous biological activities as demonstrated in cell culture-based assays, such as those described herein or prior art assays (see, for example, WO 2002/09706, the contents of which are incorporated by reference). In these assays, the compounds according to the present invention preferably exhibit and induce agonism.

In certain embodiments, the present invention provides a method for treating, preventing, or ameliorating a disease, disorder, or condition associated with abnormal activity of a P2X7 receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the formula herein or a pharmaceutically acceptable composition thereof. In certain embodiments, the disease or disorder is an autoimmune, inflammatory, or cardiovascular disease or disorder.

In certain embodiments, the disease or disorder is a neurodegenerative disease or disorder, including Parkinson's disease, multiple sclerosis (MS); Alzheimer's disease, diseases and disorders mediated or caused by neuroinflammation, such as traumatic brain injury and encephalitis; centrally mediated neuropsychiatric diseases and disorders, such as depression, bipolar disorder, anxiety disorders, schizophrenia, eating disorders, sleep disorders and cognitive impairment; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, such as urinary incontinence, urinary incontinence, diseases and disorders of the respiratory tract and airways, such as allergic rhinitis, asthma, reactive airway disease, and chronic obstructive pulmonary disease; diseases and disorders mediated or caused by inflammation, such as rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis, and atherosclerosis; pruritus/pruritus, such as psoriasis; obesity; lipid disorders; cancer; blood pressure; spinal cord injury; and kidney disease.

In certain embodiments, the disease or disorder is pain, including acute, inflammatory, and neuropathic pain, chronic pain, dental pain, and headache (including migraine, cluster headache, and tension headache).

In certain embodiments, the disease or disorder is rheumatoid arthritis, osteoarthritis, psoriasis, atopic dermatitis, asthma, airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, malignant cell growth and metastasis, myoblastic leukemia, diabetes, neurodegenerative diseases, Alzheimer's disease, multiple sclerosis, meningitis, osteoporosis, burns, ischemic heart disease, stroke, peripheral vascular disease, varicose veins, glaucoma, bipolar disorder, and neuropathic pain disorders such as diabetic neuropathy, post-hepatic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia, and spinal cord injury pain.

In certain embodiments, the present invention is used when the use of compounds that inhibit P2X7 receptors is expected to improve pathological conditions. Such conditions include, for example, the prevention and treatment of swelling, pain and deterioration of bone metabolism in rheumatoid arthritis, the prevention and treatment of inflammatory bowel disease, chronic obstructive pulmonary disease (COPD) and osteoarthritis, the prevention and treatment of inflammatory pain, cancer pain and IL-1β-related diseases, such as Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact allergies, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulcers, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption diseases, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, Cerebral ischemia, head trauma, neurotrauma, spinal cord injury, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropics or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scarring, scleritis, abnormal wound healing, burns, autoimmune diseases, Huntington's disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, Gram-negative sepsis, toxic shock syndrome, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, glomerulonephritis, graft-versus-host reaction, allograft rejection, organ transplant toxicity, ulcerative colitis, or muscle degeneration.

In certain embodiments, the present invention includes a method for treating a patient suffering from an affective disorder (including a patient suffering from treatment-resistant depression), the method comprising administering a therapeutically effective amount of a modulator having P2X7 receptor activity to a subject suffering from the affective disorder. It should be understood that a mood disorder can be one of many disorders that affect mood and behavior. For example, mood disorders include depressive disorders (including major depressive disorder, low affect), bipolar disorders (including bipolar I disorder, bipolar II disorder, cyclothymic disorder), mood disorders caused by general medical conditions, and substance-induced mood disorders (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), Fourth Edition, Text Revision. Washington, D.C., American Psychiatric Association, pages 345-428, 2000.). In certain embodiments, the disorder is a depressive disorder. The present invention also includes a method for treating a patient suffering from an anxiety disorder. Anxiety disorders include: panic attacks, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, and generalized anxiety disorder.

In certain embodiments, the disease or condition is selected from pain associated with post-mastectomy pain syndrome, residual limb pain, phantom limb pain, oral neuropathic pain, Charcot's pain, toothache, snake bites, spider bites, insect stings, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barré syndrome, meralgia paresthesia, burning mouth syndrome, bilateral peripheral neuropathy, causalgia, sciatica, peripheral neuritis, polyneuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate ganglion neuralgia, glossopharyngeal neuralgia, translocated neuralgia, idiopathic neuralgia, intercostal neuralgia, breast neuralgia, mandibular neuralgia, Morton's neuralgia neuralgia), nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headaches, tension headaches, labor, delivery, intestinal gas, menstruation, cancer, and trauma.

In certain embodiments, the disease or condition is associated with inflammation, including rheumatoid arthritis, osteoarthritis, uveitis, asthma, myocardial infarction, traumatic brain injury; septic shock, atherosclerosis, chronic obstructive pulmonary disease (COPD), acute spinal cord injury, inflammatory bowel disease, and immune dysfunction.

In certain embodiments, the disease or condition is associated with an imbalance in pain response or maintenance of basal activity of sensory nerves. The amine compounds of the present invention are useful as analgesics for treating pain of various genetic or etiological origin, such as acute inflammatory pain (e.g., pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (e.g., post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillain-Barré syndrome, fibromyalgia, phantom limb pain, post-resection pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain (e.g., pain associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological diseases), dental pain, and headaches (e.g., migraine, cluster headache, and tension headache).

In certain embodiments, the disease or condition is arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, or inflammatory bowel disease.

In certain embodiments, the disease or disorder is multiple sclerosis.

In certain embodiments, the disease or disorder is Parkinson's disease.

In certain embodiments, the disease or condition is rheumatoid arthritis.

In certain embodiments, the disease or condition is traumatic brain injury.

In certain embodiments, the disease or condition is pain.

In other embodiments, the present invention provides the use of a compound of the present invention as a medicament, particularly for treating or preventing the aforementioned conditions and diseases. Also provided herein is the use of a compound of the present invention in the preparation of a medicament for treating or preventing one of the aforementioned conditions and diseases. The present invention also provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a condition or disease selected from a condition or disease mediated by the P2X7 receptor.

When used to prevent the onset of a P2X7-related disease/disorder, the compounds of the invention are administered at dosage levels as described above to patients at risk of developing the disorder, typically under the advice and supervision of a physician. Patients at risk of developing a particular disorder typically include those with a family history of the disorder or those identified by genetic testing or screening as being particularly susceptible to developing the disorder.

The present invention also relates to combination therapies, wherein a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising the compound of the present invention is administered with one or more other therapeutic agents simultaneously or sequentially or as a combined preparation for the treatment of one or more of the conditions listed above.

The compounds of formula (I) of the present invention can be used as a single active agent or can be used in combination with other active agents. These agents include nonsteroidal anti-inflammatory drugs (NSAIDS), such as celecoxib, rofecoxib, cimicoxib, etoricoxib, lumiracoxib, valdecoxib, deracoxib, N-(2-cyclohexyloxynitrophenyl)methanesulfonamide, COX189, ABT963, JTE-522, GW-406381, LAS-34475, CS-706, PAC-10649, SVT-2016, GW-644784, tenidap, acetylsalicylic acid (aspirin), anciprid, benolate, choline Magnesium salicylate, diflunisal, fasiamine, methyl salicylate, magnesium salicylate, octylsalicylate, diclofenac, aceclofenac, acemethoxamine, bromfenac, etodolac, indomethacin, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, methoxyfenac, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinpyrazone, piroxicam, lornoxicam, meloxicam, tenoxicam, nimesulide, rifazone, or acetaminophen.

The compounds of formula (I) of the present invention can be used in combination with the following agents: TNFα inhibitors such as anti-TNF monoclonal antibodies (e.g., Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (e.g., Enbrel), low-dose methotrexate, leflunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold.

The compounds of the general formula (I) of the present invention can also be used in combination with proTNFα converting enzyme (TACE) inhibitors, such as 3-amino-N-hydroxy-α-(2-methylpropyl)-3-[4-[(2-methyl-4-quinolyl)methoxy]phenyl]-2-oxo-1-pyrrolidineacetamide, 2(S),3(S)-piperidinedicarboxamide, N3-hydroxy-1-methyl-N2-[4-[(2-methyl-4-quinolyl)methoxy]phenyl], 3-Thiomorpholinecarboxamide, 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-5-hexenoic acid, 3-[(hydroxyamino)carbonyl]-2-(2-methylpropyl)-6-phenyl-2-(2-methylpropyl)-2-(methylsulfonyl)hydrazide, (2R,3S,5E)-2-piperidinecarboxamide, N,5-dihydroxy-1-[[4-(1-naphthylmethoxy)phenyl]sulfonyl]-(2R, 5R)-pentanamide, 3-(formylhydroxyamino)-4-methyl-2-(2-methylpropyl)-N-[(1S,2S)-2-methyl-1-[(2-pyridinylamino)carbonyl]butyl]-(2R,3S)-2-acrylamide, N-hydroxy-3-[3-[[(4-methoxyphenyl)sulfonyl](1-methylethyl)amino]phenyl]-3-(3-pyridinyl)-(2E)-benzamide, N-(2,4-dioxo- -1,3,7-triazaspiro[4.4]nonan-9-yl)-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide, N-[(1-acetyl-4-piperidinyl)(2,5-dioxo-4-imidazolidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy], or 2,4-imidazolidinedione, 5-methyl-5-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]sulfonyl]methyl].

The compounds of general formula (I) of the present invention can also be used in combination with corticosteroids, such as budesonide, corticosterone, cortisol, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone acetonide, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate (doca) or aldosterone.

The compounds of formula (I) of the present invention can also be used in combination with b2-adrenergic receptor agonists, such as formoterol, salbutamol (albuterol), levosalbutamol, terbutaline, pirbuterol, procaterol, isoproterenol, fenoterol, bitolterol mesylate, bambuterol or clenbuterol.

The compounds of formula (I) of the present invention can also be used in combination with antidepressants, such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, amitriptyline, citalopram, duloxetine, mirtazapine, nortriptyline, imipramine or lithium.

The compounds of formula (I) of the present invention can also be used in combination with antipsychotics, such as chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, chlorpromazine, flupentixol, haloperidol, haloperidol, droperidol, pimozide, melperone, benperidol, trifluoperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, bifeprunox or aripiprazole.

The compounds of formula (I) of the present invention can also be used in combination with the following agents: leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, such as zileuton; ABT-761; Finlayton; tepoxalin; nicaraven; VIA-2291; etoposide; ketoprofen, Abt-79175; Abt-85761; N-(5-substituted)thiophene-2-alkylsulfonamides; TDT-070; dexamethasone; PEP-03; tenoxicam; 2,6-di-tert-butylphenolhydrazone; methoxytetrahydropyrans such as Zeneca ZD-2138; compound SB-210661; pyridyl-substituted 2-cyanonaphthalene compounds, such as L-739-010; 2-cyanoquinoline compounds, such as L-746-530; indole and quinoline compounds, such as MK-591, MK-886 and BAY x 1005.

The compounds of general formula (I) of the present invention can be used in combination with receptor antagonists of leukotrienes LTB4, LTC4, LTD4 and LTE, such as phenothiazine-3-ones, such as L-651.392; amidine compounds, such as CGS-25019c; benzoxazolamides, such as onzelast; benzimide amides, such as BIIL 284/260; and such as zafirlukast, abruptilast, montelukast, pranlukast, fluorouracil (MK-679), RG-12525, Ro-245913, iliukast (CGP 45715A), BAY x 7195 and marukast.

The compounds of general formula (I) of the present invention may also be used in combination with PDE4 inhibitors (including inhibitors of the isoform PDE4D).

The compounds of formula (I) of the present invention can also be used in combination with antihistamine H1 receptor antagonists, including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine and chlorpheniramine. The compounds of formula (I) of the present invention can also be used in combination with gastroprotective H2 receptor antagonists.

The compounds of formula (I) of the present invention can also be used in combination with α1- and α2-adrenergic receptor agonist vasoconstrictor sympathomimetic agents, including propylhexosaccharin, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride.

The compounds of formula (I) of the present invention can be used in combination with anticholinergic agents, including ipratropium bromide; tiotropium bromide; propidium oxychloride; pirenzepine and telenzepine. The present invention also relates to the use of the compounds of the present invention in combination with b1- to b4-adrenergic receptor agonists, including metaproterenol, isoproterenol, isoproterenol, salbutamol, albuterol, formoterol, salmeterol, terbutaline, metaproterenol, bitolterol mesylate and pirbuterol; or methylxanthines, including theophylline and aminoseed; sodium cromolyn; or muscarinic receptor (M1, M2 and M3) antagonists.

The compound of formula (I) of the present invention can be used in combination with insulin-like growth factor type I (IGF-1) mimetics.

The compound of formula (I) of the present invention can be administered in combination with an inhaled glucocorticoid that can reduce systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate.

The compounds of formula (I) of the present invention can be used in combination with the following agents: (a) tryptase inhibitors, (b) platelet activating factor (PAF) antagonists; (c) interleukin converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion molecule inhibitors, including VLA-4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6-phosphate dehydrogenase inhibitors; (i) kinin-B1- and B2-receptor antagonists; (j) anti-gout agents, such as colchicine; (k) xanthine oxidase inhibitors, such as allopurinol; (l) uricosurics, such as Probenecid, sulfinpyrazone and benzbromarone; (m) growth hormone secretagogues; (n) transforming growth factor (TGFBβ); (o) platelet-derived growth factor (PDGF); (p) fibroblast growth factors, such as basic fibroblast growth factor (bFGF); (q) granulocyte macrophage colony-stimulating factor (GM-CSF); (r) capsaicin cream; (s) tachykinin NK1 and NK3 receptor antagonists, such as NKP-608C, SB-233412 (talanate) and D-4418; and (t) elastase inhibitors, such as UT-77 and ZD-0892.

The compounds of the general formula (I) of the present invention can be used in combination with inhibitors of matrix metalloproteinases (MMPs), i.e., fast-dissolving stromelins, collagenases and gelatinases, and aggrecanases; in particular, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11).

The compounds of general formula (I) of the present invention can be used in combination with anticancer drugs, such as endostatin and angiostatin or cytotoxic drugs such as doxorubicin, daunomycin, cisplatin, etoposide, paclitaxel, taxotere and farnesyl transferase inhibitors, VEGF inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antitumor agents, in particular antimitotic drugs, including vinca alkaloids such as vinblastine and vincristine.

The compounds of formula (I) of the present invention can be used in combination with antiviral agents such as nelfinavir (Viracept), AZT, acyclovir and famciclovir, and antibacterial compounds such as Valant.

The compounds of formula (I) of the present invention can be used in combination with cardiovascular agents, such as calcium channel blockers, lipid-lowering agents such as statins, fibrates, beta-blockers, ACE inhibitors, angiotensin-2 receptor antagonists and platelet aggregation inhibitors.

The compounds of general formula (I) of the present invention can be used in combination with central nervous system agents, such as antidepressants (such as sertraline), anti-Parkinson drugs (such as dexamethasone, levodopa, Requip, Mirapex), MAOB inhibitors such as selegiline and rasagiline, comp inhibitors such as TasmaR, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase, and anti-Alzheimer's disease drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metrifonate.

The compounds of formula (I) of the present invention can be used in combination with the following agents, for example, osteoporosis agents such as roxofene, droloxifene, lasofoxifene or fosomax, and immunosuppressants such as FK-506, rapamycin, cyclosporine, azathioprine and methotrexate.

In certain embodiments, the compounds of the present invention may be used in combination with the agents listed below.

Nonsteroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs), including non-selective cyclooxygenase COX-1/COX-2 inhibitors (whether applied topically or systemically) (e.g., piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and fenoprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutyric acid, salicylates such as aspirin); selective COX-2 inhibitors (e.g., meloxicam, succinate, phenoxyethanol, benzodiazepine, benzophenone ... cyclooxygenase-inhibiting nitric oxide donors (CINODs); glucocorticoids (whether administered topically, orally, intramuscularly, intravenously, or intraarticularly); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intraarticular therapeutics such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention further relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with the following agents: cytokines or agonists or antagonists having cytokine function (including agents that act on cytokine signaling pathways, such as modulators of the SOCS system), including α-, β- and γ-interferons; insulin-like growth factor I (IGF-1); interleukins (ILs), including IL1 to 17, and interleukin antagonists or inhibitors, such as anakinra; tumor necrosis factor α (TNF-α) inhibitors, such as anti-TNF monoclonal antibodies (e.g., infliximab; adalimumab and CDP-870); TNF receptor antagonists, including immunoglobulin molecules (e.g., etanercept); and low molecular weight agents, such as pentoxyethylene.

Furthermore, the present invention relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with a monoclonal antibody targeting B-lymphocytes (eg, CD20 (rituximab), MRA-aIL16R and T-lymphocytes, CTLA4-Ig, HuMax I1-15).

The present invention further relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with a chemokine receptor function modulator, such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, and CCR11 of the C-C family; CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 of the C-X-C family; and CX3CR1 of the C-X3-C family.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with an inhibitor of matrix metalloproteinases (MMPs), i.e., stromelysins, collagenases and gelatinases, and aggrecanases; in particular, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), MMP-9, and MMP-12, including agents such as doxycycline.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist, such as zileuton; ABT-761; Finlayton; tepoxalin; nicaraven; VIA-2291; etoposide; ketoprofen, Abt-79175; Abt-85761; N-(5-substituted)thiophene-2-alkylsulfonamide; TDT-070; dexamethasone; PEP-03; tenoxicam; 2,6-di-tert-butylphenolhydrazone; methoxytetrahydropyrans such as Zeneca ZD-2138; compound SB-210661; pyridyl-substituted 2-cyanonaphthalene compounds, such as L-739-010; 2-cyanoquinoline compounds, such as L-746-530; indole and quinoline compounds, such as MK-591, MK-886 and BAY x 1005.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with the following agents: a receptor antagonist of leukotrienes LTB4, LTC4, LTD4 and LTE, selected from the following group: phenothiazin-3-ones, such as L-651.392; amidine compounds, such as CGS-25019c; benzoxazolamides, such as onzelast; benzimide amides, such as BIIL 284/260; and such as zafirlukast, abruptilast, montelukast, pranlukast, fluorouracil (MK-679), RG-12525, Ro-245913, ilukast (CGP 45715A), as well as BAY x 7195 and marukast.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with a phosphodiesterase (PDE) inhibitor, such as a methylxanthine, including theophylline and aminophylline; a selective PDE isoenzyme inhibitor, including a PDE4 inhibitor, an isoform PDE4D inhibitor, or a PDE5 inhibitor.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a histamine type 1 receptor antagonist, such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine or mizolastine; for oral, topical or parenteral administration.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a proton pump inhibitor (eg omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a histamine type 4 receptor antagonist.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with an α1- and α2-adrenergic receptor agonist, a vasoconstrictor, a sympathomimetic agent, such as propylhexylglycerin, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, tramazoline hydrochloride, and ethylnorepinephrine hydrochloride.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and an anticholinergic agent, including muscarinic receptor (M1, M2 and M3) antagonists, such as atropine, scopolamine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a β-adrenergic receptor agonist (including β receptor subtypes 1-4), such as isoproterenol, salbutamol, formoterol, salmeterol, terbutaline, metaproterenol, bitolterol mesylate or pirbuterol, or a chiral enantiomer thereof.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a chromone (eg sodium cromolyn or nedocromil sodium).

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention also relates to combinations of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and an agent that modulates nuclear hormone receptors, for example PPARs such as rosiglitazone.

The present invention also relates to combinations of the compounds of the present invention or pharmaceutically acceptable salts thereof with gabapentin, lidocaine, pregabalin, and equivalents and pharmaceutically active isomers and metabolites thereof.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with the following pharmaceutical agents: celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, acetaminophen and its equivalents and pharmaceutically active isomers and metabolites thereof.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof and an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody that modulates Ig function, such as anti-IgE (eg, omalizumab).

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and another systemically or topically administered anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, a dithiol or a calcipotriol.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with aminosalicylates and sulfapyridines, such as sulfasalazine, mesalazine, balsalazide, and olserazine; immunomodulators such as thiopurines; and corticosteroids such as budesonide.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with an antibacterial agent, such as a penicillin derivative, a tetracycline, a macrolide, a β-lactam, a fluoroquinolone, a metronidazole, an inhaled aminoglycoside; an antiviral agent, including acyclovir, famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamivir and oseltamivir; a protease inhibitor, such as indinavir, nelfinavir, ritonavir and saquinavir; a nucleoside reverse transcriptase inhibitor, such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor, such as nevirapine or efavirenz.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with the following agents: a cardiovascular drug, such as a calcium channel blocker, a β-adrenergic receptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid-lowering agent, such as a statin or a fibrate; a regulator of blood cell morphology, such as pentoxylamine; a thrombolytic agent, or an anticoagulant, such as a platelet aggregation inhibitor.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with a central nervous system (CNS) agent, such as an antidepressant (e.g., sertraline), an antiparkinsonian agent (e.g., benzylalanine, levodopa, ropinirole, pramipexole, MAOB inhibitors such as selegiline and rasagiline, comp inhibitors such as tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists or neuronal nitric oxide synthase inhibitors) or an anti-Alzheimer's disease agent such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, provalpromide or metribusate.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and an agent for treating acute or chronic pain, such as a centrally or peripherally acting analgesic (e.g., an opioid or a derivative thereof), carbamazepine, gabapentin, pregabalin, phenytoin, sodium valproate, amitriptyline or other antidepressant, paracetamol, CB1 agonist, muscarinic agonist, TRPV-1 antagonist, mGluR5 agonist or nonsteroidal anti-inflammatory agent.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and a local anesthetic, for parenteral or topically applied (including inhaled) such as lidocaine or a derivative thereof.

The present invention also relates to combinations of a compound of the present invention or a pharmaceutically acceptable salt thereof with an anti-osteoporosis drug, including hormonal drugs such as raloxifene, or bisphosphonates such as alendronate.

The present invention also relates to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with the following agents: a) (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin-converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor, including a VLA-4 antagonist; (vi) a cathepsin; (vii) a kinase inhibitor, such as a tyrosine kinase inhibitor (e.g., Btk, Itk, Jak3, or MAP, such as gefitinib or imatinib mesylate); (viii) inhibitors of glucose-6-phosphate dehydrogenase; (ix) kinin-B1- or B2-receptor antagonists; (x) antigout agents, such as colchicine; (xi) xanthine oxidase inhibitors, such as allopurinol; (xii) uricosuric agents, such as probenecid, sulfinpyrazone or benzbromarone; (xii) i) growth hormone secretagogues; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factors, such as basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony-stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK1 or NK3 receptor antagonists, such as NKP-608C, SB-233412 (talnetant), or D-4418; (xx) tamponade (xxi) TNF-α converting enzyme inhibitors (TACE inhibitors); (xxii) inducible nitric oxide synthase (iNOS) inhibitors; (xxiii) chemoattractant receptor homologs expressed on TH2 cells (e.g., CRTH2 antagonists); (xxiv) p38 inhibitors; (xxv) agents that modulate Toll-like receptor (TLR) function, or (xxvi) inhibitors of transcription factor activation, such as NFkB, API, or STATS.

The compounds of the present invention or their pharmaceutically acceptable salts can also be used in combination with existing therapeutic agents for treating cancer. For example, suitable agents include:

(i) antiproliferative/antineoplastic drugs or combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan or nitrosoureas); antimetabolites (e.g., antifolates, such as 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, gemcitabine or paclitaxel); antitumor antibiotics (e.g., anthracyclines, such as doxorubicin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin or mithramycin); antimitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine or vinorelbine, or taxanes, such as paclitaxel or taxotere); or topoisomerase inhibitors. (ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, or iodurophene), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, or cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, or buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, or exemestane), or 5α-reductase inhibitors, such as finasteride; (iii) agents that inhibit cancer cell invasion (e.g., metalloproteinases). protease inhibitors, such as marimastat or inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example: growth factor antibodies (for example, the anti-ErbB2 antibody trastuzumab or the anti-ErbB1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors or serine/threonine kinase inhibitors, inhibitors of the epidermal growth factor family (for example, EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholino-4-propoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (v) anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab, a tricarboxyaminoquinoline, an inhibitor of integrin αvb3 function, or angiostatin); (vi) vascular damaging agents, such as combretastatin A4; (vii) agents for antisense therapy, such as agents directed against one of the above targets, such as ISIS 2503, anti-ras antisense; (viii) agents for use in gene therapy methods, such as methods for replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2), such as GDEPT (gene-directed enzyme prodrug therapy) methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods for increasing a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; or (ix) agents for use in immunotherapy methods, such as in vitro and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, methods for reducing T cell anergy, methods using transfected immune cells (such as cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines and methods using anti-idiotypic antibodies.

The methods of the present invention can be performed in vitro or in vivo. In vitro assays can be used to determine the sensitivity of specific cells to treatment with the compounds of the present invention during research and clinical applications. Cell cultures are typically incubated with various concentrations of the compounds of the present invention for a sufficient time to allow the active drug to antagonize P2X7 activity, typically between one hour and one week. In vitro treatments can be performed using biopsy samples or cultured cells from cell lines.

The host or patient can be a mammal, such as a primate, particularly a human; a rodent, including mice, rats, and hamsters; a rabbit, a horse, a cow, a dog, a cat, etc. Animal models of interest for experimental research can provide models for treating human diseases.

To identify signal transduction pathways and examine the interactions between various signal transduction pathways, many scientists have developed appropriate models or model systems, such as cell culture models and transgenic animal models. To examine specific stages of the signal transduction cascade, interacting compounds can be used to modulate the signal. The compounds of the present invention can be used as reagents to examine the status of P2X7-dependent signal transduction pathways in animal models and/or cell culture models or in clinical diseases described in this application.

The applications described in the preceding paragraphs of this specification can be performed in vitro or in vivo models. Regulation can be monitored by the techniques described throughout this specification. In certain embodiments, in vitro applications are preferably used for samples from people suffering from P2X7-related diseases. By testing several specific compounds and/or their derivatives, the active ingredient most suitable for treating human subjects can be selected. Advantageously, the in vivo dose rate of the selected derivative is pre-adjusted based on in vitro data on P2X7 susceptibility and/or severity of the disease in the corresponding subject. In this way, the therapeutic effect will be significantly increased. In addition, the following teachings of this specification relating to the use of compounds of formula (1) and their derivatives in the preparation of drugs for preventing, treating and/or controlling the course of a disease are valid and applicable and, if it seems reasonable, may not be limited to the use of the compounds of the present invention to antagonize P2X7 activity.

The present invention also relates to the use of compounds of Formula I and/or physiologically acceptable salts thereof in the preventive or therapeutic treatment and/or monitoring of diseases caused, mediated and/or spread by P2X7 activity. In addition, the present invention relates to the use of compounds of Formula I and/or physiologically acceptable salts thereof in the preparation of medicaments for the preventive or therapeutic treatment and/or monitoring of diseases caused, mediated and/or spread by P2X7 activity. In certain embodiments, the present invention provides the use of compounds of Formula I and/or physiologically acceptable salts thereof in the preparation of medicaments for the preventive or therapeutic treatment of diseases mediated by P2X7.

The compounds of formula I and/or their physiologically acceptable salts can be used as intermediates for the preparation of other active pharmaceutical ingredients. The pharmaceuticals are preferably prepared by non-chemical methods, for example by combining the active ingredient with at least one solid, liquid and/or semi-liquid carrier or excipient, optionally admixed with one or more other active substances in a suitable dosage form.

The compounds of Formula I of the present invention can be administered once or multiple times as a treatment before or after the onset of disease. The above-mentioned compounds and medical products of the present invention are particularly useful for therapeutic treatment. A therapeutically relevant effect refers to the relief of one or more disease symptoms to some extent, or the partial or complete reversal of one or more physiological or biochemical parameters associated with or causing the disease or pathology to a normal state. If the compounds are administered at different time intervals, monitoring can be considered a treatment to enhance the response and completely eradicate the disease pathogens and/or symptoms. The same or different compounds can be administered. Medications can also be used to reduce the progression of the disease or even prevent the occurrence of symptoms related to P2X7 activity in advance, or to treat existing or ongoing symptoms.

In the sense of the present invention, if the subject has pre-existing conditions for the above physiological or pathological conditions, such as a familial predisposition, a genetic defect, or a past history of the disease, it is advisable to administer a preventive treatment.

The present invention also relates to a medicament containing at least one compound of the present invention and/or its pharmaceutically acceptable derivatives, salts, solvates and stereoisomers, including mixtures thereof in various ratios. In certain embodiments, the present invention also relates to a medicament containing at least one compound of the present invention and/or its physiologically acceptable salts.

"Drug" within the meaning of the present invention is any pharmaceutical agent in the pharmaceutical field, including one or more compounds of formula I or their preparations (e.g. pharmaceutical compositions or pharmaceutical preparations), which can be used for the prevention, treatment, follow-up or post-treatment care of patients suffering from diseases associated with P2X7 activity, said patients at least temporarily showing pathological changes in the overall condition or in individual parts of the patient's body.

Another aspect of the present invention provides a kit comprising separately packaged effective amounts of a compound of the present invention and/or its pharmaceutically acceptable salts, derivatives, solvates, and stereoisomers, including mixtures thereof in various ratios, and optionally an effective amount of other active ingredients. The kit comprises a suitable container, for example, a box, various bottles, bags, or ampoules. For example, the kit may comprise separate ampoules, each containing an effective amount of a compound of the present invention and/or its pharmaceutically acceptable salts, derivatives, solvates, and stereoisomers, including mixtures thereof in various ratios, in dissolved or lyophilized form, and an effective amount of other active compounds.

As used herein, the term "treat" refers to reversing, slowing down, delaying the appearance of a disease or condition described herein or one or more symptoms, or inhibiting the development of a disease or condition described herein or one or more symptoms. In some embodiments, treatment is given after one or more symptoms have appeared. In other embodiments, treatment is given in the absence of symptoms. For example, treatment is given before the onset of symptoms in a susceptible individual (e.g., based on symptom history and/or genetic or other sensory factors). Treatment can be continued after symptoms disappear, for example to prevent or delay their recurrence.

The compounds and compositions according to the methods of the present invention are administered in any dosage amount and by any route of administration that is effective in treating or alleviating the severity of the aforementioned conditions. The exact amount required will vary from subject to subject, depending on the race, age, and general condition of the subject, the severity of the infection, the specific drug, the route of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable for administering a single dose to the patient to be treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific dosage level for any particular patient or organism will depend on a variety of factors, including the specific condition to be treated and its severity, the activity of the specific compound selected, the specific composition used, age, weight, health status, sex, dietary status, time and route of administration, the excretion rate of the specific compound, the duration of treatment, drugs used in conjunction with or in combination with the specific compound, and other factors well known in the art.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, orally or nasally by spray, etc., depending on the severity of the infection. In certain embodiments, the compounds of the present invention are administered orally or parenterally at a dosage level of about 0.01 mg/kg to 100 mg/kg of subject weight, preferably about 1 mg/kg to 50 mg/kg of subject weight, once or more daily to achieve the desired therapeutic effect.

Liquid dosage forms suitable for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form optionally contains inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl ethylene glycol, 1,3-butyl ethylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

Injectable preparations, such as sterile injectable aqueous or oily suspensions, are prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be prepared as sterile injectable solutions, suspensions or emulsions using non-toxic parenteral acceptable diluents or solvents (e.g., solutions in 1,3-butanediol). Among the acceptable carriers and solvents that can be used are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are generally used as oil solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injections.

Prior to use, the injectable preparations are sterilized by passing through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media.

In order to prolong the effect of the compounds of the present invention, the absorption of the compounds by subcutaneous or intramuscular injection is generally slowed. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn varies depending on the crystal size and crystalline form. Alternatively, the absorption of the compound administered parenterally can be delayed by dissolving or suspending the compound in an oil carrier. A microcapsule matrix of the compound is formed in a biodegradable polymer (polylactide-polyglycolide) to prepare a reservoir form of injection. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-type injectable preparations can also be prepared by embedding the compound in liposomes or microemulsions compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, wherein the excipients are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, which includes sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannose, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and gum arabic, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution blockers such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets or pills, the dosage form may also contain buffering agents.

The solid composition of similar type can also be used as filler for soft or hard filled gelatin capsules, and described capsule uses for example lactose or milk sugar, and the polyethylene glycol of high molecular weight etc. as excipient.The solid dosage form of tablet, dragee, capsule, pill and granule can adopt coating and shell preparation, for example other coating known in the field of enteric coating and pharmaceutical preparation.They optionally contain opacifier, and become composition, optionally in a delayed manner, only (or preferably) release active ingredient in the specific position of intestinal tract.The example of spendable embedding composition comprises polymer and wax.The solid composition of similar type can also be used as filler for soft or hard filled gelatin capsules, and described capsule uses for example lactose or milk sugar, and the polyethylene glycol of high molecular weight etc. as excipient.

The active compound can also be formulated into a microcapsule form together with one or more excipients, such as the excipients described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells, such as enteric coatings, controlled release coatings and other coatings known in the field of pharmaceutical formulation. In the solid dosage form, the active compound is mixed with at least one inert diluent, such as sucrose, lactose or starch. In normal practice, such dosage forms also include tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, in addition to the inert diluent. In the case of capsules, tablets or pills, a buffer can also be contained in the dosage form. They optionally contain an opacifying agent and become a composition, optionally in a delayed manner, only (or preferably) releasing the active ingredient in a specific part of the intestinal tract. Examples of usable embedding compositions include polymers and waxes.

The dosage forms of the compounds of the present invention for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed with a pharmaceutically acceptable carrier and any required preservatives, buffers or propellants under sterile conditions. Ophthalmic preparations, ear drops and eye drops are also within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of being able to controllably deliver the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate.

The compounds of the present invention can also be used as commercial research reagents for various medical research and diagnostic applications. Such uses include, but are not limited to: use as calibration standards for quantifying the activity of candidate P2X7 antagonists in various functional assays; use as blocking agents in random compound screening, i.e., when searching for a new family of P2X7 receptor ligands, compounds can be used to block the recovery of the P2X7 compounds claimed in the present invention; use in co-crystallization with the P2X7 receptor, i.e., compounds of the present invention allow the compounds to bind to P2X7 to form crystals, thereby determining the structure of the enzyme/compound by X-ray crystallography; use in other research and diagnostic applications; use as probes in assays to determine the expression of P2X7 in cells; and use in the development of compounds for detecting the site where P2X7 binds to a ligand in assays.

The compounds of general formula (I) and their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and/or metabolites are characterized by high specificity and stability, low manufacturing costs and convenient handling. These characteristics form the basis for their reproducible action, including the absence of cross-reactivity, and reliable and safe interaction with the target structure.

As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsy material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

Antagonizing the activity of P2X7 in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological testing.

DETAILED DESCRIPTION

As described in the Examples below, in certain exemplary embodiments, compounds were prepared according to the following general procedures. It should be understood that although the general methods describe the synthesis of certain compounds of the present invention, the following general methods, as well as other methods known to those of ordinary skill in the art, are also applicable to the synthesis of all compounds described herein and subclasses and species of each compound.

The compound numbers used in the following examples correspond to the compound numbers above.

^1H NMR (Nuclear Magnetic Resonance) ^1H NMR spectrometers were recorded on a Bruker 400 MHz spectrometer using the residual signal of the deuterated solvent as the internal standard. Chemical shifts were reported relative to tetramethylsilane and expressed in parts per million (ppm). ^1H NMR data were reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogen atoms). Multiplicities were expressed as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

LCMS analysis was performed under the following conditions.

Method A (Fast LC): Analyses were performed at 50°C using a Shimadzu Shim-pack XR-ODS (3.0×30 mm, 2.2 μm) at a flow rate of 1.5 mL/min and an injection volume of 2 μL. Mobile phases were (A) 0.1% formic acid and 1% acetonitrile in water, and (B) 0.1% formic acid in methanol. Retention times were expressed in minutes. Method details: (I) Analyses were performed using a binary pump G1312B with a UV/Vis diode array detector G1315C and an Agilent 6130 mass spectrometer in positive and negative ion electrospray mode. UV detection was performed at 220 and 254 nm. The gradient was linear from 15% to 95% (B) over 2.2 minutes. (II) 95% (B) was held for 0.8 minutes. (III) 95% (B) was held for 0.1 minutes. (IV) 15% (B) was held for 0.29 minutes.

Method B: A: 0.1% TFA in water, B: 0.1% TFA in ACN:

Run time: 6.5 minutes

Flow rate: 1.0 mL/min

Gradient: 5-95% B, 4.5 min, wavelength: 254 and 215 nM.

Column: Waters Sunfire C18, 3.0x50mm, 3.5um positive ion mode

Mass spectrometry scan: 100-900Da

Chiral analysis/separation conditions:

Mobile phase: hexane: hexanol: DEA = 70:30:0.1; flow rate: 1.0 mL/min; run time: 25 min

Column: Chiral PAK AY-H (250 x 4.6 mm, 5 μm).

Chiral analysis/separation conditions:

Column: AS-H (250*4.6mm 5um)

Mobile phase: hexane: hexanol: DEA = 90:10:0.1

Flow rate: 1ml/min

Temperature: 40

Run time: 30 minutes

Chiral-HPLC conditions:

Co-solvent: 30% methanol; Column: AD-H (4.6*250mm, 5um); _CO2 flow rate: 2.1mL/min

Co-solvent flow rate: 0.9 mL/min; total flow rate: 3 mL/min; run time: 9 min

Example 1: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (5)

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.163 g, 0.50 mmol), 2-bromo-1,1,1-trifluoroethane (0.204 g, 1.25 mmol), and _{Cs₂CO₃ (} 489 mg, 1.50 mmol) in anhydrous DMF (2 ml) was stirred at 120°C under microwave irradiation for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (3 x 20 mL). The separated organic layer was dried _{over Na₂SO₄} and concentrated in vacuo. The residue was purified by preparative HPLC to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (0.067 g, 33%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.29-8.27 (m, 1H), 7.73 (s, 1H), 7.68-7.66 (m, 1H), 7.28-7.20 (m, 2H), 5.32-5.27 (m, 2H), 3.17-3.15 (m, 2H), 2.04-2.02 (m, 2H), 1.85-1.70 (m, 5H) 1.29-1.24 (m, 2H) ppm; [M+H] ⁺ 409.1; LC-MS (254 nm) purity: 97.98%; t _R =2.10 min; HPLC (254 nm) purity: >99%; t _R =10.10 min.

Example 2: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (4)

Step 1: Preparation of 1-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

A mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2 _{-trifluoroethanone (0.500 g, 2.0 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.57 mL, 4.0 mmol), K₂CO₃ (} 0.828 g, 6.0 mmol), and DMF (2 mL) was stirred at 80°C under microwave conditions for 50 minutes. The mixture was cooled to room temperature and partitioned between water (30 mL) and ethyl acetate (80 mL). The separated organic layer was dried _over anhydrous _Na₂SO₄ , filtered, and concentrated to afford the title compound (0.600 g, 90%) as a green solid.

Step 2: Preparation of 4-chloro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylic acid

1-(4-Chloro-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.600 g, 1.8 mmol), ethanol (10 mL), and 10% NaOH (4 mL) were stirred at 80°C for 2 hours. The mixture was partitioned between water (50 mL) and ethyl acetate (30 mL). The aqueous phase was adjusted to pH 5 with 1 M HCl and extracted with ethyl acetate (100 mL). The separated organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated to afford 4-chloro- _1- (2,2,2-trifluoroethyl)-1H-indole-3-carboxylic acid (0.377 g, 75%) as a white solid.

Step 3: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylic acid (0.100 g, 0.36 mmol), 1-(aminomethyl)-4,4-difluorocyclohexanol (0.060 g, 0.36 mmol), EDCI (0.084 g, 0.47 mmol), HOBt (0.064 g, 0.47 mmol) and triethylamine (1.5 mL) in CH ₃ CN (20 mL) was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and extracted with DCM (100 mL). The separated organic layer was dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1) to obtain 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (0.052 g, 35%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.14 (t, J=6.0 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.29-7.22 (m, 2H), 5.30 (q, J=9.0 Hz, 2H), 4.71 (s, 1H), 3.32 (s, 2H), 2.08-1.88 (m, 4H), 1.66-1.64 (m, 4H) ppm; [M+H] ⁺ 425.1; LC-MS: purity (254 nm): 98%; t _R =1.44 min; HPLC purity (254 nm): 99%; t _R =4.43 min.

Example 3: Preparation of 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (3)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylic acid (0.100 g, 0.36 mmol), (1S,3S)-1-(aminomethyl)-3-methylcyclohexanol (0.052 g, 0.36 mmol), EDCI (0.084 g, 0.47 mmol), HOBt (0.064 g, 0.47 mmol) and triethylamine (1.5 mL) in _CH3CN (2.0 mL) to afford 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (0.060 g, 41%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.95 (t, J=6.0Hz, 1H), 7.79 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.29-7.21 (m, 2H), 5.33-5.27 (q, J=9.3Hz, 2H), 4.23 (s, 1H), 3.20 (d, J=6.0 [M+H] ⁺ 403.1; LC-MS purity (254 nm): 98%; t _R =1.51 min; HPLC purity (254 nm): 99%; t _R =4.74 min.

Example 4: Preparation of 4-chloro-N-(((1S,3S)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (2)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylic acid (0.100 g, 0.36 mmol), (1S,3S)-1-(aminomethyl)-3-methylcyclohexanol (0.052 g, 0.36 mmol), EDCI (0.083 g, 0.43 mmol), HOBt (0.059 g, 0.84 mmol) and DIPEA (0.186 g, 1.44 mmol) in DCM (10 mL) to afford 4-chloro-N-(((1S,3S)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (0.085 g, 73%) as a white solid.

1H NMR (500MHz, DMSO-d ₆ )δ7.96 (t, J=6.0Hz, 1H), 7.79 (s, 1H), 7.67 (d, J=8.0Hz, 1H), 7.29-7.21 (m, 2H), 5.33-5.27 (m, 2H), 4.23 (s, 1H), 3.20 (t , J=6.5Hz, 2H), 1.73-1.45(m, 6H), 1.28-1.20(m, 1H), 1.00-0.94(m, 1H), 0.84-0.82(m, 3H), 0.80-0.74(m, 1H)ppm; [M+H] ^+403.1 .

Example 5: 4-Chloro-N-((3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (1) (HATU coupling example)

To a stirred solution of 4-chloro-1-(2,2,2-trifluoro-ethyl)-1H-indole-3-carboxylic acid (200.00 mg; 0.72 mmol; 1.00 eq.), HATU (301.31 mg; 0.79 mmol; 1.10 eq.), and 1-aminomethyl-3,3-difluoro-5-methyl-cyclohexanol (142.01 mg; 0.79 mmol; 1.10 eq.) in DMF (3 ml) was added DIEA (0.38 ml; 2.16 mmol; 3.00 eq.). The mixture was stirred at room temperature overnight. The reaction was quenched with water (15 mL) and extracted with DCM/methanol (10:1, 30 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol = 80:1) to obtain 4-chloro-N-((3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide (62%, 20%) as a white solid. [M+H] ⁺ 439.

Example 6: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxamide (37)

Step 1: Preparation of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone

To a solution of 4-chloro-1H-indole (10.0 g, 66.2 mmol) in DMF (25 mL) at 0°C was added 2,2,2-trifluoroacetic anhydride (14 mL, 100 mmol). The reaction was heated to 40°C for 5 hours, then cooled to room temperature, and water (50 mL) was added. The precipitate was collected by filtration and dried under vacuum to afford 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (12.8 g, 78.8%), which was used in the next step without purification. LCMS m/z: 248.1 [M+H] ⁺ .

Step 2: Preparation of 1-(4-chloro-1-(2-methoxyethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone

To a mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (5.00 g, 20.2 mmol) and KOH (1.70 g, 29.8 mmol) in _CH₃CN (20 mL) was added 1-bromo-2-methoxyethane (4.2 g, 30.4 mmol) at room temperature. The reaction was stirred at room temperature for 6 hours, after which water (50 mL) was added. The precipitate was collected by filtration and dried under vacuum to afford 1-(4-chloro-1-(2-methoxyethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (6.4 g, 61.2%) as a white solid, which was used in the next step without purification. LCMS m/z: 306.1 [M+H] ^⁺ .

Step 3: Preparation of 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid

A mixture of 1-(4-chloro-1-(2-methoxyethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.100 g, 0.33 mmol) and 30% aqueous NaOH (5.0 mL) was heated at 105°C for 2 hours and then cooled to room temperature. The pH of the aqueous solution was adjusted to 3 with concentrated hydrochloric acid. The precipitate was collected by filtration and dried under vacuum to give 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid (0.051 g, 61.0%) as a white solid, which was used in the next step without purification. LCMS m/z: 254.1 [M+H] ⁺ .

Step 4: Preparation of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid (0.050 g, 0.198 mmol), EDCI (0.049 g, 0.257 mmol), HOBt (0.0347 g, 0.257 mmol), TEA (0.1 mL) and 1-(aminomethyl)-3,3-difluorocyclohexanol (0.0354 g, 0.198 mmol) in DCM to afford 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (0.044 g, 50.6%) as a light yellow solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.91 (t, J=6.0Hz, 1H), 7.80 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.19 (t, J=8.0Hz, 1H), 7.15 (d, J=7.5Hz, 1H), 4.69 (s, 1H), 4.39 (t, J=5 .0Hz, 2H), 3.67 (t, J=5.0Hz, 2H), 3.40-3.35 (m, 2H), 3.25 (s, 3H), 2.02-1.89 (m, 3H), 1.76-1.71 (m, 2H), 1.61-1.47 (m, 3H)ppm; [M+H] ^+401.1 .

Example 7: (R)-4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (21)

130 mg of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide was isolated, yielding 57 mg of the title compound. [M+H]^⁺ 401.1. Chiral HPLC conditions: Cosolvent: 30% methanol; Column: AD-H (4.6 x 250 mm, 5 μm).

_CO2 flow rate: 2.1 mL/min; co-solvent flow rate: 0.9 mL/min; total flow rate: 3 mL/min

Running time: 9 minutes.

Example 8: (S)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (20)

130 mg of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide was isolated to obtain 56 mg of the title compound. [M+H] ⁺ 401. (For isolation conditions, see Example 7).

Example 9: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (41)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid (0.300 g, 1.18 mmol), HATU (0.450 g, 1.18 mmol), (4,4-difluorocyclohexyl)methanamine (0.177 g, 1.18 mmol) and DIPEA (0.306 g, 0.4 mL, 2.37 mmol) in DMF (4.0 mL) to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (0.330 g, 72%) as a cream solid.

¹ H NMR (500MHz, CDCl ₃ )δ7.87 (s, 1H), 7.33 (d, J=8.0Hz, 1H), 7.22-7.15 (m, 2H), 6.83 (brs, 1H), 4.28 (t, J=5.0Hz, 2H), 3.71 (t, J=5.0Hz, 2H), 3 .40(t, J=6.5Hz, 2H), 3.30(s, 3H), 2.14-2.09(m, 2H), 1.91-1.89(m, 2H), 1.78-1.66(m, 3H), 1.43-1.35(m, 2H)ppm; [M+H] ^+384.9 .

Example 10: 4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (40)

The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid and 1-(aminomethyl)-4,4-difluorocyclohexanol, HATU and DIEA.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.97 (t, J=6.0Hz, 1H), 7.77 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.19-7.13 (m, 2H), 4.75 (s, 1H), 4.38 (t, J=5.0Hz, 2H), 3.66 (t, J=5.5Hz, 2H), 3.30 (d, J=7.0Hz, 2H), 3.21 (s, 3H), 2.06-1.95 (m, 2H), 1.89-1.84 (m, 2H), 1.64-1.62 (m, 4H)ppm; [M+H] ^+400.8 .

Example 11: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-methoxy-cyclohexylmethyl)-amide (17)

The reaction mixture was prepared by using 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (90 mg, 0.35 mmol, 1.00 eq), C-(4,4-difluoro-1-methoxy-cyclohexyl)-methylamine hydrochloride (114 mg, 0.53 mmol, 1.50 eq), EDC (115.62 mg, 0.60 mmol, 1.70 eq), benzotriazole-1-ol (76 mg, 0.56 mmol, 1.6 The title compound was synthesized from a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-methoxy-cyclohexylmethyl)-amide (41 mg, 0.10 mmol, 28.5%) in dry THF (10 mL, 111.11 V) to obtain 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-methoxy-cyclohexylmethyl)-amide (41 mg, 0.10 mmol, 28.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.92 (t, J=6.40Hz, 1H), 7.72 (s, 1H), 7.54 (m, 1H), 7.19-7.12 (m, 2H), 4.37 (t, J=5.20Hz, 2H), 3.65 (t, J=5.2 0Hz, 2H), 3.40-3.37(m, 2H), 3.21(s, 3H), 3.18(s, 3H), 1.90-1.83(m, 6H), 1.59-1.54(m, 2H)ppm; [M+H]+415.2.

Example 12: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide (19)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (100 mg, 0.39 mmol, 1.00 eq), 1-aminomethylcyclohexanol hydrochloride (97 mg, 0.59 mmol, 1.50 eq), EDC (128 mg, 0.66 mmol, 1.70 eq), benzotriazol-1-ol (85 mg, 0.62 mmol, 1.60 eq) and DIPEA (0.37 mL, 2.15 mmol, 5.50 eq) in dry THF (10 mL, 100 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide (60 mg, 0.16 mmol, 41.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.78 (s, 1H), 7.73 (t, J=5.96Hz, 1H), 7.55 (dd, J=1.24, 7.86Hz, 1H), 7.19-7.12 (m, 2H), 4.39-4.36 (m, 3H), 3. 67-3.64(m, 2H), 3.25-3.21(m, 5H), 1.57-1.51(m, 2H), 1.48-1.37(m, 7H), 2.26-1.24(m, 1H), ppm; [M+H]+365.2.

Example 13: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (14)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (100 mg, 0.39 mmol, 1.00 eq), (1S,3S)-1-aminomethyl-3-methyl-cyclohexanol (84 mg, 0.59 mmol, 1.50 eq), EDC (128 mg, 0.66 mmol, 1.70 eq), benzotriazol-1-ol (85 mg, 0.62 mmol, 1.60 eq) and DIPEA (0.37 mL, 2.15 mmol, 5.50 eq) in dry THF (10 mL, 100 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (20 mg, 0.05 mmol, 13.5%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ7.79-7.76 (m, 1H), 7.55 (dd, J=1.20, 8.00Hz, 1H), 7.19-7.12 (m, 2H), 4.39-4.36 (m, 1H), 4.26 (s, 1H), 3.66 (t, J=5.20Hz, 2H), 3.21-0.00 (m, 5H), 1.71-1.69 (m, 1H), 1.59-1.50 (m, 4H), 1.45-1.43 (m, 1H), 1.23 -1.17(m, 2H), 0.97-0.91(m, 1H), 0.83-0.81(m, 3H)ppm; [M+H]+379.2.

Example 14: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (15)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (100 mg, 0.39 mmol, 1.00 eq), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (84 mg, 0.59 mmol, 1.50 eq), EDC (128 mg, 0.66 mmol, 1.70 eq), benzotriazol-1-ol (85 mg, 0.62 mmol, 1.60 eq) and DIPEA (0.37 mL, 2.15 mmol, 5.50 eq) in dry THF (10 mL, 100 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (12 mg, 0.04 mmol, 10.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.79-7.76 (m, 1H), 7.55 (dd, J=1.20, 8.00Hz, 1H), 7.19-7.12 (m, 2H), 4.39-4.36 (m, 1H), 4.26 (s, 1H), 3.66 (t, J=5.20Hz, 2H), 3.21-3. 00(m,5H),1.71-1.69(m,1H),1.59-1.50(m,4H),1.45-1.43(m,1H),1 .23-1.17(m,2H),0.97-0.91(m,1H),0.83-0.81(m,3H)[M+H]+379.2.

Example 15: Preparation of 4-chloro-N-((3-ethyl-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (22)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.20 mmol; 1.00 eq.), 1-(aminomethyl)-3-ethylcyclohexanol (37.19 mg; 0.24 mmol; 1.20 eq.), EDC (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF (2.0 mL) to obtain 4-chloro-N-((3-ethyl-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.00(1H), 8.07(m, 1H), 7.97(1H), 7.86(s, 1H), 7.58(1H), 7.51(1H), 7.43(1H), 7.21(2H), 4.85(m, 2H), 4.41(2H), 3.69(2H), 3.27(3H). m/z: 393[M+H].

Example 16: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (1,2-dihydroxy-cyclohexylmethyl)-amide (18)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (200 mg, 0.78 mmol, 1.00 eq), 1-aminomethylcyclohexane-1,2-diol (170 mg, 1.17 mmol, 1.50 eq), EDC (256 mg, 1.33 mmol, 1.70 eq), benzotriazol-1-ol (170 mg, 1.25 mmol, 1.60 eq) and DIPEA (0.74 mL, 4.29 mmol, 5.50 eq) in dry THF (10 mL, 50 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (1,2-dihydroxy-cyclohexylmethyl)-amide (120 mg, 0.31 mmol, 40.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.05-7.85(m, 1H), 7.82-7.77(m, 1H), 7.57-7.54(m, 1H), 7.20-7.13(m, 2H), 4.83-4.60(m, 1H), 4.59-4 .06(m, 3H), 3.67-3.64(m, 2H), 3.53-3.45(m, 1H), 3.10-3.05(m, 4H), 1.59-1.25(m, 8H)ppm; [M+H]+381.2.

Example 17: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid 2-fluoro-benzylamide (25)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), 2-fluoro-benzylamine (112 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazol-1-ol (142 mg, 0.88 mmol, 1.50 eq) and EDC (170 mg, 0.88 mmol, 1.50 eq) in dry THF to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid 2-fluoro-benzylamide (50 mg, 0.14 mmol, 23.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.57 (t, J=5.88Hz, 1H), 7.79 (s, 1H), 7.56 (dd, J=8.00, 1.08Hz, 1H), 7.47 (dd, J=10.86, 1.52Hz, 1H), 7.33-7.29 (m, 1H), 7.21-7.13 (m, 4H), 4.49 (d, J=5.60Hz, 2H), 4.39 (t, J=5.16Hz, 2H), 3.67 (t, J=5.12Hz, 2H), 3.22 (s, 3H)ppm; [M+H] ^+361.2 .

Example 18: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid 2-trifluoromethyl-benzylamide (24)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), 2-trifluoromethyl-benzylamine (156 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazol-1-ol (142 mg, 0.88 mmol, 1.50 eq) and EDC (170 mg, 0.88 mmol, 1.50 eq) in dry THF (5 mL, 33 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid 2-trifluoromethyl-benzylamide (60 mg, 0.15 mmol, 24.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.68 (t, J=5.92Hz, 1H), 7.86 (s, 1H), 7.74 (d, J=7.68Hz, 1H), 7.69-7.65 (m, 2H), 7.58 (dd, J=7.94, 1.16Hz, 1H), 7.51-7. 47 (m, 1H), 7.22-7.15 (m, 2H), 4.64 (d, J=5.76Hz, 2H), 4.41 (t, J=5.20Hz, 2H), 3.68 (t, J=5.16Hz, 2H), 3.23 (s, 3H)ppm; [M+H] ^+411.0 .

Example 19: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid 4-trifluoromethyl-benzylamide (26)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), 4-trifluoromethyl-benzylamine (156 mg, 0.88 mmol, 1.50 eq), benzotriazol-1-ol (142.95 mg, 0.88 mmol, 1.50 eq) and EDC (170 mg, 0.88 mmol, 1.50 eq) in dry THF (5 mL, 33 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid 4-trifluoromethyl-benzylamide (60 mg, 0.15 mmol, 24.9%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.69 (t, J=6.08Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=8.08Hz, 2H), 7.60-7.56 (m, 3H), 7.21-7.14 (m , 2H), 4.53 (d, J=5.96Hz, 2H), 4.39 (t, J=5.20Hz, 2H), 3.67 (t, J=5.12Hz, 2H), 3.22 (s, 3H), [M+H] ^+411.0 .

Example 20: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-amide (23)

The reaction mixture was prepared by mixing 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methylamine hydrochloride (186 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazole-1-ol (142.95 mg, 0.88 mmol), and benzotriazole-1-ol (142.95 mg, 0.88 mmol). , 1.50 eq) and EDC (170 mg, 0.88 mmol, 1.50 eq) in dry THF (5 mL, 33.33 V) were used to synthesize the title compound according to the procedure described in Example 2 to obtain 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-amide (155 mg, 0.38 mmol, 65.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.35 (t, J=5.88Hz, 1H), 7.78 (s, 1H), 7.55 (d, J=7.36Hz, 1H), 7.19-7.12 (m, 2H), 6.88 (dd, J=6.94, 2.00Hz, 1H), 6.79-6.73 (m, 2H), 4.38 (t, J=4.56Hz, 4H), 4.30-4.28 (m, 2H), 4.24-4.23 (m, 2H), 3.66 (t, J=5.12Hz, 2H), 3.21 (s, 3H), ppm; [M+H]+401.2.

Example 21: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide (27)

The reaction mixture was prepared by mixing 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), C-benzo[1,3]dioxol-5-yl-ethylamine (136 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazole-1-ol (142 mg, 0.88 mmol, 1. To the mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide (105 mg, 0.27 mmol, 46.1%) in dry THF (5 mL, 33 V) was added 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide (105 mg, 0.27 mmol, 46.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.52 (t, J=6.00Hz, 1H), 7.75 (s, 1H), 7.55 (dd, J=7.98, 1.12Hz, 1H), 7.20-7.12 (m, 2H), 6.94 (d, J= 1.24Hz, 1H), 6.88-6.82 (m, 2H), 5.99 (s, 2H), 4.39-4.34 (m, 4H), 3.66 (t, J=5.12Hz, 2H), 3.22 (s, 3H).

Example 22: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid chroman-3-ylamide (29)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), chroman-3-ylamine hydrochloride (168.06 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazol-1-ol (142.95 mg, 0.88 mmol, 1.50 eq) and EDC (170.03 mg, 0.88 mmol, 1.50 eq) in dry THF (5 mL, 33.33 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid chroman-3-ylamide (30 mg, 0.08 mmol, 13.2%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ8.13 (d, J=7.20Hz, 1H), 7.76 (s, 1H), 7.56 (dd, J=1.20, 7.88Hz, 1H), 7.2 0-7.08(m, 4H), 6.88-6.84(m, 1H), 6.80(d, J=8.04Hz, 1H), 4.35-4.32(m, 2H) , 4.31(brs, 1H), 4.27-4.24(m, 1H), 3.93-3.88(m, 1H), 3.66(t, J=5.12Hz, 2H ), 3.22 (s, 3H), 3.06 (dd, J=16.36, 5.12Hz, 1H), 2.91-2.85 (m, 1H)ppm; [M+H] ^+385.2 .

Example 23: N-(Benzo[d]thiazol-2-ylmethyl)-4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxamide (31)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.20 mmol; 1.00 eq.), benzo[d]thiazol-2-ylmethylamine (46.61 mg; 0.24 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF (2.0 mL) to obtain N-(benzo[d]thiazol-2-ylmethyl)-4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.00(1H), 8.07(m, 1H), 7.97(1H), 7.86(s, 1H), 7.58(1H), 7.51(1H), 7.43(1H), 7.21(2H), 4.85(m, 2H), 4.41(2H), 3.69(2H), 3.27(3H). m/z: 400[M+H].

Example 24: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (furan-2-ylmethyl)-amide (28)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), C-furan-2-yl-methylamine (86.14 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazol-1-ol (142.95 mg, 0.88 mmol, 1.50 eq) and EDC (170 mg, 0.88 mmol, 1.50 eq) in dry THF (5 mL, 33 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (furan-2-ylmethyl)-amide (60 mg, 0.18 mmol, 30.8%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.50 (t, J=5.72Hz, 1H), 7.75 (s, 1H), 7.60-7.59 (m, 1H), 7.55 (dd, J=7.96, 1.08Hz, 1H), 7.20-7.12 (m, 2H), 6.41 (dd, J=3.14, 1.84 [M+H] ^+333.2 .

Example 25: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (2-thiophen-2-yl-ethyl)-amide (30)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (150 mg, 0.59 mmol, 1.00 eq), 2-thiophen-2-yl-ethylamine (113.98 mg, 0.88 mmol, 1.50 eq), triethylamine (0.25 mL, 1.76 mmol, 3.00 eq), benzotriazol-1-ol (142.95 mg, 0.88 mmol, 1.50 eq) and EDC (170.03 mg, 0.88 mmol, 1.50 eq) in dry THF (5 mL, 33.33 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (2-thiophen-2-yl-ethyl)-amide (45 mg, 0.12 mmol, 21.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.20 (t, J=5.60Hz, 1H), 7.69 (s, 1H), 7.55 (dd, J=7.96, 1.16Hz, 1H), 7.36 (dd, J=4.98, 1.32Hz, 1H), 7.20-7.12 (m, 2H), 6. 98-6.95 (m, 2H), 4.38 (t, J = 5.16Hz, 2H), 3.66 (t, J = 5.08Hz, 2H), 3.48 (m, 2H), 3.23 (s, 3H), 3.06 (t, J = 7.36Hz, 2H) ppm; [M+H] ^+363.3 .

Example 26: 4-Chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid [2-(2-chloro-phenyl)-ethyl]-amide (35)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.20 mmol; 1.00 eq.), 2-(2-chloro-phenyl)-ethylamine (36.81 mg; 0.24 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF (2.0 mL) to obtain 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid [2-(2-chloro-phenyl)-ethyl]-amide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.14(m, 1H), 7.67(s, 1H), 7.56(s, 1H), 7.42(2H), 7.29(2H), 7.14-7.18(m, 2H), 4.37(m, 2H), 3.66(2H), 3.47(2H), 3.24(s, 3H), 2.97(2H). m/z: 392[M+H].

Example 27: 4-Chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid [2-(4-fluoro-2-chloro-phenyl)-ethyl]-amide (34)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.20 mmol; 1.00 eq.), 2-(4-fluoro-2-chloro-phenyl)-ethylamine (31.95 mg; 0.24 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF to obtain 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid [2-(4-fluoro-2-chloro-phenyl)-ethyl]-amide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.11 (m, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.42 (2H), 7.14-7.18 (m, 3H), 4.37 (m, 2H), 3.66 (2H), 3.47 (2H), 3.24 (s, 3H), 2.97 (2H). m/z: 410[M+H].

Example 28: 4-Chloro-N-(2-(2-chlorophenyl)propyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (33)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.20 mmol; 1.00 eq.), 2-(2-chlorophenyl)propan-1-amine (40.12 mg; 0.24 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF (2.0 mL) to obtain 4-chloro-N-(2-(2-chlorophenyl)propyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.10(s, 1H), 7.65(s, 1H), 7.54(s, 1H), 7.48(1H), 7.42(1H), 7.34(1H), 7.24(1H), 7.16( m, 1H), 7.12 (1H), 4.36 (m, 2H), 3.64 (2H), 3.56 (1H), 3.49 (2H), 3, 24 (s, 3H), 1.25 (m, 3H). m/z: 405[M+H].

Example 29: 4-Chloro-N-(1-(2-chloro-3-(trifluoromethyl)phenyl)-2-hydroxyethyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide (32)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.20 mmol; 1.00 eq.), 2-amino-2-(2-chloro-3-(trifluoromethyl)phenyl)ethanol (58.12 mg; 0.24 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF (2.0 mL) to obtain the desired product.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.56(1H), 7.93(2H), 7.78(s, 1H), 7.79(1H), 7.57(2H), 5.55(1H), 5.06(1H), 4.41(2H), 3. 63(4H), 3.24(s, 3H), 3.19(1H), 4.36(m, 2H), 3.64(2H), 3.56(1H), 3.49(2H), 3, 24(s, 3H). m/z: 475[M+H].

Example 30: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid [2-(1-hydroxy-cyclopentyl)-ethyl]-amide (16)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (200 mg, 0.79 mmol, 1.00 eq), 1-(2-aminoethyl)-cyclopentanol (199 mg, 1.18 mmol, 1.50 eq), DIPEA (0.42 mL, 2.37 mmol, 3.00 eq), EDC (457 mg, 2.37 mmol, 3.00 eq) and benzotriazol-1-ol (192 mg, 1.18 mmol, 1.50 eq) in dry DMF (5 mL, 25 V) to afford 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid [2-(1-hydroxy-cyclopentyl)-ethyl]-amide (180 mg, 0.47 mmol, 60.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.92 (t, J=5.48Hz, 1H), 7.66 (s, 1H), 7.53 (dd, J=7.92, 1.16Hz, 1H), 7.18-7.10 (m, 2H), 4.36 (t, J=5.20Hz, 2H), 4.17 (s, 1H), 3 .64(t, J=5.12Hz, 2H), 3.33-3.32(m, 2H), 3.21(s, 3H), 1.76-1.68(m, 4H), 1.61-1.61(m, 2H), 1.58-1.48(m, 4H)ppm; [M+H]+365.2.

Example 31: Preparation of 4-chloro-1-(2-cyclopropyloxyethyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (149)

Step 1: Preparation of 4-chloro-1-(2-cyclopropyloxyethyl)-1H-indole

To a solution of 2-(4-chloro-1H-indol-1-yl)ethanol (1.95 g, 10 mmol) in THF (13 mL) at 0°C was added NaH (0.80 g, 20 mmol, 60% solution in mineral oil) and cyclopropane bromide (1.82 g, 15 mmol). The resulting reaction mixture was refluxed for 6 hours and then concentrated to dryness in vacuo. The residue was redissolved in ethyl acetate (20 mL) and washed twice with water (20 mL x 2) and then with brine (20 mL). The organic layer was dried over _MgSO₄ , filtered, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain 4-chloro-1-(2-cyclopropyloxyethyl)-1H-indole (1.53 g, 65%) as a yellow solid. LC-MS purity: >95%; t _R =1.73 min; [M+H] ⁺ 236.

Step 2: Preparation of 1-(4-chloro-1-(2-cyclopropyloxyethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone

A solution of 4-chloro-1-(2-cyclopropyloxyethyl)-1H-indole (1.50 g, 6.3 mmol) and 2,2,2-trifluoroacetic anhydride (2.10 g, 10 mmol) in acetonitrile (15 mL) was stirred at 45°C for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1 to 1:2) to obtain 1-(4-chloro-1-(2-cyclopropyloxyethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (1.35 g, 65%) as a yellow solid. LC-MS purity (254 nm): >95%; [M+H] ⁺ 332; t _R = 1.24 min.

Step 3: Preparation of 4-chloro-1-(2-cyclopropyloxyethyl)-1H-indole-3-carboxylic acid

A mixture of 1-(4-chloro-1-(2-cyclopropyloxyethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (1.0 g, 3 mmol) and 10% aqueous sodium hydroxide solution (10 mL) was stirred at 100°C for 18 hours and then cooled to room temperature. The pH of the mixture was adjusted to 2 with 1N HCl and extracted with DCM (15 mL x 2). The organic layers were combined, dried over _MgSO₄ , filtered, and concentrated in vacuo to obtain 4-chloro-1-(2-cyclopropyloxyethyl)-1H-indole-3-carboxylic acid (0.560 g, 66%) as a yellow solid, which was used in the next step without purification.

Step 4: Preparation of 4-chloro-1-(2-cyclopropyloxyethyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

To a solution of 4-chloro-1-(2-cyclopropyloxyethyl)-1H-indole-3-carboxylic acid (0.560 g, 2.0 mmol), EDCI (0.800 g, 0.42 mmol), and HOBt (0.425 g, 3.1 mmol) in DCM (10 mL) was added triethylamine (0.525 g, 5.2 mmol) and (4,4-difluorocyclohexyl)methanamine (0.298 g, 2.0 mmol) with stirring at room temperature. After stirring at room temperature for 3 hours, the reaction was quenched with water (10 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried _{over Na₂SO₄} , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (DCM:methanol=20:1) to obtain 4-chloro-1-(2-cyclopropyloxyethyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.150 g, 18%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.09 (s, 1H), 7.69 (s, 1H), 7.53 (d, J=7.5Hz, 1H), 7.17-7.12 (m, 2H), 4.35 (t, J=10.5Hz, 2H), 3.76 (t, J=10.5Hz, 2H), 3. [M+Na] ⁺⁴³³ .

Example 32: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxamide (95)

Step 1: Preparation of methyl 4-chloro-1-(2-hydroxyethyl)-1H-indole-3-carboxylate

To a mixture of 4-chloro-1-(2-hydroxyethyl)-1H-indole-3-carboxylic acid (2.00 g, 8.37 mmol) and potassium carbonate (4.62 g, 33.47 mmol, 510 mL) in anhydrous DMF (20 mL) was added iodomethane (1.18 g, 8.37 mmol) with stirring at room temperature and stirred for 4 hours. The reaction was quenched with brine (25 mL) and extracted with ether (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain methyl 4-chloro-1-(2-hydroxyethyl)-1H-indole-3-carboxylate (1.50 g, 73%) as a white solid. [M+H] ^⁺ 254.2.

Step 2: Preparation of methyl 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxylate

To a solution of methyl 4-chloro-1-(2-hydroxyethyl)-1H-indole-3-carboxylate (0.500 g, 1.98 mmol) in acetonitrile (100 mL) was added iodide (I) (0.075 g, 0.4 mmol) at room temperature with stirring. The system was stirred at 55 ° C. under a nitrogen atmosphere for several minutes, and then a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.407 g, 7.90 mmol) in acetonitrile (20 mL) was added dropwise. The reactants were stirred at 55 ° C. under a nitrogen atmosphere for 3 hours, and then the solvent was removed in vacuo. The residue was redissolved in dichloromethane (10 mL). The precipitate was filtered off and washed with dichloromethane (10 mL x 3). The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain methyl 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxylate (0.120 g, 20%) as a colorless oil. [M+H] ⁺ 304.1.

Step 3: Preparation of 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxylic acid

To a solution of methyl 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxylate (0.100 g, 0.33 mmol) in methanol (50 mL) was added sodium hydroxide (10%, 5 mL) with stirring at room temperature. The mixture was stirred at 60°C overnight, cooled to room temperature, and the solvent removed in vacuo. The pH of the residue was adjusted to 1 with hydrochloric acid (1N) and extracted with ethyl acetate (20 mL x 3). The extract was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxylic acid (0.090 g, 98%) as a yellow solid. [M+H] ⁺ 290.1.

Step 4: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxamide

A solution of 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxylic acid (0.09 g, 0.31 mmol), (4,4-difluorocyclohexyl)methanamine (0.046 g, 0.31 mmol), HOBt (0.126 g, 0.93 mmol), EDCI (0.090 g, 0.47 mmol) and triethylamine (0.063 g, 0.62 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours, then quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-(difluoromethoxy)ethyl)-1H-indole-3-carboxamide (0.050 g, 38%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.12(t, J＝6.0Hz, 1H), 7.74(s, 1H), 7.58(d, J＝8.0Hz, 1H), 7.20(t, J＝7.5Hz, 1H), 7.15(d, J＝7.5Hz, 1H), 6.79-6.49(m, 1H), 4.50(t, J=5.0Hz, 2H), 4.18 (t, J=5.0Hz, 2H), 3.16 (t, J=6.5Hz, 2H), 2.06-2.00 (m, 2H), 1.85-1.70 (m, 5H), 1.30-1.21 (m, 2H)ppm; [M+H]+421.0.

Example 33: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-1H-indole-3-carboxamide (117)

CMTP reaction example

Step 1: Preparation of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate

A mixture of 3,4-dihydro-2H-pyran (20.4 g, 242.3 mmol), ethyl 2-hydroxyacetate (24.0 g, 230.8 mmol), and TsOH (0.794 g, 4.6 mmol) in toluene (150 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to obtain ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (25.2 g, 58%) as a colorless oil.

Step 2: Preparation of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol

To a solution of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (1.0 g, 5.32 mmol) in anhydrous ether (30 mL) was added dropwise Ti(Oi-Pr) _₄ (0.997 g, 3.51 mmol) and ethylmagnesium bromide (13.1 mmol, 1 M solution in ether) at 0°C with stirring. After stirring at room temperature for 2 hours, the resulting mixture was quenched with water (10 mL) at 0°C and extracted with ethyl acetate (50 mL x ₃ ). The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (4% ethyl acetate in petroleum ether) to afford 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (0.5 g, 54%) as a colorless oil.

Step 3: Preparation of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropylbenzoate

To a solution of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (0.500 g, 2.9 mmol) in anhydrous DCM (15 mL) was added benzoyl chloride (0.494 g, 3.5 mmol) and TEA (0.879 g, 8.7 mmol) dropwise with stirring at 0° C. After stirring overnight at room temperature, the resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to afford 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropyl benzoate (0.6 g, 75%) as a yellow oil.

Step 4: Preparation of 1-(hydroxymethyl)cyclopropylbenzoate

A mixture of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropylbenzoate (0.6 g, 2.17 mmol) and PPTS (0.055 g, 0.22 mmol) in methanol (50 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to afford 1-(hydroxymethyl)cyclopropylbenzoate (0.200 g, 47%) as a colorless oil.

Step 5: Preparation of 1-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)cyclopropylbenzoate (CMTP-Example)

A mixture of 1-(hydroxymethyl)cyclopropylbenzoate (0.100 g, 0.52 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.085 g, 0.26 mmol), and cyanomethylenetributylphosphorane (CMTP) (0.188 g, 0.78 mmol) in anhydrous toluene (4 mL) was stirred at 110° C. under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-5% methanol in DCM) to afford 1-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)-cyclopropylbenzoate (0.050 g, 38%) as a white solid.

Step 6: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-1H-indole-3-carboxamide

A solution of 1-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)cyclopropyl benzoate (0.044 g, 0.088 mmol) and NaOH (1.0 mL, 2 M) in ethanol (2.0 mL) was stirred at 50 °C for 2 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-1H-indole-3-carboxamide (0.006 g, 17%) as a white solid.

¹ H NMR (500MHz, CDCl ₃ )δ7.98 (s, 1H), 7.45-7.42 (m, 1H), 7.25-7.20 (m, 2H), 6.87-6.85 (m, 1H), 4.29 (s, 2H), 3.43 (t, J=8.3Hz, 2H), 2.24-2 .14(m, 3H), 1.94-1.92(m, 2H) 1.82-1.70(m, 3H), 1.47-1.28(m, 2H), 1.00-0.98(m, 2H), 0.86-0.83(m, 2H)ppm; [M+H] ^+397.2 .

Example 34: Preparation of 1-(2-aminoethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (6)

Step 1: Preparation of tert-butyl 2-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)ethylcarbamate

A solution of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.15 g, 0.46 mmol), tert-butyl 2-hydroxyethylcarbamate (0.148 g, 0.92 mmol), and (CMTP) (0.443 g, 1.84 mmol) in toluene (2 mL) was stirred at 110°C under a nitrogen atmosphere for 4 hours. The resulting mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 _mL x 3). The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and concentrated to obtain a residue, which was purified by preparative TLC to obtain tert-butyl 2-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)ethylcarbamate (0.200 g, 80%) as a white solid.

Step 2: Preparation of 1-(2-aminoethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

To a solution of tert-butyl 2-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)ethylcarbamate (0.200 g, 0.43 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The volume was reduced to approximately 2 mL. The residual liquid was partitioned between saturated aqueous _NaHCO₃ solution (10 mL) and DCM (30 mL). The organic layer was dried over _{anhydrous Na₂SO₄} , concentrated, and purified by preparative HPLC to afford 1-(2-aminoethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.080 g, 51%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )8.07 (t, J=5.5Hz, 1H), 7.72 (s, 1H), 7.54 (d, J=7.5Hz, 1H), 7.16 (t, J=7.5Hz, 1H), 7.12 (d, J=7.0Hz, 1H), 4.16 (t, J=6.5Hz, 2H), 3 .15(t, J＝6.5Hz, 2H), 2.88(t, J＝6.5Hz, 2H), 2.05-1.99(m, 2H), 1.85-1.68(m, 5H), 1.57-1.34(m, 2H), 1.28-1.20(m, 2H)ppm; [M+H] ^+370.1 .

Example 35. 4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (178)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 2-(pyrrolidin-1-yl)ethanol (35.28 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL) and heated at 110° C. for 4 hours.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 7.88(2H), 7.55(1H), 7.20(2H), 4.67(s, 1H), 4.30(2H), 3.39(1H), 3.21(1H), 2, 81(2H), 2.03(m, 3H), 1.75(3H), 1.59(4H). m/z: 440[M+H].

Example 36: (R)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (176)

The racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide was separated by chiral column to afford the title compound.

Chiral HPLC conditions: co-solvent: 30% methanol; column: AD-H (4.6*250 mm, 5 um); CO ₂ flow rate: 2.1 mL/min; co-solvent flow rate: 0.9 mL/min; total flow rate: 3 mL/min; run time: 9 min.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 7.88(2H), 7.55(1H), 7.20(2H), 4.67(s, 1H), 4.30(2H), 3.39(1H), 3.21(1H), 2, 81(2H), 2.03(m, 3H), 1.75(3H), 1.59(4H). m/z：440[M+H]

Example 37: (S)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (177)

The racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide was isolated to provide the title compound (see Example 36).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 7.88(2H), 7.55(1H), 7.20(2H), 4.67(s, 1H), 4.30(2H), 3.39(1H), 3.21(1H), 2, 81(2H), 2.03(m, 3H), 1.75(3H), 1.59(4H). m/z: 440[M+H].

Example 38: Preparation of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (188)

The title compound was synthesized using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 2-hydroxyethyl-pyrrolidin-2-one (39.56 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphanylidene)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL) and stirred at 110° C. for 4 hours according to the procedure described in Example 33 to obtain the desired product.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.05(s, 1H), 7.74(s, 1H), 7.52(s, 1H), 7.21(1H), 7.16(m, 1H), 4.33(m, 2H), 3.55(2H), 3.14( 2H), 3.10(2H), 2.12(2H), 2.03(m, 2H), 1.86-1.75(6H), 1.45(m, 2H), 1.23(m, 2H), 0.89(1H). m/z: 454[M+H].

Example 39: (R)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (186)

The racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide was separated by chiral column to afford the title compound.

Chiral HPLC conditions: co-solvent: 25% methanol; column: OD-H (4.6*250 mm, 5 um); CO2 flow rate: 2.25 mL/min; co-solvent flow rate: 0.75 mL/min; total flow rate: 3 mL/min; run time: 9 min.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.05(s, 1H), 7.74(s, 1H), 7.52(s, 1H), 7.21(1H), 7.16(m, 1H), 4.33(m, 2H), 3.55(2H), 3.14( 2H), 3.10(2H), 2.12(2H), 2.03(m, 2H), 1.86-1.75(6H), 1.45(m, 2H), 1.23(m, 2H), 0.89(1H). m/z: 454[M+H].

Example 40: (S)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (187)

The racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide was isolated to provide the title compound (see Example 39).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.05(s, 1H), 7.74(s, 1H), 7.52(s, 1H), 7.21(1H), 7.16(m, 1H), 4.33(m, 2H), 3.55(2H), 3.14( 2H), 3.10(2H), 2.12(2H), 2.03(m, 2H), 1.86-1.75(6H), 1.45(m, 2H), 1.23(m, 2H), 0.89(1H). m/z: 454[M+H].

Example 41: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (179)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 2-pyrrolidin-1-yl-ethanol (44.06 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.54(m, 1H), 8.15(s, 1H), 7.82(s, 1H), 7.62(s, 1H), 7.20-7.27(m, 2H), 4.61(m, 2H) , 3.57-3.62(4H), 3.19(2H), 3.06(2H), 2.02(2H), 1.86(2H), 1.71(m, 1H), 1.25(m, 1H). m/z: 424[M+H].

Example 42: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indole-3-carboxamide (189)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 2-hydroxyethyl-pyrrolidin-2-one (49.41 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.05(s, 1H), 7.74(s, 1H), 7.52(s, 1H), 7.21(1H), 7.16(m, 1H), 4.33(m, 2H), 3.55(2H), 3.14( 2H), 3.10(2H), 2.12(2H), 2.03(m, 2H), 1.86-1.75(6H), 1.45(m, 2H), 1.23(m, 2H), 0.89(1H). m/z: 438[M+H].

Example 43: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-(piperidin-1-yl)ethyl)-1H-indole-3-carboxamide (193)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 2-piperidin-1-yl-ethanol (49.42 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.54(m, 1H), 8.15(s, 1H), 7.82(s, 1H), 7.62(s, 1H), 7.20-7.27(m, 2H), 4.61(m, 2H), 3.57-3.62(4H), 3.19(2H), 3.06(2H), 2.02(2H), 1.86(2H), 1.71(m, 1H), 1.25(m, 1H). m/z: 438[M+H].

Example 44: Preparation of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-(piperidin-1-yl)ethyl)-1H-indole-3-carboxamide (192)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 2-piperidin-1-yl-ethanol (39.56 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 7.88(m, 1H), 7.85(s, 1H), 7.56(1H), 7.19-7.15(m, 2H), 4.61(m, 2H), 3.57-3. 62(4H), 3.19(2H), 3.06(2H), 2.02(2H), 1.86(2H), 1.71(m, 1H), 1.25(m, 1H). m/z: 454[M+H].

Example 45: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxamide (12)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxylic acid (0.050 g, 0.172 mmol), EDCI (0.049 g, 0.223 mmol), HOBt (0.0457 g, 0.223 mmol), TEA (0.1 mL) and 1-(aminomethyl)-4,4-difluorocyclohexanol hydrochloride (0.0219 mg, 0.172 mmol) in DCM to afford 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxamide (40 mg, 55%) as a light yellow solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.93 (t, J=6.0Hz, 1H), 7.88 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.23 (t, J=7.5Hz, 1H), 7.18 (d, J=7.0Hz, 1H), 4.73 (s, 1H), 4.51 (t, J=7.0Hz, 2H), 3.31 (t, J=5.5Hz, 2H), 2.90-2.84 (m, 2H), 2.07-1.99 (m, 2H), 1.90-1.86 (m, 2H), 1.66-1.64 (m, 4H)ppm; [M+H] ^+439.1 .

Example 46: Preparation of 4-chloro-1-((3,3-difluorocyclobutyl)methyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (127)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 3,3-difluorocyclobutyl-methanol (20.55 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.54(m, 1H), 8.10(s, 1H), 7.78(s, 1H), 7.60(s, 1H), 7.15-7.19(m, 2H), 4.31(m, 2H), 3. 17(2H), 2.60(2H), 2.03(2H), 1.85(2H), 1.71(m, 1H), 1.60(1H), 1.37(1H), 1.25(m, 1H). m/z: 432[M+H].

Example 47: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxamide (13)

Step 1: Preparation of 3,3,3-trifluoropropyl trifluoromethanesulfonate

To a solution of 3,3,3-trifluoropropan-1-ol (0.684 g, 6 mmol) and pyridine (0.48 g, 6 mmol) in dry DCM (5 mL) was added trifluoromethanesulfonic anhydride (1.86 g, 6.6 mmol) dropwise at 0°C. The reaction was stirred at 0°C for 1 hour, then ice water (10 mL) was added. The pH was adjusted to ₇ with saturated NaHCO₃ solution, and the solution was extracted with DCM (10 mL x 3), dried _over anhydrous _Na₂SO₄ , filtered, and concentrated to afford 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.98 g, 66%) as a light yellow oil.

Step 2: Preparation of 1-(4-chloro-1-(3,3,3-trifluoropropyl)-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

A mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.5 g, 2 mmol ₎ , _Cs₂CO₃ (2.6 g, 8 mmol), and 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.74 g, 3 mmol) in DMF (10 mL) was heated at 80°C under microwave conditions for 1 hour. The reaction was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 1-(4-chloro-1-(3,3,3-trifluoropropyl)-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (1.20 g, 71%) as a light yellow solid.

Step 3: Preparation of 4-chloro-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxylic acid

A mixture of 1-(4-chloro-1-(3,3,3-trifluoropropyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.650 g, 1.9 mmol) and 10% aqueous NaOH (6 mL) was refluxed for 1 hour. The reaction was then cooled to room temperature and the pH was adjusted to 3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford 4-chloro-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxylic acid (0.320 g, 58%) as a white solid.

Step 4: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxylic acid (0.050 g, 0.17 mmol), EDCI (0.043 g, 0.22 mmol), HOBt (0.023 g, 0.22 mmol), and TEA (0.1 mL, 0.7 mmol) in DCM (1.0 mL) was stirred at room temperature for 1 hour. Cyclohexylmethylamine hydrochloride (0.032 g, 0.17 mmol) was then added, and the reaction was stirred at room temperature for 3 hours. The mixture was diluted with DCM (10 mL) and washed with water (3 mL x 3). The organic layer was dried _{over Na2SO4} , filtered, concentrated to dryness and the residue was purified by preparative HPLC to give 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-carboxamide (0.020 g, 38%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.09 (t, J=6.0Hz, 1H), 7.81 (s, 1H), 7.55 (d, J=8.0Hz, 1H), 7.21 (t, J=8.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 4.49 (t, J=7 .0Hz, 2H), 3.31 (t, J=6.0Hz, 2H), 2.83-2.89 (m, 2H), 2.01-2.04 (m, 2H), 1.69-1.85 (m, 5H), 1.26-1.28 (m, 2H)ppm; [M+H] ^+423.1 .

Example 48: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (11)

Step 1: Preparation of 4-chloro-1-(3,3-dimethoxy-propyl)-1H-indole

To a solution of 4-chloro-1H-indole (1.50 g, 9.70 mmol, 1.00 eq) and 3-bromo-1,1-dimethoxy-propane (3.75 g, 18.42 mmol, 1.90 eq) in dry DMF (15 mL, 10.00 V) was added KOH (2.56 g, 38.79 mmol, 4.00 eq) at room temperature. The mixture was stirred at 50°C for ₅ hours. TLC confirmed the reaction was complete, and water (1 x 50 mL) was added to quench the reaction. The reaction was then extracted with ethyl acetate (1 x 100 mL). The extracts were combined, washed with water (50 mL) and brine solution (50 mL), dried over _Na₂SO₄ , filtered, and evaporated to obtain the crude product. The crude product was further purified by column chromatography using 15% ethyl acetate in petroleum ether as eluent to obtain 4-chloro-1-(3,3-dimethoxypropyl)-1H-indole (2.45 g, 9.60 mmol, 99.0%) as a yellow liquid. ^1H NMR (400 MHz, DMSO-d6): δ 7.49-7.43 (m, 2H), 7.15-7.07 (m, 2H), 6.47 (s, 2H), 4.26-4.19 (m, 3H), 3.20 (s, 6H), 2.03-1.98 (m, 2H) ppm.

Step 2: Preparation of 1-[4-chloro-1-(3,3-dimethoxy-propyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone

To a solution of 4-chloro-1-(3,3-dimethoxy-propyl)-1H-indole (2.45 g, 9.60 mmol, 1.00 eq) in DMF (20 mL) was added trifluoroacetic anhydride (2.75 mL, 19.20 mmol, 2.00 eq) at room temperature. The reaction was stirred at 45°C overnight. After completion of the reaction as determined by TLC, the reaction was quenched with water (1 x 50 mL) and extracted with ethyl acetate (1 x 100 mL). The extracts were combined, washed with water (1 x 50 mL) and brine solution (1 x 50 mL), dried over _{Na₂SO₄ ,} filtered, and evaporated to afford the crude product, 1-[4-chloro-1-(3,3-dimethoxy-propyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (3.10 g, 6.16 mmol, 64.2%), as a light yellow liquid. The crude product was used directly in the next step without purification. [M+H] ⁺ 350.0.

Step 3: Preparation of 3-[4-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-propanal

To a solution of 1-[4-chloro-1-(3,3-dimethoxypropyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (3.10 g, 6.16 mmol, 1.00 eq) in dry THF (20 mL) was added dropwise 1.5 M aqueous hydrochloric acid (25 mL, 37.50 mmol, 6.09 eq). After stirring at 80°C for 30 minutes, the reaction mixture was cooled to room temperature, saturated aqueous _NaHCO₃ was added, and the solvent was removed under reduced pressure. The remaining aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over _{Na₂SO₄ ,} filtered, and the solvent was removed under reduced pressure to obtain 3-[4-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-propanal (1.80 g, 5.74 mmol, 93.2%) as a light yellow solid, which was used in the next step without purification. [M+H] ⁺ 322.2.

Step 4: Preparation of 1-[4-chloro-1-(3,3-difluoro-propyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone

To a solution of 3-[4-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-propanal (1.80 g, 5.74 mmol, 1.00 eq) in DCM (20 mL) was added diethylaminosulfur trifluoride (1.69 mL, 11.48 mmol, 2.00 eq) with stirring at -78°C and stirred for 3 hours. After completion of the reaction as determined by TLC, the reaction mixture was diluted with DCM (120 mL) and extracted with water (1 x 20 mL) and brine solution (1 x 20 mL). The separated organic layer was dried over _{Na₂SO₄ and} concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography using a 9:1 ratio of DCM and methanol as eluent to afford 1-[4-chloro-1-(3,3-difluoro-propyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (1.40 g, 4.30 mmol, 75%) as a light brown solid. ^1H NMR (400 MHz, DMSO- _d₆ ): δ 8.67 (s, 1H), 7.74-7.72 (m, 1H), 7.42-7.37 (m, 2H), 6.37-6.07 (m, 1H), 4.58 (t, J = 7.00 Hz, 2H), 2.50-2.41 (m, 2H) ppm.

Step 5: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid

A suspension of 1-[4-chloro-1-(3,3-difluoro-propyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (1.40 g, 4.30 mmol, 1.00 eq) and 1N KOH solution (20 mL) was stirred at 100°C overnight. After completion of the reaction as determined by TLC, the pH of the reaction mixture was adjusted to 1-3 with aqueous hydrochloric acid (1.5 N, 10 mL). The resulting precipitate was collected by filtration to afford 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (0.90 g, 3.24 mmol, 75.4%) as a creamy white solid. [M+H] ⁺ 274.0; LC-MS purity (254 nm): 98.5%; t _R = 3.37 min.

Step 6: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide

To a solution of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (0.20 g, 0.72 mmol, 1.00 eq) and C-(4,4-difluoro-cyclohexyl)-methylamine hydrochloride (0.16 g, 0.86 mmol, 1.20 eq) in THF (10 mL) at 0°C was added triethylamine (0.30 mL, 2.16 mmol, 3.00 eq), EDC (0.28 g, 1.44 mmol, 2.00 eq), and benzotriazole-1-ol (0.18 g, 1.08 mmol, 1.50 eq). The reaction mixture was stirred at room temperature overnight. After completion of the reaction as determined by TLC, the reaction mixture was diluted with ethyl acetate (1 x 10 mL) and washed with aqueous NaHCO ₃ solution (10%, 1 x 10 mL), followed by water and brine solution, dried over Na ₂ SO ₄ , and concentrated in vacuo. The crude product was further purified by silica gel column chromatography with 45% ethyl acetate in petroleum ether as eluent to afford 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (0.15 g, 0.35 mmol, 49.0%) as a cream solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.10 (t, J=5.9Hz, 1H), 7.76 (d, J=7.4Hz, 1H), 7.53 (d, J=7.7Hz, 1H), 7.19 (t, J=8.0Hz, 1H), 7.14 (d, J=7.1Hz, 1H), 6.28-5.98 (m, 1H), [M+H] ^+405.1 .

Example 49: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide (9)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (0.20 g, 0.72 mmol, 1.00 eq), C-(3,3-difluoro-cyclohexyl)-methylamine hydrochloride (0.16 g, 0.86 mmol, 1.20 eq), triethylamine (0.30 mL, 2.16 mmol, 3.00 eq), EDC (0.28 g, 1.44 mmol, 2.00 eq) and benzotriazol-1-ol (0.18 g, 1.08 mmol, 1.50 eq) to give 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide (0.09 g, 0.22 mmol, 30.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.11 (t, J=5.84Hz, 1H), 7.78 (s, 1H), 7.55-7.53 (m, 1H), 7.22-7.13 (m, 2H), 6.29-5.98 (m, 1H), 4.37 (d, J=7.36Hz, 2H), 3.21-3.10 (m, 2H), 2.50-2.31(m, 2H), 2.14(d, J=9.08Hz, 1H), 1.97(s, 1H), 1.80-1.74(m, 3H), 1.55-1.37(m, 3H), 1.12-0.86(m, 1H)ppm; [M+H]+405.2.

Example 50: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (10)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (0.20 g, 0.72 mmol, 1.00 eq), 1-aminomethyl-4,4-difluoro-cyclohexanol (0.14 g, 0.86 mmol, 1.20 eq), triethylamine (0.30 mL, 2.16 mmol, 3.00 eq), EDC (0.28 gm 1.44 mmol, 2.00 eq) and benzotriazol-1-ol (0.18 g, 1.08 mmol, 1.50 eq) to afford 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (0.25 mL, 0.59 mmol, 81.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.96 (t, J=6.12Hz, 1H), 7.83 (s, 1H), 7.56-7.54 (m, 1H), 7.23-7.14 (m, 2H), 6.29-5.99 (m, 1H), 4.72 (s, 1H), 4.38 (t, J=7. [M+H] ^+421.0 .

Example 51: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (79MSC2526161)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (150 mg, 0.54 mmol, 1.00 eq), (1S,3S)-1-aminomethyl-3-methyl-cyclohexanol (77.41 mg, 0.54 mmol, 1.00 eq), triethylamine (0.23 mL, 1.62 mmol, 3.00 eq), HOBt (109.54 mg, 0.81 mmol, 1.50 eq) and EDC (209.30 mg, 1.08 mmol, 2.00 eq) in dry THF to give 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (65 mg, 0.19 mmol, 34.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.83-8.80 (m, 1H), 7.96 (d, J=9.2Hz, 1H), 4.29 (d, J=9.3Hz, 1H), 7.71 (d, J=9.0Hz, 1H), 7.15 (d, J=9.1Hz, 1H), 4.55-4.52 (m, 2H), 3.7 2-3.70 (m, 2H), 3.31 (d, J=7.2Hz, 3H), 3.26 (t, J=12.4Hz, 2H), 2.04-1.98 (m, 2H), 1.86-1.73 (m, 5H), 1.32-1.23 (m, 2H)ppm; [M+H]+413.2.

Example 52: Preparation of 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (8)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid (150 mg 0.54 mmol, 1.00 eq), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (77.41 mg, 0.54 mmol, 1.00 eq), triethylamine (0.23 mL, 1.62 mmol, 3.00 eq), HOBt (109.54 mg, 0.81 mmol, 1.50 eq) and EDC (209 mg, 1.08 mmol, 2.00 eq) to give 4-chloro-1-(3,3-difluoro-propyl)-1H-indole-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (75.00 mg, 0.19 mmol, 34.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.83 (s, 1H), 7.79-7.76 (m, 1H), 7.54 (dd, J=8.9, Hz, 1H), 7.22-7.14 (m, 1H), 6. 29-5.99 (m, 1H), 4.38-4.36 (m, 2H), 4.24 (s, 1H), 3.18 (d, J=6.1Hz, 2H), 2.41-2.31 (m, 2H), 1.71-1.69 (m, 1H), 1.60-1.50 (m, 4H), 1.44 (d, J=10.00Hz, 1H), 1.24-1.17 (m, 1H), 0.94 (t, J=8Hz, 1H), 0.82 (d, J=6.60Hz, 3H), 0.77-0.73 (m, 1H), ppm; [M+H] ^+399.0 .

Example 53: Preparation of 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (208)

Barium hydroxide octahydrate (241.35 mg; 0.77 mmol; 2.00 eq.) was added to a solution of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (125.00 mg; 0.38 mmol; 1.00 eq.) and 2-chloro-N,N-dimethylacetamide (58.13 mg; 0.48 mmol; 1.25 eq.) in DMF (3.90 ml; 50.54 mmol; 132.13 eq.). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with DMSO (1 ml) and water (1 ml) and then loaded on a medium pressure liquid chromatography for purification (chromatograph: Yamazen, column: Interchim 100 g polymer reverse phase column, alkaline buffer) to obtain the desired product 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl) -amide (130.00 mg; 0.32 mmol) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.73(s, 1H), 7.25(s, 1H), 7.02(d, J=5.4Hz, 1H), 6.87–6.68(m, 2H), 4.85(s, 2H), 2.87–2.67(m, 5 [M+H] ⁺ 412.1. LC-MS (254nm) t _R =4.37min; HPLC (254nm) purity: 97.6%; t _R =4.24min.

Example 54: 4-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-

Preparation of amide (205)

Step 1: Preparation of 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid

2-Chloro-N,N-dimethylacetamide (0.19 ml; 1.84 mmol; 1.20 eq.) was added to a solution of 4-chloro-1H-indole-3-carboxylic acid (300.00 mg; 1.53 mmol; 1.00 eq.) and barium hydroxide octahydrate (967.67 mg; 3.07 mmol; 2.00 eq.) in DMF (15.63 ml; 202.65 mmol; 132.13 eq.) at 50° C. The reaction mixture was stirred overnight. The reaction mixture was diluted with DMSO (1 ml) and water (1 ml) and then loaded on a medium pressure liquid chromatography for purification (chromatograph: Yamazen, column: Interchim 100 g polymer reverse phase column, alkaline buffer) to obtain the desired product, 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (426.00 mg; 1.52 mmol) as a white solid.

¹ H NMR (400MHz, MeOD) δ7.42 (s, 1H), 6.89–6.79 (m, 1H), 6.78–6.64 (m, 2H), 4.73 (s, 2H), 2.73 (s, 3H), 2.57–2.49 (m, 4H)ppm; [M+H] ⁺ 281.1.LC-MS (254nm) t _R =3.47min; HPLC (254nm) purity: >99%; t _R =2.68min.

Step 2: Preparation of 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid

O-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84.66 mg; 0.22 mmol; 1.25 eq.) (HATU) was added to a solution of 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (50.00 mg; 0.18 mmol; 1.00 eq.), 1-aminomethyl-4,4-difluoro-cyclohexanol (32.36 mg; 0.20 mmol; 1.10 eq.) and N,N-diisopropylethylamine (0.12 ml; 0.71 mmol; 4.00 eq.) in DMF (1.81 ml; 23.54 mmol; 132.13 eq.) at 25° C. The reaction mixture was stirred overnight and evaporated to dryness under high vacuum. The residue was dissolved in methanol (8 ml) and water (2 ml), and the solution was purified by medium-pressure liquid chromatography (Chromatograph: Yamazen, Column: Interchim 150 g polymer reversed-phase column, alkaline buffer) to obtain the desired product, 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (30.00 mg; 0.07 mmol). ¹ H NMR [M+H] ⁺ 428.1. LC-MS (254 nm) t _R = 3.94 min; HPLC (254 nm) purity: >99%; t _R = 3.40 min.

Example 55: Preparation of 4-chloro-1-diethylcarbamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (207)

The title compound was synthesized according to the procedure described in Example 53 using N,N-diethylchloroacetamide (41.21 mg; 0.28 mmol; 1.20 eq.) and 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (75.00 mg; 0.23 mmol; 1.00 eq.) to obtain 4-chloro-1-diethylcarbamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (100.80 mg; 0.23 mmol) as a white amorphous solid.

¹ H NMR (400MHz, CDCl ₃ )δ7.72(s, 1H), 7.31–7.05(m, 3H), 6.76(s, 1H), 4.88(s, 2H), 3.52–3.29(m, 5H), 2.20–2.01(m, 2H), 1. 97–1.50 (m, 6H), 1.38 (dd, J=23.7, 11.1Hz, 2H), 1.27 (t, J=7.2Hz, 3H), 1.13 (t, J=7.1Hz, 3H)ppm; [M+H] ⁺ 440.1. LC-MS (254nm) t _R =4.77min; HPLC (254nm) purity: 98%.

Example 56: Preparation of 4-chloro-1-[(isopropyl-methyl-carbamoyl)-methyl]-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (203)

The title compound was synthesized according to the procedure described in Example 54 using a mixture of 2-chloro-N-isopropyl-n-methylacetamide (41.21 mg; 0.28 mmol; 1.20 eq.) and (4,4-difluorocyclohexyl)methanamine (75.00 mg; 0.23 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-[(isopropyl-methyl-carbamoyl)-methyl]-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (35.00 mg; 0.08 mmol). [M+H] ⁺ 440.2 LC-MS (254 nm) t _R = 3.94 min; HPLC (254 nm) purity: 99.0%; t _R = 4.46 min.

Example 57: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(1-(dimethylamino)-1-oxopropan-2-yl)-1H-indole-3-carboxamide (200)

The title compound was synthesized using a mixture of 2-bromo-N,N-dimethyl-propionamide (60.61 mg; 0.37 mmol; 1.20 eq.), 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (100.00 mg; 0.31 mmol; 1.00 eq.) and barium hydroxide octahydrate (193.08 mg; 0.61 mmol; 2.00 eq.) in DMF (10 mL) according to the procedure described in Example 53 at 50°C to give the desired product as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.10(1H), 7.72(s, 1H), 7.53(1H), 7.19(m, 2H), 5.85(1H), 3.15(1H), 3.04 (3H), 2.86(3H), 2.03(2H), 1.85(2H), 1.71(m, 1H), 1.60(2H), 1.25(m, 2H). m/z：426[M+H]

Example 58: Preparation of 1-(2-azetidin-1-yl-2-oxo-ethyl)-4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (201)

The title compound was synthesized according to the procedure described in Example 54 using 1-azetidin-1-yl-2-chloro-ethanone (33.72 mg; 0.25 mmol; 1.10 eq.) and (4,4-difluorocyclohexyl)methanamine (75.00 mg; 0.23 mmol; 1.00 eq.) to give the desired product, 1-(2-azetidin-1-yl-2-oxo-ethyl)-4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (34.50 mg; 0.08 mmol). [M+H] ⁺ 424.1; LC-MS (254 nm) t _R = 3.54 min; HPLC (254 nm) purity: 99.4%; t _R = 3.97 min.

Example 59: Preparation of 4-chloro-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (185)

The title compound was synthesized according to the procedure described in Example 54 using a mixture of 2-chloro-1-pyrrolidin-1-yl-ethanone (37.27 mg; 0.25 mmol; 1.10 eq.) and (4,4-difluorocyclohexyl)methanamine (75.00 mg; 0.23 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (65.00 mg; 0.15 mmol). [M+H] ^⁺ 438.1. LC-MS (254 nm) t _{_R} = 3.74 min; HPLC (254 nm) purity: 99.5%; t _{_R} = 4.18 min.

Example 60: Preparation of 4-chloro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (190)

The title compound was synthesized according to the procedure described in Example 53 using a mixture of 4-(bromoacetyl)morpholine (57.30 mg; 0.28 mmol; 1.20 eq.) and 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (75.00 mg; 0.23 mmol; 1.00 eq.) to afford 4-chloro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (54.00 mg; 0.12 mmol) as a white amorphous solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.69–7.46(m, 1H), 7.23(t, J=34.2Hz, 1H), 4.95(s, 1H), 3.89–2.96(m, 1H), 2 .13(s, 1H), 1.83(d, J=72.4Hz, 1H), 1.40(s, 1H), 0.12--0.11(m, 1H)ppm; [M+H] ⁺ 454.1.LC-MS (254nm) t _R =4.35min; HPLC (254nm) purity: 98.7%; t _R =3.97min.

Example 61: Preparation of 4-chloro-1-(2-oxo-2-piperidin-1-yl-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (195)

The title compound was synthesized according to the procedure described in Example 54 using a mixture of 2-chloro-1-piperidin-1-yl-ethanone (40.81 mg; 0.25 mmol; 1.10 eq.) and (4,4-difluorocyclohexyl)methanamine (75.00 mg; 0.23 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-(2-oxo-2-piperidin-1-yl-ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (95.00 mg; 0.21 mmol). [M+H] ⁺ 452.1. LC-MS (254 nm) _tR = 4.83 min; HPLC (254 nm) purity: 99.2%; _tR = 4.53 min.

Example 62: Preparation of 4-chloro-1-(2-methoxyethyl)-N-((1-phenylcyclohexyl)methyl)-1H-indole-3-carboxamide (39)

Step 1: Preparation of (1-phenylcyclohexyl)methylamine hydrochloride

To a stirred solution of 1-phenylcyclohexanecarbonitrile (0.500 g, 2.70 mmol) in methanol (10 mL) was added Raney nickel (0.100 g). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours and then filtered through celite. Hydrochloric acid (5 mL, 20 mmol, 4 M solution in dioxane) was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was triturated in ethyl acetate (20 mL), and the precipitate was filtered off to obtain (1-phenylcyclohexyl)methanamine hydrochloride (0.400 g, 65.8%) as a white solid.

Step 2: Preparation of 4-chloro-1-(2-methoxyethyl)-N-((1-phenylcyclohexyl)methyl)-1H-indole-3-carboxamide

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid (0.100 g, 0.40 mmol), HATU (0.225 g, 0.59 mmol) and (1-phenylcyclohexyl)methanamine hydrochloride (0.116 g, 0.51 mmol) in DMF (5 mL) to afford 4-chloro-1-(2-methoxyethyl)-N-((1-phenylcyclohexyl)methyl)-1H-indole-3-carboxamide (0.130 g, 77%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.63 (s, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.47 (t, J = 6.0Hz, 1H), 7.43-7.41 (d, J = 8.0Hz, 2H), 7.34 (t, J=7.5Hz, 2H), 7.19 (t, J=7.5Hz, 1H), 7.15 (t, J=7.5Hz, 1H), 7.09 (d, J=7.5Hz, 1H), 4.35 (t, J=5.0Hz, 2H), 3.64 (t, J=5.5Hz, 2H), 3.33 (d, J=6.5Hz, 2H), 3.22 (s, 3H), 2.13-2.1 0(m, 2H), 1.73-1.69(m, 2H), 1.58-1.55(m, 2H), 1.44(brs, 1H), 1.36-1.23(m, 3H)ppm; [M+H] ^+425.1 .

Example 63: Preparation of 4-chloro-1-(2-methoxyethyl)-N-((4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxamide (80)

Step 1: Preparation of 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonitrile

To a solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (2.0 g, 10.8 mmol) in DMF (10 mL) at 0°C under a nitrogen atmosphere was slowly added a suspension of NaH (60%, 0.95 g, 23.7 mmol) in DMF (10 mL) over 10 minutes. The reaction was allowed to warm to room temperature and stirred for 0.5 hours. The reaction was then cooled to 0°C, and a solution of 2,2'-dibromodiethyl ether (1.5 mL, 11.8 mmol) in DMF (20 mL) was added dropwise over 60 minutes. The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to obtain 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonitrile (2.30 g, 83%) as a red oil. GC-MS: [M] ⁺ 255; t _R = 10.39 min.

Step 2: Preparation of (4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-yl)methanamine

To a solution of 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonitrile (1.0 g, 3.9 mmol) in THF (20 mL) was added lithium aluminum hydride (0.3 g, 7.8 mmol) portionwise with stirring at 0°C. The reaction was stirred at 60°C for 2 hours. The mixture was cooled to 0°C, and methanol (2 mL) was slowly added to quench the reaction. Magnesium sulfate (0.500 g) was added, and the system was stirred at room temperature for 0.5 hours. The mixture was filtered through celite, and the filtrate was concentrated to provide (4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-yl)methanamine (0.55 g, 48%) as a red oil. [M+H] ⁺ 260.1; LC-MS purity (254 nm): >99%; t _R = 1.16 min.

Step 3: Preparation of 4-chloro-1-(2-methoxyethyl)-N-((4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxamide

The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic acid (0.150 g, 0.59 mmol), HATU (0.247 g, 0.65 mmol), (4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-yl)methanamine (0.168 g, 0.65 mmol) and DIPEA (0.3 mL, 1.77 mmol) to give 4-chloro-1-(2-methoxyethyl)-N-((4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxamide (0.205 g, 70%) as a cream-colored solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.77(t, J=6.0Hz, 1H), 7.70-7.68(m, 2H), 7.65-7.64(m, 2H), 7.59(s, 1H), 7. 52 (d, J=8.0Hz, 1H), 7.15 (t, J=8.0Hz, 1H), 7.09 (t, J=8.0Hz, 1H), 4.35 (t, J=5. 0Hz, 2H), 3.81-3.77 (m, 2H), 3.65 (t, J=5.0Hz, 2H), 3.52 (d, J=6.0Hz, 2H), 3.42 (t, J=8.5Hz, 2H), 3.22 (s, 3H), 2.10-2.07 (m, 2H), 2.03-1.96 (m, 2H)ppm; [M+H] ^+495.1 .

Example 64: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (94)

Step 1: Preparation of 4-chloro-1-(oxetan-3-yl)-1H-indole

To a solution of 4-chloro-1H-indole (0.90 g, 5.93 mmol) and 3-bromooxetane (1.22 g, 8.90 mmol) in DMF (10.0 mL) was added potassium hydroxide (1.00 g, 17.81 mmol) at room temperature with stirring. The mixture was stirred at 50°C overnight. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The extracts were combined, washed with water (10 mL) and brine ( ₁₀ mL), dried over _Na₂SO₄ , and concentrated in vacuo to afford 4-chloro-1-(oxetan-3-yl)-1H-indole (0.70 g, 47%) as a brown oil, which was used in the next step without purification. [M+H] ^⁺ 208.0.

Step 2: Preparation of 1-(4-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)-2,2,2-trifluoroethanone

To a solution of 4-chloro-1-(oxetan-3-yl)-1H-indole (0.70 g, 3.37 mmol) in DMF (10.0 mL) was added trifluoroacetic anhydride (1.06 g, 5.05 mmol) with stirring at room temperature. The mixture was stirred at 50°C overnight. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The extracts were combined, washed with water (10 mL) and brine (10 mL), dried over _Na₂SO₄ , and concentrated in _vacuo to afford 1-(4-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.90 g, 87%) as a purple oil, which was used in the next step without purification. [M+H] ^⁺ 304.0.

Step 3: Preparation of 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid

To a solution of 1-(4-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.90 g, 2.96 mmol) in ethanol (5.0 mL) was added 20% aqueous potassium hydroxide solution (10 mL) at room temperature with stirring. The mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was extracted with ethyl acetate (10 mL x 2). The aqueous layer was acidified to pH 2-3 with concentrated hydrochloric acid (3.0 mL). The combined organic layers were washed with brine (10 mL), dried over _Na₂SO₄ , and concentrated in vacuo to afford ₄ -chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (0.60 g, 80%) as a creamy white solid, which was used in the next step without purification. [M+H] ^⁺ 252.0.

Step 4: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide

A mixture of 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (0.120 g, 0.47 mmol), HOBt (0.070 g, 0.52 mmol), EDCI (0.100 g, 0.52 mmol), and TEA (0.144 g, 1.43 mmol) in DCM (20 mL) was stirred at room temperature for 1 hour, followed by the addition of (4,4-difluorocyclohexyl)methanamine (0.71 g, 0.47 mmol). The mixture was stirred at room temperature overnight, and the volatiles were removed in vacuo. The residue was taken up in water (10 mL) and extracted with DCM/methanol (10:1, 30 mL x 3). The combined organic layers were washed with brine (10 mL), dried _{over Na₂SO₄} , and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol=100:1) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (0.110 g, 60%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.18(t, J＝5.5Hz, 1H), 8.10(s, 1H), 7.56(d, J＝8.0Hz, 1H), 7.22-7.16(m, 2H), 5.83-5.77(m, 1H), 5.05(t, J＝7.5Hz, 2H), 4.92 (t, J=7.5Hz, 2H), 3.16 (t, J=6.5Hz, 2H), 2.05-1.98 (m, 2H), 1.86-1.69 (m, 5H), 1.29-1.17 (m, 2H)ppm; [M+H] ⁺ 383.1; LC-MS Purity (254nm): >-99%; t _R =4.15 min; HPLC purity (254 nm): >99%; t _R =4.31 min.

Example 65: 4-Chloro-N-(cyclohexylmethyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (48)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (200.00 mg; 0.79 mmol; 1.00 eq.), C-cyclohexyl-methylamine (103.46 mg; 0.91 mmol; 1.15 eq.), EDC (198.05 mg; 1.03 mmol; 1.30 eq.), benzotriazol-1-ol (139.60 mg; 1.03 mmol; 1.30 eq.) and ethyl-diisopropyl-amine (0.39 ml; 2.38 mmol; 3.00 eq.) in DCM (20 mL) to give 4-chloro-N-(cyclohexylmethyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (215, 78%).

¹ H NMR (400MHz, chloroform-d) δ8.11 (s, 1H), 7.40 (d, J=8.0Hz, 1H), 7.32–7.16 (m, 2H), 6.72 (s, 1H), 5.57 (p, J=6.9Hz, 1H), 5.19 (t, J=7 .4Hz, 2H), 5.06 (t, J=6.7Hz, 2H), 3.38 (t, J=6.3Hz, 2H), 1.89–1.59 (m, 6H), 1.37–1.14 (m, 4H), 1.05 (qd, J=11.7, 3.1Hz, 3H). [M+H]+:347.

Example 66: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2,2-difluoro-ethyl)-amide (76)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 2,2-difluoroethylamine hydrochloride (52.54 mg; 0.45 mmol; 1.5 eq.) to obtain the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2,2-difluoro-ethyl)-amide (89 mg; 0.28 mmol). [M+H] ⁺ 315.1; LC-MS (254 nm); t _R = 3.22 min; HPLC (254 nm); purity: >99%; t _R = 3.27 min.

Example 66: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (3,3,3-trifluoro-propyl)-amide (77)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 3,3,3-trifluoropropylamine (37.07 mg; 0.33 mmol; 1.1 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (3,3,3-trifluoro-propyl)-amide (10 mg; 0.03 mmol). [M+H] ⁺ 347.1. LC-MS (254 nm) t _R = 3.52 min; HPLC (254 nm) purity: 95.79%; t _R = 3.76 min.

Example 67: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (4,4,4-trifluoro-butyl)-amide (73)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 4,4,4-trifluorobutylamine (45.46 mg; 0.36 mmol; 1.20 eq.) to obtain the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (4,4,4-trifluoro-butyl)-amide (59.0 mg; 0.16 mmol). [M+H] ⁺ 361.1 LC-MS (254 nm) t _R = 4.48 min; HPLC (254 nm) purity: 99.82%; t _R = 4.03 min.

Example 68: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-ethoxy-propyl)-amide (78)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.) and 2-ethoxy-propylamine hydrochloride (27.74 mg; 0.2 mmol; 0.5 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-ethoxy-propyl)-amide (8.00 mg; 0.02 mmol). [M+H] ⁺ 337.1. LC-MS (254 nm) t _R = 4.14 min; HPLC (254 nm) purity: 96.69%; t _R = 3.50 min.

Example 69: Preparation of 4,4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (tetrahydro-pyran-3-ylmethyl)-amide (74)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and C-(tetrahydro-pyran-3-yl)-methylamine hydrochloride (54.23 mg; 0.36 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (tetrahydro-pyran-3-ylmethyl)-amide (72.0 mg; 0.21 mmol). [M+H] ⁺ 349.1. LC-MS (254 nm) t _R = 3.83 min; HPLC (254 nm) purity: >99%; t _R = 3.18 min.

Example 70: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclopentylmethyl)-amide (81)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.) and 1-(aminomethyl)cyclopentanol (22.88 mg; 0.2 mmol; 0.5 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclopentylmethyl)-amide (40.0 mg; 0.11 mmol). [M+H] ⁺ 349.1. LC-MS (254 nm) t _R = 3.12 min; HPLC (254 nm) purity: 97.70%; t _R = 3.20 min.

Example 71: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid [2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-amide (71)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 2-methyl-1,3-dioxolane-2-ethylamine (46.91 mg; 0.36 mmol; 1.20 eq.) to obtain the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid [2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-amide (26.0 mg; 0.07 mmol). [M+H] ⁺ 365.2. LC-MS (254 nm) t _R = 3.87 min; HPLC (254 nm) purity: 98.94%; t _R = 3.22 min.

Example 72: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-ethyl)-amide (82)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.) and 2-cyclopentyl-ethylamine (22.49 mg; 0.2 mmol; 0.5 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-ethyl)-amide (35.0 mg; 0.1 mmol). [M+H] ⁺ 347.2. LC-MS (254 nm) t _R = 4.23 min; HPLC (254 nm) purity: 95.97%; t _R = 4.65 min.

Example 73: Preparation of trans-4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid-2-hydroxy-cyclohexylmethyl)-amide (87)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.) and trans-2-aminomethyl-1-cyclohexanol (61.61 mg; 0.48 mmol; 1.20 eq.) to obtain the desired product (trans-4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid-2-hydroxy-cyclohexylmethyl) ^-amide (121.50 mg; 0.33 mmol). NMR (400MHz, DMSO) δ8.12 (s, 1H), 8.03 (t, J=5.8Hz, 1H), 7.64–7.51 (m, 1H), 7.29–7. 12(m, 2H), 5.88–5.72(m, 1H), 5.07(t, J＝7.3Hz, 2H), 4.93(td, J＝6.6, 3.3Hz, 2H), 4.7 5 (d, J＝4.8Hz, 1H), 3.43 (dt, J＝13.2, 4.6Hz, 1H), 3.36–3.26 (m, 1H), 3.19 (dt, J＝14. 2, 4.7Hz, 1H), 1.83 (m, 2H), 1.74–1.55 (m, 2H), 1.40 (m, 1H), 1.28–0.92 (m, 4H); [M+H] ⁺ 363.1LC-MS (254nm) t _R =3.30min; HPLC (254nm) purity: >99%; t _R =3.55min.

Example 74: Preparation of cis-4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexylmethyl)-amide (88)

The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.), cis-2-aminomethyl-cyclohexanol hydrochloride (65.83 mg; 0.40 mmol; 1.00 eq.) and HATU (188.86 mg; 0.50 mmol; 1.25 eq.) and N,N-diisopropylethylamine (0.20 ml; 1.19 mmol; 3.00 eq.) in DMF (4.05 ml; 52.50 mmol; 132.13 eq.) to obtain the desired product, cis-4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexylmethyl)-amide (86.50 mg; 0.24 mmol). ¹ H NMR (400MHz, DMSO) δ8.12 (s, 1H), 8.07 (t, J=5.9Hz, 1H), 7.64–7.52 (m, 1H), 7.28–7.12 (m, 2H), 5.87–5.72 (m, 1H), 5.06 (t, J=7.3Hz, 2H), 4.93 (td, J=6. 7, 1.7Hz, 2H), 4.36 (t, J=7.3Hz, 1H), 3.85 (s, 1H), 3.35–3.23 (m, 1H), 3.19– 3.04(m, 1H), 1.77–1.48(m, 4H), 1.46–1.29(m, 4H), 1.27–1.09(m, 1H); [M+H] ⁺ 363.1 LC-MS (254 nm) t _R =3.36 min; HPLC (254 nm) purity: 98.8%; t _R =3.57 min.

Example 75: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyloxy-ethyl)-amide (72)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 2-(cyclopentyloxy)ethylamine (46.20 mg; 0.36 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyloxy-ethyl)-amide (37.0 mg; 0.10 mmol). [M+H] ⁺ 363.2 LC-MS (254 nm) t _R = 4.86 min; HPLC (254 nm) purity: >99%; t _R = 4.11 min.

Example 76: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide (58)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-(aminomethyl)cyclohexanol (42.35 mg; 0.33 mmol; 1.10 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide (49.0 mg; 0.14 mmol). [M+H] ⁺ 363.2 LC-MS (254 nm) t _R = 4.12 min; HPLC (254 nm) purity: >99%; t _R = 3.53 min.

Example 77: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((1S,4R)-1-bicyclo[2.2.1]hept-2-ylmethyl)-amide (59)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and c-bicyclo[2.2.1]hept-2-yl-methylamine hydrobromide (67.57 mg; 0.33 mmol; 1.10 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((1S,4R)-1-bicyclo[2.2.1]hept-2-ylmethyl)-amide (65.0 mg; 0.18 mmol). [M+H] ⁺ 360.2; LC-MS (254 nm); t _R = 5.14 min; HPLC (254 nm); purity: >99%; t _R = 4.67 min.

Example 78: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((S)-1-cyclohexyl-2,2,2-trifluoro-ethyl)-amide (52)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-(aminomethyl)cyclohexanol (56.70 mg; 0.31 mmol; 1.05 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((S)-1-cyclohexyl-2,2,2-trifluoro-ethyl)-amide (19.7 mg; 0.05 mmol). [M+H] ⁺ 415.0 LC-MS (254 nm) t _R = 5.61 min; HPLC (254 nm) purity: >99%; t _R = 5.27 min.

Example 79: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (4-trifluoromethyl-cyclohexylmethyl)-amide (53)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-aminomethyl-4-trifluoromethylcyclohexane (56.70 mg; 0.31 mmol; 1.05 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (4-trifluoromethyl-cyclohexylmethyl)-amide (85.5 mg; 0.21 mmol). [M+H] ⁺ 415.0 LC-MS (254 nm) t _R = 5.11 min; HPLC (254 nm) purity: >99%; t _R = 4.79 min.

Example 80: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (3-trifluoromethyl-cyclohexylmethyl)-amide (56)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and [3-(trifluoromethyl)cyclohexyl]methanamine (56.70 mg; 0.31 mmol; 1.05 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (3-trifluoromethyl-cyclohexylmethyl)-amide (93.3 mg; 0.22 mmol). [M+H] ⁺ 415.0. LC-MS (254 nm) t _R = 5.13 min; HPLC (254 nm) purity: >99%; t _R = 4.01 min.

Example 81: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((R)-1-cyclohexyl-2-hydroxy-ethyl)-amide (63)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and d-cyclohexylglycinol (46.95 mg; 0.33 mmol; 1.10 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((R)-1-cyclohexyl-2-hydroxy-ethyl)-amide (75.0 mg; 0.20 mmol). [M+H] ^⁺ 377.2. LC-MS (254 nm) t _{_R} = 4.39 min; HPLC (254 nm) purity: >99%;t_{_R} = 3.94 min.

Example 82: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-hydroxy-propyl)-amide (49)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-amino-2-cyclopentylpropan-2-ol (42.68 mg; 0.30 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-hydroxy-propyl)-amide (86.6 mg; 0.23 mmol). [M+H] ^⁺ 377.1. LC-MS (254 nm) t _{_R} = 3.63 min; HPLC (254 nm) purity: >99%;t_{_R} = 3.90 min.

Example 83: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-cycloheptylmethyl)-amide (65)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-aminomethyl-cycloheptanol hydrochloride (64.26 mg; 0.36 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-phenyl-ethyl)-amide (24.0 mg; 0.06 mmol). [M+H] ^⁺ 377.1. LC-MS (254 nm) t _{_R} = 4.37 min; HPLC (254 nm) purity: >99%; t _{_R} = 3.81 min.

Example 84: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((1S,2S,4S)-2-bicyclo[2.2.1]hept-5-en-2-yl-ethyl)-amide (75)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 2-[(1s,2s,4s)-bicyclo[2.2.1]hept-5-en-2-yl]ethanamine (46.20 mg; 0.36 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((1S,2S,4S)-2-bicyclo[2.2.1]hept-5-en-2-yl-ethyl)-amide (53.0 mg; 0.14 mmol). [M+H] ⁺ 371.2. LC-MS (254 nm) t _R =5.16 min; HPLC (254 nm) purity: 97.14%; t _R =4.75 min.

Example 85: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-methyl-propyl)-amide (50)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 2-cyclopentyl-2-methylpropan-1-amine (42.10 mg; 0.30 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-methyl-propyl)-amide (76.4 mg; 0.20 mmol). [M+H] ⁺ 375.2. LC-MS (254 nm) t _R = 4.69 min; HPLC (254 nm) purity: >99%; t _R = 5.21 min.

Example 86: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-cyclohexyl-cyclopropyl)-amide (55)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-cyclohexyl-cyclopropylamine hydrochloride (57.6 mg; 0.33 mmol; 1.10 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-cyclohexyl-cyclopropyl)-amide (42.5 mg; 0.11 mmol). [M+H] ⁺ 473.2. LC-MS (254 nm) _tR = 5.39 min; HPLC (254 nm) purity: >99%; _tR = 4.84 min.

Example 87: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-amide (64)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-aminomethyl-3,3-dimethyl-cyclohexanol (56.24 mg; 0.36 mmol; 1.20 eq.) to afford the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-amide (105.9 mg; 0.27 mmol). [M+H] ^⁺ 391.2. LC-MS (254 nm) t _^R = 4.77 min; HPLC (254 nm) purity: >99%; t _^R = 4.28 min.

Example 88: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-adamantan-1-yl-ethyl)-amide (62)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and rimantadine hydrochloride (70.73 mg; 0.33 mmol; 1.10 eq.) to afford the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-adamantan-1-yl-ethyl)-amide (84.0 mg; 0.20 mmol). [M+H] ^⁺ 413.2. LC-MS (254 nm) t_{_R} = 5.98 min; HPLC (254 nm) purity: >99%;t_{_R} = 5.45 min.

Example 89: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid [(3-hydroxy-adamantan-1-yl)-ethyl]-amide (61)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and (1S,3R,5R,7S)-3-(1-amino-ethyl)-adamantan-1-ol hydrochloride (75.98 mg; 0.33 mmol; 1.10 eq.) to afford the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid [(3-hydroxy-adamantan-1-yl)-ethyl]-amide (96.0 mg; 0.22 mmol). [M+H] ⁺ 429.2. LC-MS (254 nm) t _R = 4.24 min; HPLC (254 nm) purity: >99%; t _R = 3.75 min.

Example 90: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-adamantan-1-yl-1-methyl-ethyl)-amide (54)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-adamantan-1-yl-1-methyl-ethylamine hydrochloride (75.33 mg; 0.33 mmol; 1.1 eq.) to afford the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-adamantan-1-yl-1-methyl-ethyl)-amide (78.0 mg; 0.18 mmol). [M+H] ⁺ 427.2. LC-MS (254 nm) t _R = 5.30 min; HPLC (254 nm) purity: >99%; t _R = 5.84 min.

Example 91: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (cyclohexyl-thiophen-2-yl-methyl)-amide (60)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and C-cyclohexyl-C-thiophen-2-yl-methylamine hydrochloride (75.98 mg; 0.33 mmol; 1.10 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (cyclohexyl-thiophen-2-yl-methyl)-amide (98.0 mg; 0.23 mmol). [M+H] ⁺ 429.1. LC-MS (254 nm) t _R = 5.69 min; HPLC (254 nm) purity: >99%; t _R = 5.32 min.

Example 92: Preparation of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-phenyl-ethyl)-amide (70)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and (2-cyclopentyl-2-phenylethyl)amine (67.70 mg; 0.36 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cyclopentyl-2-phenylethyl)-amide (24.0 mg; 0.06 mmol). [M+H] ⁺ 423.2. LC-MS (254 nm) t _R = 5.71 min; HPLC (254 nm) purity: >99%; t _R = 5.35 min.

Example 93: 4-Chloro-N-(2-(1-hydroxycyclopentyl)ethyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (45)

The title compound (230, 80%) was synthesized according to the procedure described in Example 2 using 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (200.00 mg; 0.79 mmol; 1.00 eq.), 1-(2-amino-ethyl)-cyclopentanol (118.08 mg; 0.91 mmol; 1.15 eq.), 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (198.05 mg; 1.03 mmol; 1.30 eq.), benzotriazol-1-ol (139.60 mg; 1.03 mmol; 1.30 eq.) and ethyl-diisopropyl-amine (0.39 ml; 2.38 mmol; 3.00 eq.).

¹ H NMR (400MHz, DMSO-d6) δ8.10 (s, 1H), 8.01 (t, J = 5.6Hz, 1H), 7.56 (d, J = 7.5Hz, 1H), 7.35–7.07 (m, 2H), 5. 80 (p, J=6.9Hz, 1H), 5.06 (t, J=7.2Hz, 2H), 4.92 (t, J=6.6Hz, 2H), 3.50–3.31 (m, 2H), 2.02–1.39 (m, 10H). [M+H]+:363.

Example 94: 4-Chloro-N-(1-cyclopentyl-2,2,2-trifluoroethyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (42)

The reaction mixture was prepared by using 4-chloro-1-oxetane-3-yl-1H-indole-3-carboxylic acid (175.00 mg; 0.70 mmol; 1.00 eq.), 1-cyclopentyl-2,2,2-trifluoro-ethylamine hydrochloride (162.84 mg; 0.80 mmol; 1.15 eq.), EDC (173.29 mg; 0.90 mmol; 1.30 eq.), benzotriazole-1-ol (122.15 mg; 0. The title compound was synthesized from a mixture of 4-chloro-N-(1-cyclopentyl-2,2,2-trifluoroethyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (47, 17%).

¹ H NMR (400 MHz, chloroform-d) δ 8.21 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.32–7.04 (m, 3H), 5.56 (m, 1H), 5.29–4.82 (m, 6H), 2.33 (m, 1H), 1.93 (m, 2H), 1.79–1.33 (m, 5H). [M+H]+: 401.

Example 95: 4-Chloro-N-(1-cyclohexyl-2,2,2-trifluoroethyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (43)

The reaction mixture was prepared by using 4-chloro-1-oxetane-3-yl-1H-indole-3-carboxylic acid (150.00 mg; 0.60 mmol; 1.00 eq.), 1-cyclohexyl-2,2,2-trifluoro-ethylamine hydrochloride (149.19 mg; 0.69 mmol; 1.15 eq.), EDC (148.54 mg; 0.77 mmol; 1.30 eq.), benzotriazole-1-ol (104.70 mg; 0. From a mixture of 4-chloro-N-(1-cyclohexyl-2,2,2-trifluoroethyl)-1-(oxetane-3-yl)-1H-indole-3-carboxamide (84, 34%), 4-nitro-2-nitro-1-nitro-2-nitro-1-nitro-1-nitro-2-nitro-1-nitro-2-nitro-1-nitro-2-nitro-1-nitro-2-nitro-1-nitro-2-nitro-2-nitro-1-nitro-2-nitro-2-nitro-1-nitro-2-nitro-2-nitro-3-nitro-2-nitro-1-nitro-2-nitro-2-nitro-3-nitro-2-nitro-1-nitro-2-nitro-2-nitro-2-nitro-3 ...

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.36–7.04 (m, 3H), 5.74–5.51 (m, 1H), 5.20 (t, J = 7.4 Hz, 2H), 5.07 (m, 2H), 4.89 (pd, J = 9.0, 4.3 Hz, 1H), 2.04–1.53 (m, 7H), 1.43–0.99 (m, 4H), [M+H]+: 415.

Example 96: Preparation of 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (93)

To a stirred solution of 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (0.070 g, 0.27 mmol), HATU (0.116 g, 0.30 mmol), and (1R,3R)-1-(aminomethyl)-3-methylcyclohexanol (0.040 g, 0.27 mmol) in DMF (1.5 mL) was added DIPEA (0.107 g, 0.83 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and extracted with DCM/methanol (10:1, 30 mL x 3). The combined organic layers were washed with water (20 mL x 2) and brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol=80:1) to obtain 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (0.06 mg, 57%) as a white solid.

¹ H NMR (500MHz, DMSO-δ ₆ )δ8.17 (s, 1H), 7.86 (t, J=7.5Hz, 1H), 7.56 (dd, J=10.0, 1.5Hz, 1H), 7.22-7.16 (m, 2 H), 5.83-5.77 (m, 1H), 5.05 (t, J=9.0Hz, 2H), 4.92 (t, J=8.0Hz, 2H), 4.23 (s, 1H), 3. 20(d, J=7.5Hz, 2H), 1.73-1.66(m, 1H), 1.60-1.52(m, 4H), 1.46-1.43(m, 1H), 1.25- 1.17(m, 1H), 0.98-0.92(m, 1H), 0.82(d, J=8.0Hz, 3H), 0.77-0.70(m, 1H)ppm; [M+H] ^+377.1 .

Example 97: Preparation of 4-chloro-N-(((1S,3S)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (90)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (0.080 g, 0.31 mmol), HOBt (0.047 g, 0.35 mmol), DIPEA (0.123 g, 0.95 mmol), EDCI (0.067 g, 0.35 mmol) and (1S,3S)-1-(aminomethyl)-3-methylcyclohexanol (0.045 g, 0.31 mmol) in DCM to afford 4-chloro-N-(((1S,3S)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (0.060 g, 50%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.19 (s, 1H), 7.88 (t, J=6.0Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.23-7.18 (m, 2H), 5 .84-5.79(m, 1H), 5.07(t, J＝7.5Hz, 2H), 4.93(t, J＝6.5Hz, 2H), 4.24(s, 1H), 3.21( d, J=6.5Hz, 2H), 1.75-1.70 (m, 1H), 1.64-1.54 (m, 4H), 1.47-1.45 (m, 1H), 1.28-1 .20(m, 1H), 0.99-0.94(m, 1H), 0.84(d, J=6.5Hz, 3H), 0.81-0.72(m, 1H)ppm; [M+H] ^+377.1 .

Example 98: 4-Chloro-N-((1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (83)

The title compound was synthesized using 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (250.00 mg; 0.99 mmol; 1.00 eq.), (HATU) (415.49 mg; 1.09 mmol; 1.10 eq.), DIEA (0.33 ml; 1.99 mmol; 2.00 eq.) and 1-aminomethyl-3-methyl-cyclohexanol (156.51 mg; 1.09 mmol; 1.10 eq.) according to the procedure described in Example 5. The reaction mixture was stirred for 3 hours to give 4-chloro-N-((1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (63 mg, 16.8%).

¹ H NMR (400 MHz, chloroform-d) δ 8.13 (s, 1H), 7.39 (dd, J = 8.0, 1.2 Hz, 1H), 7.32-7.16 (m, 2H), 5.55 (tt, J = 7.5, 6.1 Hz, 1H), 5.17 (t, J = 7.4 Hz, 2H), 5.04 (dd, J = 7.3, 6.1 Hz, 2H), 3.55-3.45 (m, 2H), 1.84-1.56 (m, 8H), 1.37-1.17 (m, 1H), 1.07-0.76 (d, 4H). [M+H]+377.

Example 99: Preparation of 4-chloro-N-((3,3-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (69)

The title compound (130 mg, 90% yield) was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.), (3,3-difluorocyclohexyl)methanamine (91.41 mg; 0.48 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (91.41 mg; 0.48 mmol; 1.20 eq.), benzotriazol-1-ol (64.43 mg; 0.48 mmol; 1.20 eq.) and DIPEA (0.154 g, 1.19 mmol) in DMF (6.0 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.20(1H), 8.12(s, 1H), 7.58(1H), 7.20(2H), 5.80(1H), 5.09(m, 2H), 4.94 (2H), 3.23-3.15(2H), 2.12-1.96(m, 3H), 1.77(2H), 1.59(2H), 1.01(1H). m/z: 383[M+H].

Example 100: Preparation of 4-chloro-N-(((R)-3,3-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (66)

The racemic 4-chloro-N-((3,3-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide was separated using a chiral column to provide the title compound. Separation: 200 mg of the racemic compound was dissolved in 30 mL of a solvent consisting of methanol:IPA:ACN (2:3:5). Column: Chiral Pac IC-H 2-x250 mm. Mobile phase: 30% 2-methanol containing 0.5% DMEA in CO2. Flow rate: 70 mL/min.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.20(1H), 8.12(s, 1H), 7.58(1H), 7.20(2H), 5.80(1H), 5.09(m, 2H), 4.94 (2H), 3.23-3.15(2H), 2.12-1.96(m, 3H), 1.77(2H), 1.59(2H), 1.01(1H). m/z: 383[M+H].

Example 101: Preparation of 4-chloro-N-(((S)-3,3-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (67)

The racemic 4-chloro-N-((3,3-difluorocyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide was isolated to provide the title compound (see Example 100).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.20(1H), 8.12(s, 1H), 7.58(1H), 7.20(2H), 5.80(1H), 5.09(m, 2H), 4.94 (2H), 3.23-3.15(2H), 2.12-1.96(m, 3H), 1.77(2H), 1.59(2H), 1.01(1H). m/z：383[M+H]

Example 102: 4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (86)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (50.00 mg; 0.20 mmol; 1.00 eq.), 1-(aminomethyl)-3-difluorocyclohexanol (36.13 mg; 0.25 mmol; 2.50 eq.) and (tributyl-λ5-phosphinilide)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.22(1H), 8.01(s, 1H), 7.58(1H), 7.20(2H), 5.80(1H), 5.05(m, 2H), 4.94(2H), 4. 65(s, 1H), 3.43(1H), 3.23(1H), 2.02-1.96(m, 3H), 1.77(2H), 1.59(2H), 1.51(1H). m/z: 399[M+H].

Example 103: (R)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (84)

The racemic compound of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide was separated using a chiral column to obtain the title compound. Separation: Mobile phase: hexane:hexanol:DEA = 70:30:0.1; flow rate: 1.0 mL/min; run time: 25 min. Column: Chiral PAK AY-H (250 x 4.6 mm, 5 μm).

¹ H NMR (400MHz, chloroform-d) δ8.07 (d, J=7.6Hz, 1H), 7.39 (t, J=7.4Hz, 2H), 7.32–7.06 (m, 1H), 5.56 (d, J=6.9Hz, 1H), 5.17 (q, J=7.3Hz, 2H) , 5.03 (t, J=6.8Hz, 2H), 3.78–3.33 (m, 1H), 2.21–2.02 (m, 1H), 1.99–1.74 (m, 4H), 1.65 (q, J=11.5, 9.6Hz, 5H), 1.37–1.12 (m, 5H). [M+H] ⁺³⁹⁹ .

Example 104: (S)-4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (85)

The racemic compound of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide was isolated (see Example 103). [M+H] ⁺ 399.

Example 105: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (92)

The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (0.070 g, 0.27 mmol), HATU (0.116 g, 0.30 mmol) and a mixture of 1-(aminomethyl)-4,4-difluorocyclohexanol hydrochloride (0.056 g, 0.27 mmol) and DIPEA (0.107 g, 0.83 mmol) in DMF to afford 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (0.06 mg, 54%) as a white solid.

¹ H NMR (500MHz, DMSO-δ ₆ )δ8.19 (s, 1H), 8.05 (t, J=6.0Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.23-7.18 (m, 2H), 5.85-5.79 (m, 1H), 5.07 (t, J=7.0Hz, 2H), [M+H] ^+399.1 .

Example 106: Preparation of 4-chloro-N-((3,3-difluoro-5-(trifluoromethyl)cyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (91)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(oxetan-3-yl)-1H-indole-3-carboxylic acid (0.050 g, 0.20 mmol), (3,3-difluoro-5-(trifluoromethyl)cyclohexyl)methanamine (0.043 g, 0.20 mmol), HATU (0.083 g, 0.22 mmol) and DIPEA (0.077 g, 0.60 mmol) in DMF to afford 4-chloro-N-((3,3-difluoro-5-(trifluoromethyl)cyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (0.030 g, 33%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.26 (t, J=6.0Hz, 1H), 8.13-8.11 (m, 1H), 7.58 (d, J=8.0Hz, 1H), 7.23-7.18 (m, 2H), 5.84-5.78 (m, 1H), 5.06 (t, J=7.5Hz, 2H), 4.93 (t, J =6.5Hz, 2H), 3.35-3.22(m, 2H), 2.66-2.64(m, 1H), 2.23-2.18(m, 2H), 2.03-1.82(m, 3H), 1.74-1.61(m, 1H), 1.26-1.19(m, 1H)ppm; [M+H] ⁺ 451.1.

Example 107: Preparation of 4-chloro-N-((3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (89)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.), (EDCI) (91.41 mg; 0.48 mmol; 1.20 eq.), HOBt (64.4 g, 0.48 mmol), TEA (80.42 mg; 0.79 mmol; 2.00 eq.) and 1-aminomethyl-3,3-difluoro-5-methyl-cyclohexanol (78.33 mg; 0.44 mmol; 1.10 eq.) to give 4-chloro-N-((3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (40 mg, 24%).

^1H NMR (400 MHz, CHLOROFORM-d) δ 8.24–8.09 (m, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.27 (ddd, J=24.3, 13.2, 6.2 Hz, 3H), 5.55 (p, J=7.2 Hz, 1H), 5.18 (t, J=7.6 Hz, 2H), 5.10–4.92 (m, 2H), 3.79 (dd, J=14.7, 6.3 Hz, 1H), 3.51–3.34 (m, 2H), 2.55–2.34 (m, 1H), 2.19–1.66 (m, 5H), 1.52–1.15 (m, 3H), 1.03 (d, J=6.5 Hz, 2H). [M+H]+413.

Example 108: Preparation of 4-chloro-1-(oxetan-3-yl)-N-(spiro[2.5]octan-5-ylmethyl)-1H-indole-3-carboxamide (68)

The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (150.00 mg; 0.60 mmol; 1.00 eq.), HATU (249.29 mg; 0.66 mmol; 1.10 eq.), DIEA (0.20 ml; 1.19 mmol; 2.00 eq.) and C-spiro[2.5]octan-5-yl-methylamine (91.29 mg; 0.66 mmol; 1.10 eq.) to afford 4-chloro-1-(oxetan-3-yl)-N-(spiro[2.5]octan-5-ylmethyl)-1H-indole-3-carboxamide (140 mg, 63%). [M+H]+ 373.

Example 109: Preparation of 4-chloro-N-((5-hydroxyspiro[2.5]octan-5-yl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (57)

The reaction mixture was prepared by mixing 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (150.00 mg; 0.60 mmol; 1.00 eq.), 5-aminomethyl-spiro[2.5]octan-5-ol hydrochloride (131.40 mg; 0.69 mmol; 1.15 eq.), EDC (148.54 mg; 0.77 mmol; 1.30 eq.), benzotriazole-1-ol (104.70 mg; From the mixture of 4-chloro-N-((5-hydroxyspiro[2.5]octan-5-yl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (50 mg, 20%), 4-chloro-N-((5-hydroxyspiro[2.5]octan-5-yl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (50 mg, 20%).

¹ H NMR (400MHz, chloroform-d) δ 8.11 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.33–7.16 (m, 2H), 7.09 (d, J = 6.3Hz, 1H), 5.56 (p, J = 6.8Hz, 1H) , 5.12 (dt, J=50.5, 7.0Hz, 4H), 3.76–3.46 (m, 2H), 1.83–1.53 (m, 6H), 1.48–1.11 (m, 4H), 0.49–0.17 (m, 4H), [M+H]+389.

Example 110: Preparation of 4-chloro-N-((1-hydroxy-3-(trifluoromethyl)cyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (47)

The reaction mixture was prepared by mixing 4-chloro-1-oxetane-3-yl-1H-indole-3-carboxylic acid (200.00 mg; 0.79 mmol; 1.00 eq.), 1-aminomethyl-3-trifluoromethyl-cyclohexanol hydrochloride (213.54 mg; 0.91 mmol; 1.15 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (198.05 mg; 1.03 mmol; 1.30 eq.), benzene The title compound was synthesized according to the procedure described in Example 2 using 1-triazole-1-ol (139.60 mg; 1.03 mmol; 1.30 eq.) and ethyl-diisopropyl-amine (0.39 ml; 2.38 mmol; 3.00 eq.) to obtain 4-chloro-N-((1-hydroxy-3-(trifluoromethyl)cyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (125 mg, 36%).

¹ H NMR (400 MHz, chloroform-d) δ 8.04–7.92 (m, 1H), 7.40–7.26 (m, 2H), 7.23–7.04 (m, 2H), 5.58–5.41 (m, 1H), 5.10 (t, J = 7.3 Hz, 2H), 4.95 (q, J = 6.7, 6.0 Hz, 2H), 3.62 (dd, J = 14.0, 6.3 Hz, 1H), 3 .44 (dd, J＝14.1, 5.4Hz, 1H), 2.39–2.15 (m, 1H), 2.39–2.17 (m, 1H), 2.29 (dpd, J＝12.8, 8.5 , 4.4Hz, 1H), 2.41–2.15(m, 1H), 2.11–1.97(m, 1H), 1.91–1.65(m, 2H), 1.57–1.02(m, 4H). [M+H]+:431.

Example 111: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (46)

The reaction mixture was prepared by using 4-chloro-1-oxetane-3-yl-1H-indole-3-carboxylic acid (200.00 mg; 0.79 mmol; 1.00 eq.), 1-aminomethyl-4,4-difluoro-3-methyl-cyclohexanol hydrochloride (197.10 mg; 0.91 mmol; 1.15 eq.), 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (198.05 mg; 1.03 mmol; 1.30 eq.), benzotriazole-1-ol (139. A mixture of 4-chloro-N-((4,4-difluoro-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetane-3-yl)-1H-indole-3-carboxamide (177 mg, 54%) was prepared from 4-chloro-N-((4,4-difluoro-1-hydroxy-3-methylcyclohexyl)methyl)-1-(oxetane-3-yl)-1H-indole-3-carboxamide (177 mg, 54%).

1H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 8.04 (t, J=6.2Hz, 1H), 7.58 (dd, J=7.6, 1.6Hz, 1H), 7.34–7.07 (m, 2H), 5.91–5. 73 (m, 1H), 5.08 (t, J = 7.3Hz, 2H), 4.94 (t, J = 6.6Hz, 2H), 3.64–3.42 (m, 1H), 2.36–1.25 (m, 7H), 0.96 (d, J = 6.6Hz, 3H). [M+H]+:413.

Example 112: Preparation of 4-chloro-1-(oxetan-3-yl)-N-((1-(4-phenylpiperazin-1-yl)cyclohexyl)methyl)-1H-indole-3-carboxamide (51)

The reaction mixture was prepared by using 4-chloro-1-oxetane-3-yl-1H-indole-3-carboxylic acid (150.00 mg; 0.60 mmol; 1.00 eq.), C-[1-(4-phenyl-piperazin-1-yl)-cyclohexyl]-methylamine (187.41 mg; 0.69 mmol; 1.15 eq.), (EDC) (148.54 mg; 0.77 mmol; 1.30 eq.), benzotriazole-1-ol (10 The title compound was synthesized from a mixture of 4-chloro-1-(oxetane-3-yl)-N-((1-(4-phenylpiperazin-1-yl)cyclohexyl)methyl)-1H-indole-3-carboxamide (245, 81%).

¹ H NMR (400MHz, chloroform-d) δ8.06 (d, J=19.6Hz, 1H), 7.39 (d, J=7.9Hz, 1H), 7.35–7.08 (m, 5H), 7.00–6.78 (m, 3H), 5.63–5.46 (m, 1H), 5 .18 (t, J=7.4Hz, 2H), 5.07 (t, J=6.7Hz, 2H), 3.86–3.61 (m, 2H), 3.34–3.02 (m, 4H), 2.88 (d, J=15.7Hz, 4H), 1.84–1.41 (m, 10H). [M+H]+:508.

Example 113: Preparation of 4-chloro-1-(oxetan-3-yl)-N-((4-(4-phenylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxamide (44)

The title compound (75 mg, 25%) was synthesized according to the procedure described in Example 2 using 4-chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (150.00 mg; 0.60 mmol; 1.00 eq.), C-[4-(4-phenyl-piperazin-1-yl)-tetrahydro-pyran-4-yl]-methylamine (188.76 mg; 0.69 mmol; 1.15 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (EDC) (148.54 mg; 0.77 mmol; 1.30 eq.), benzotriazol-1-ol (104.70 mg; 0.77 mmol; 1.30 eq.) and ethyl-diisopropyl-amine (0.29 ml; 1.79 mmol; 3.00 eq.).

¹ H NMR (400MHz, chloroform-d) δ8.13 (s, 1H), 7.40 (d, J=7.8Hz, 1H), 7.33–7.12 (m, 4H), 6.91 (dd, J=21.3, 7.7Hz, 4H), 5.56 (p, J=6.9Hz, 1H), 5.18 (t, J=7.4H z, 2H), 5.07 (t, J=6.7Hz, 2H), 4.04-3.63 (m, 6H), 3.20 (t, J=4.6Hz, 4H), 2.88 (t, J=4.8Hz, 4H), 1.99 (ddd, J=13.6, 9.8, 4.4Hz, 2H), 1.70 (s, 2H). [M+H]+:510.

Example 114: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxamide (116MSC2498716)

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.050 g, 0.15 mmol), oxetan-2-ylmethanol (0.027 g, 0.31 mmol), and CMTP (0.074 g, 0.31 mmol) in toluene (2 mL) was stirred at 110° C. under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated to a residue, which was purified by preparative TLC (methanol:DCM=1:10) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxamide (0.040 g, 43%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.13 (t, J=6.0Hz 1H), 7.71 (s, 1H), 7.60 (d, J=8.0Hz1H), 7.18-7.12 (m, 2H), 5.03-4.98 (m, 1H), 4.53-4.40 (m, 3H), 4.33-4.29 (m, 1H), 3.15 ( t, J=6.5Hz, 2H), 2.68-2.61(m, 1H), 2.36-2.30(m, 1H), 2.05-1.99(m, 2H), 1.84-1.78(m, 4H), 1.28-1.20(m, 3H)ppm; [M+H] ⁺³⁹⁷ .

Example 115: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxamide (115)

Step 1: Preparation of 4-chloro-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxylic acid

To a round-bottom flask was added 1-(4-chloro-1-(oxetan-2-ylmethyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (0.650 g, 2.05 mmol) and 30% aqueous NaOH (6 mL). The mixture was heated at 105°C for 2 hours and then cooled to room temperature. The pH of the mixture was adjusted to 3 with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried under vacuum to obtain 4-chloro-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxylic acid (0.160 g, 29.5%). LCMS m/z: 266.1 [M+H] ⁺ .

Step 2: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-1-(oxetan-2-ylmethyl)-1H-indole-3-carboxylic acid (0.090 g, 0.34 mmol), HOBt (0.0687 mg, 0.51 mmol), EDCI (0.130 g, 0.68 mmol), and TEA (0.138 g, 1.02 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour, and 1-(aminomethyl)-4,4-difluorocyclohexanol (0.0819 g, 0.38 mmol) was added. The reaction was stirred at room temperature for 3 hours, diluted with DCM (20 ml), washed with water (3 x 3 mL), dried (Na ₂ SO ₄ ), and concentrated in vacuo. The residue was purified by preparative HPLC to afford a white solid (0.060 g, 40.8%).

¹ H NMR (500 MHz, DMSO-d ₆ )δ7.98 (t, J=5.5Hz, 1H), 7.79 (s, 1H), 7.61 (d, J=8.0Hz, 1H), 7.19 (t, J=7. 5Hz, 1H), 7.15 (d, J=9.0Hz, 1H), 5.01 (s, 1H), 4.74 (s, 1H), 4.54-4.45 (m, 3H ), 4.32-4.29(m, 1H), 3.32-3.30(m, 2H), 2.67-2.64(m, 1H), 2.38-2.32(m, 1H), 2.09-1.96(m, 2H), 1.90-1.88(m, 2H), 1.65(t, J=8.0Hz, 4H)ppm; [M+H] ⁺ 413.1.

Example 116: 4-Chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (99)

The reaction mixture was prepared by using 4-chloro-1-(tetrahydro-furan-2-yl)-1H-indole-3-carboxylic acid (150.00 mg; 0.56 mmol; 1.00 eq.), C-(4,4-difluoro-cyclohexyl)-methylamine hydrochloride (120.53 mg; 0.65 mmol; 1.15 eq.), EDC (140.70 mg; 0.73 mmol; 1.30 eq.), benzotriazole-1-ol (99.17 mg; 0 .73mmol; 1.30eq.) and ethyl-diisopropyl-amine (0.28ml; 1.69mmol; 3.00eq.) in N,N-dimethyl-formamide (3.00ml) were used to synthesize the title compound according to the procedure described in Example 2 to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (210mg, 94%).

¹ H NMR (400MHz, DMSO-d6) δ8.18 (t, J=6.1Hz, 1H), 7.77 (s, 1H), 7.59 (d, J=7.8Hz, 1H), 7.29–7.06 (m, 2H), 6.45–6.24 (m, 1H), 3. 99 (dq, J=62.8, 7.5Hz, 2H), 3.16 (t, J=6.5Hz, 2H), 2.46–1.95 (m, 6H), 1.93–1.59 (m, 5H), 1.25 (q, J=15.1, 13.6Hz, 2H), [M+H] ⁺³⁹⁷ .

Example 117: 4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (98)

The reaction mixture was prepared by using 4-chloro-1-(tetrahydro-furan-2-yl)-1H-indole-3-carboxylic acid (150.00 mg; 0.56 mmol; 1.00 eq.), 1-aminomethyl-4,4-difluoro-cyclohexanol hydrochloride (130.92 mg; 0.65 mmol; 1.15 eq.), EDC (140.70 mg; 0.73 mmol; 1.30 eq.), benzotriazole-1-ol (99.17 mg; 0.73 From a mixture of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (210 mg, 90%), and ethyl-diisopropyl-amine (0.28 ml; 1.69 mmol; 3.00 eq.) in N,N-dimethylformamide (3.00 ml), the title compound was synthesized according to the procedure described in Example 2 to obtain 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (210 mg, 90%).

¹ H NMR (400MHz, DMSO-d6) δ8.06 (t, J=6.3Hz, 1H), 7.84 (s, 1H), 7.60 (d, J=7.7Hz, 1H), 7.33–7.08 (m, 2H), 6 .36(t, J=5.2Hz, 1H), 4.16–3.85(m, 2H), 2.49–2.26(m, 3H), 2.21–1.77(m, 7H), 1.73–1.57(m, 4H), [M+H] ⁺⁴¹³ .

Example 118: 4-Chloro-N-((4,4-difluoro-1-hydroxy-3-methylcyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (97)

The reaction mixture was prepared by mixing 4-chloro-1-(tetrahydro-furan-2-yl)-1H-indole-3-carboxylic acid (200.00 mg; 0.75 mmol; 1.00 eq.), 1-aminomethyl-4,4-difluoro-3-methyl-cyclohexanol hydrochloride (186.70 mg; 0.87 mmol; 1.15 eq.), EDC (187.59 mg; 0.98 mmol; 1.30 eq.), benzotriazole-1-ol (132.23 mg; 0. The title compound was synthesized from a mixture of 4-chloro-N-((4,4-difluoro-1-hydroxy-3-methylcyclohexyl)methyl)-1-(tetrahydrofuran-2-yl)-1H-indole-3-carboxamide (205, 65%).

¹ H NMR (400MHz, DMSO-d6) δ8.06 (t, J=6.3Hz, 1H), 7.89 (s, 1H), 7.61 (d, J=7.5Hz, 1H), 7.31–7.10 (m, 2H), 6.36 (dd, J=6.7, 3.6Hz, 1H), 4.84 (s, 1H), 4.00 (m, 2H), 3.63–3.39 (m, 2H), 2.49–1.27 (m, 9H), 0.97 (d, J=6.6Hz, 3H), [M+H] ⁺⁴²⁷ .

Example 119: 4-Chloro-N-(cyclohexylmethyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (101)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (150.00 mg; 0.56 mmol; 1.00 eq.), C-cyclohexyl-methylamine (73.50 mg; 0.65 mmol; 1.15 eq.), EDC (140.70 mg; 0.73 mmol; 1.30 eq.), benzotriazol-1-ol (99.17 mg; 0.73 mmol; 1.30 eq.) and ethyl-diisopropyl-amine (0.28 ml; 1.69 mmol; 3.00 eq.) in N,N-dimethyl-formamide (3.00 ml) to give 4-chloro-N-(cyclohexylmethyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (140 mg, 69%).

¹ H NMR (400MHz, chloroform-d) δ7.93 (s, 1H), 7.39 (d, J = 7.9Hz, 1H), 7.22 (dt, J = 15.7, 7.7Hz, 2H), 6.64 (d, J = 6.8Hz, 1H), 5.07 (ddt, J = 8.4, 5.9, 3.2H z, 1H), 4.28–3.88 (m, 5H), 3.37 (t, J=6.4Hz, 2H), 2.69–2.42 (m, 1H), 2.25 (tt, J=13.4, 5.8Hz, 1H), 1.92–1.61 (m, 5H), 1.36–0.94 (m, 5H). [M+H] ⁺ 361.

Example 120: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (3-trifluoromethyl-cyclohexylmethyl)-amide (112)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (75.00 mg; 0.28 mmol; 1.00 eq.), HATU (214.67 mg; 0.56 mmol; 2.00 eq.), [3-(trifluoromethyl)cyclohexyl]methanamine (53.71 mg; 0.30 mmol; 1.05 eq.) and n,n-diisopropylethylamine (DIPEA) (0.19 ml; 1.13 mmol; 4.00 eq.) in DMF (2.88 ml; 37.30 mmol; 132.13 eq.) to give 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (3-trifluoromethyl-cyclohexylmethyl)-amide (75.00 mg; 0.17 mmol). [M+H] ⁺ 429.2; LC-MS (254 nm) t _R =4.39 min; HPLC (254 nm) purity: 97.53%; t _R =97.53 min.

Example 121: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (1-cyclohexyl-3-hydroxy-propyl)-amide (110)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (75.00 mg; 0.28 mmol; 1.00 eq.) and 3-amino-3-cyclohexyl-propan-1-ol (46.61 mg; 0.30 mmol; 1.05 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (1-cyclohexyl-3-hydroxy-propyl)-amide (19.0 mg; 0.05 mmol). [M+H] ⁺ 405.3 LC-MS (254 nm) t _R = 3.92 min; HPLC (254 nm) purity: >99%; t _R = 4.31 min.

Example 122: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclohexyl-2-dimethylamino-ethyl)-amide (111)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and n-(2-amino-1-cyclohexylethyl)-n,n-dimethylamine (50.47 mg; 0.30 mmol; 1.05 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclohexyl-2-dimethylamino-ethyl)-amide (51 mg; 0.12 mmol). [M+H] ⁺ 418.1. LC-MS (254 nm) _tR = 2.97 min; HPLC (254 nm) purity: 96.30%; _tR = 3.37 min.

Example 123: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid ((1R,4S)-1-bicyclo[2.2.1]hept-2-yl-ethyl)-amide (109)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (75.00 mg; 0.28 mmol; 1.00 eq.) and 1-bicyclo[2.2.1]hept-2-yl-ethylamine hydrochloride (52.08 mg; 0.30 mmol; 1.05 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid ((1R,4S)-1-bicyclo[2.2.1]hept-2-yl-ethyl)-amide (52.0 mg; 0.13 mmol). [M+H] ^⁺ 387.1. LC-MS (254 nm) t_{_R} = 5.56 min; HPLC (254 nm) purity: >99%;t_{_R} = 5.10 min.

Example 124: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-ethyl)-amide (108)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and 2-cyclopentyl-ethylamine hydrochloride (46.47 mg; 0.31 mmol; 1.10 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-ethyl)-amide (40.0 mg; 0.11 mmol). [M+H] ⁺ 361.1. LC-MS (254 nm) t _R = 4.39 min; HPLC (254 nm) purity: >99%; t _R = 4.06 min.

Example 125: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-amide (107)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and 1-aminomethyl-3,3-dimethyl-cyclohexanol hydrochloride (65.62 mg; 0.34 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-amide (51.0 mg; 0.13 mmol). [M+H]^⁺ 405.2. LC-MS (254 nm) t _{_R} = 4.10 min; HPLC (254 nm) purity: 97.80%; t_{_R} = 4.50 min.

Example 126: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (106)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (75.00 mg; 0.28 mmol; 1.00 eq.) and 1-aminomethyl-3,3-dimethyl-cyclohexanol hydrochloride (65.62 mg; 0.34 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (58.0 mg; 0.14 mmol). [M+H] ^⁺ 427.1. LC-MS (254 nm) t_{_R} = 3.72 min; HPLC (254 nm) purity: 97.07%; t_{_R} = 4.09 min.

Example 127: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (104)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and 1-aminomethyl-4,4-difluoro-cyclohexanol hydrochloride (68.30 mg; 0.34 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (45.0 mg; 0.11 mmol). [M+H] ⁺ 413.1. LC-MS (254 nm) _tR = 3.54 min; HPLC (254 nm) purity: 96.35%; _tR = 3.82 min.

Example 128: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid ((1S,4R)-1-bicyclo[2.2.1]hept-2-ylmethyl)-amide (105)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and c-bicyclo[2.2.1]hept-2-yl-methylamine hydrobromide (69.82 mg; 0.34 mmol; 1.20 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid ((1S,4R)-1-bicyclo[2.2.1]hept-2-ylmethyl)-amide (62.0 mg; 0.17 mmol). [M+H] ⁺ 373.1. LC-MS (254 nm) t _R = 4.43 min; HPLC (254 nm) purity: 98.79%; t _R = 4.88 min.

Example 129: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-2-methyl-propyl)-amide (103)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and 2-cyclopentyl-2-methylpropan-1-amine (39.87 mg; 0.28 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-2-methyl-propyl)-amide (67.1 mg; 0.17 mmol). [M+H] ^⁺ 389.2. LC-MS (254 nm) t _{_R} = 4.87 min; HPLC (254 nm) purity: >99%; t _{_R} = 5.41 min.

Example 130: Preparation of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-2-hydroxy-propyl)-amide (102)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and 1-amino-2-cyclopentylpropan-2-ol (40.43 mg; 0.28 mmol; 1.00 eq.) to give the desired product, 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-2-hydroxy-propyl)-amide (48.0 mg; 0.12 mmol). [M+H] ^⁺ 391.1. LC-MS (254 nm) t _{_R} = 3.81 min; HPLC (254 nm) purity: >99%; t _{_R} = 4.10 min.

Example 131: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (114)

The title compound was synthesized according to the procedure described in Example 33 using tetrahydrofuran-3-ol (0.055 g, 0.62 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.100 g, 0.31 mmol) and cyanomethylenetributylphosphorane (0.296 g, 1.24 mmol) to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (0.045 g, 30%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.14 (s, 1H), 7.72 (s, 1H), 7.62 (d, J=7.0Hz, 1H), 7.21-7.17 (m, 2H), 5.30 (s, 1H), 4.10 (d, J=6.0Hz, 1H), 3.98-3.95 (m, [M+H] ^+397.1 .

Example 132: Preparation of 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (113)

The reaction mixture was prepared by using 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (150.00 mg; 0.56 mmol; 1.00 eq.), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (92.99 mg; 0.65 mmol; 1.15 eq.), EDCI (140.70 mg; 0.73 mmol; 1.30 eq.), benzotriazole-1-ol (99.17 mg; 0.73 mmol; 1.30 eq.), and 1-amino-2-methyl-3-methyl-cyclohexanol (92.99 mg; 0.65 mmol; 1.15 eq.). From a mixture of 1H-(4-chloro-2-nitro-1H-indole-3-carboxamide (4-nitro-1H-indole-3-carboxamide) (1.57 ml; 1.30 eq.) and ethyl-diisopropyl-amine (0.28 ml; 1.69 mmol; 3.00 eq.) in N,N-dimethylformamide (3.00 ml), the title compound was synthesized according to the procedure described in Example 2 to obtain 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (167 mg, 76%).

¹ H NMR (400MHz, chloroform-d) δ8.03 (s, 1H), 7.40 (d, J=7.9Hz, 1H), 7.24 (dt, J=15.6, 7.6Hz, 2H), 5.08 (ddt, J=8.7, 6.0, 3.0Hz, 1H) , 4.30–3.91 (m, 4H), 3.57–3.42 (m, 2H), 2.69–2.47 (m, 4H), 2.33–2.15 (m, 1H), 1.89–1.58 (m, 6H), 0.92 (d, J=6.2Hz, 4H). [M+H] ⁺³⁹¹ .

Example 133: Preparation of 4-chloro-N-((1-hydroxy-3-(trifluoromethyl)cyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (100)

The reaction mixture was prepared using 4-chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (200.00 mg; 0.75 mmol; 1.00 eq.), 1-aminomethyl-3-trifluoromethyl-cyclohexanol hydrochloride (202.27 mg; 0.87 mmol; 1.15 eq.), EDC (187.59 mg; 0.98 mmol; 1.30 eq.), benzotriazole-1-ol (132.23 mg; 0.98 From a mixture of 4-chloro-N-((1-hydroxy-3-(trifluoromethyl)cyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (40 mg, 13%), 4-chloro-N-((1-hydroxy-3-(trifluoromethyl)cyclohexyl)methyl)-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxamide (40 mg, 13%).

1H NMR (400MHz, chloroform-d) δ7.85 (d, J=9.1Hz, 1H), 7.40–7.06 (m, 4H), 5.13–4.91 (m, 1H), 4.09 (m, 4H), 3 .91(m, 5.5Hz, 1H), 3.75–3.30(m, 2H), 2.66–2.44(m, 1H), 2.42–1.70(m, 6H), 1.58–1.09(m, 4H). [M+H] ⁺⁴⁴⁵ .

Example 134: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (144)

Step 1: Preparation of 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole

To a solution of 4-chloro-1H-indole (0.500 g, 3.29 mmol) and 2-(bromomethyl)-tetrahydrofuran (0.816 g, 4.94 mmol) in DMF (6 mL) was added KOH (0.739 g, 13.16 mmol) with stirring at room temperature. The mixture was heated with stirring at 40°C for 2.5 hours. The mixture was diluted with ethyl acetate (100 mL), washed with water (3 x 30 _mL ), dried ( _Na₂SO₄ ), and concentrated in vacuo to afford 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole (1.17 g, 94%), which was used directly in the next step without purification.

Step 2: Preparation of 1-(4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone

To a solution of 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole (1.17 g, 4.78 mmol) in DMF (8.0 mL) was added 2,2,2-trifluoroacetic anhydride (4.01 g, 19.12 mmol) with stirring at room temperature. After stirring at 50°C for 1 hour, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×30 mL), dried _{over Na₂SO₄} , and concentrated in vacuo to afford 1-(4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (1.5 g, 94%), which was used directly in the next step without purification.

Step 3: Preparation of 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid

To a solution of 1-(4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (1.5 g, 4.52 mmol) in water (4.2 mL) was added NaOH (1.81 g, 45.2 mmol). After stirring at 100° C. for 0.5 h, the reaction mixture was acidified to pH 2 with 1 M HCl. The resulting precipitate was collected by filtration, washed with water, and dried to afford 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (0.700 g, 55.5%) as a white solid.

Step 4: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide

To a solution of 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (0.200 g, 0.717 mmol) in DMF (2 ml) at room temperature was added (4,4-difluorocyclohexyl)methanamine (0.117 g, 0.788 mmol), HATU (0.327 g, 0.86 mmol), and TEA (0.217 mg, 2.15 mmol ₎ . After stirring at room temperature for 2 hours, the reaction was quenched with water and extracted with DCM/methanol (10/1, 20 mL x 3). The extracts were combined, dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.104 g, 35.3%).

¹ H NMR (500MHz, DMSO-d ₆ )δ8.11(t, J＝5.5Hz, 1H), 7.70(s, 1H), 7.57(d, J＝7.5Hz, 1H), 7.18-7.12(m, 2H), 4.33-4.30(m, 1H), 4.22-4.13(m, 2H), 3.76-3.73( [M+H] ^+411.1 .

Example 135: (S)-4-Chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (132)

4-Chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide was separated by chiral HPLC to afford the title compound. Chiral HPLC conditions: cosolvent: 35% methanol; column: OZ-H (4.6 x 250 mm, 5 μm) _{; CO} flow rate: 1.95 mL/min; cosolvent flow rate: 1.05 mL/min; total flow rate: 3 mL/min.

¹ H NMR (500 MHz, DMSO-d ₆ )δ8.09 (t, J=5.5Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.16 (t, J=8. 0Hz, 1H), 7.12 (d, J=7.5Hz, 1H), 4.33-4.29 (m, 1H), 4.21-4.11 (m, 2H), 3.74 (q, J=7.0Hz, 1H), 3.61 (q, J=7.0Hz, 1H), 3.14 (t, J=6.0Hz, 2H), 2.03-1.92 (m, 3H), 1.83-1.65 (m, 7H), 1.58-1.51 (m, 1H), 1.28-1.20 (m, 2H)ppm; [M+H] ⁺ 411.1.

Example 136: (R)-4-Chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (135)

4-Chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide was separated by chiral HPLC to provide the title compound.

¹ H NMR (500 MHz, DMSO-d ₆ )δ8.09 (t, J=5.5Hz, 1H), 7.69 (s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.16 (t, J=8. 0Hz, 1H), 7.12 (d, J=7.0Hz, 1H), 4.33-4.29 (m, 1H), 4.21-4.11 (m, 2H), 3.74 (q, J=7.5Hz, 1H), 3.61 (q, J=7.5Hz, 1H), 3.14 (t, J=6.0Hz, 2H), 2.05-1.92 (m, 3H), 1.84-1.69 (m, 7H), 1.58-1.51 (m, 1H), 1.28-1.18 (m, 2H)ppm; [M+H] ⁺ 411.1; LC-MS purity (254 nm): >99%; t _R =4.44 min; HPLC purity (254 nm): >99%; t _R =4.74 min; Chiral-HPLC purity (254 nm): >99%; t _R =4.67 min.

Example 137: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (142)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (0.279 g, 1 mmol), HOBt (0.202 g, 1.5 mmol), EDCI (0.382 g, 2 mmol), TEA (0.404 g, 4 mmol) and 1-(aminomethyl)-4,4-difluorocyclohexanol hydrochloride (0.230 g, 1.2 mmol) to give 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.320 g, 75%) as a light yellow solid.

4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide was separated by chiral HPLC to give (S)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.120 g) and (R)-4-chloro-N-((4,4-di-fluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.140 g).

Chiral-HPLC conditions: co-solvent: 30% methanol; column: AD-H (4.6*250mm, 5um)

_CO2 flow rate: 2.1 mL/min; co-solvent flow rate: 0.9 mL/min; total flow rate: 3 mL/min; run time: 9 min.

Example 138: (S)-4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (134)

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.95 (t, J=6.5Hz, 1H), 7.78 (s, 1H), 7.58 (d, J=7.0Hz, 1H), 7.19 (t, J=7.0Hz, 1H), 7. 15 (d, J=7.0Hz, 1H), 4.75 (s, 1H), 4.35-4.31 (m, 1H), 4.23-4.14 (m, 2H), 3.75 (dd, J=6.5 , 14.5Hz, 1H), 3.62 (d, J=7, 15Hz, 1H), 3.30 (s, 2H), 2.07-2.03 (m, 1H), 2.01-1.97 (m, 2H ), 1.96-1.88(m, 2H), 1.82-1.76(m, 2H), 1.65-1.63(m, 4H), 1.58-1.54(m, 1H)ppm; [M+H] ⁺ 427.1.

Example 139: (R)-4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (MSC2506160) (131)

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.95 (t, J=6.5Hz, 1H), 7.78 (s, 1H), 7.58 (d, J=7.0Hz, 1H), 7.19 (t, J=7.0Hz, 1H), 7. 15 (d, J=7.0Hz, 1H), 4.75 (s, 1H), 4.35-4.31 (m, 1H), 4.23-4.14 (m, 2H), 3.75 (dd, J=6.5 , 14.5Hz, 1H), 3.62 (d, J=7, 15Hz, 1H), 3.30 (s, 2H), 2.07-2.03 (m, 1H), 2.01-1.97 (m, 2H ), 1.96-1.88(m, 2H), 1.82-1.76(m, 2H), 1.65-1.63(m, 4H), 1.58-1.54(m, 1H)ppm; [M+H] ^+427.1 .

Example 140: 4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (139)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-indole-3-carboxylic acid (150.00 mg; 0.54 mmol; 1.00 eq.), EDC (EDC) (123.36 mg; 0.64 mmol; 1.20 eq.), triethyl-amine (0.15 ml; 1.07 mmol; 2.00 eq.) and 1-aminomethyl-3,3-difluoro-cyclohexanol (97.44 mg; 0.59 mmol; 1.10 eq.) to give 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (43 mg, 19%).

¹ H NMR (400 MHz, Methanol-d4) δ 7.83–7.74 (m, 1H), 7.59–7.44 (m, 1H), 7.21 (t, J=5.0 Hz, 2H), 4.49–4.09 (m, 3H), 3.92–3.67 (m, 3H), 3.50 (dd, J=85.1, 13.8 Hz, 2H), 2.20–1.51 (m, 12H), [M+H] ⁺ 427.

Example 141: 4-Chloro-N-(((S)-3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (130)

50 mg of racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide was isolated to yield 8 mg of the title compound. [M+H]^⁺ 427. Cosolvent: 30% methanol; Column: AD-H (4.6 x 250 mm, 5 μm); CO _₂ flow rate: 2.1 mL/min; Cosolvent flow rate: 0.9 mL/min; Total flow rate: 3 mL/min; Run time: 9 min.

Example 142: 4-Chloro-N-(((R)-3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (96)

50 mg of racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide were isolated to give 4 mg of the title compound. [M+H] ^⁺ 427. (Isolation: see Example 141).

Example 143: 4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (133)

50 mg of racemic 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide were isolated to give 7 mg of the title compound. [M+H] ⁺ 427. (Isolation: see Example 141).

Example 144: Preparation of 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (143)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (0.07 g, 0.25 mmol), (1R,3R)-1-(aminomethyl)-3-methylcyclohexanol (0.045 g, 0.25 mmol), HOBt (0.044 g, 0.30 mmol), EDCI (0.058 g, 0.30 mmol) and triethylamine (0.076 g, 0.75 mmol) in acetonitrile (20 mL) to afford 4-chloro-N-(((1R,3R)-1-hydroxy-3-methylcyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.060 g, 50%) as a white solid.

¹ HNMR (400MHz, DMSO-d ₆ ,) δ7.78-7.76 (t, J=4.8Hz, 2H), 7.58 (d, J=6.4Hz, 1H), 7.19-7.14 (m, 2H), 4.35-4.32 (m, 1H), 4.27 (s , 1H), 4.24-4.13(m, 2H), 3.78-3.74(m, 1H), 3.65-3.60(m, 1H), 3.21(d, J=4.8Hz, 2H), 3.21-3.18(m, 1H), 2.00-1.94(m, 1H), 1.82-1.76(m, 2H), 1.73-1.68(m, 1H), 1.64-1.52(m, 5H), 1.47-1.45(m, 1H), [M+H] ^+405.1 .

Example 145: Preparation of 4-chloro-N-(((1S,3S)-1-hydroxy-3-methylcyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (140)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (0.100 g, 0.358 mmol), EDCI (0.102 g, 0.466 mmol), HOBt (0.0952 mg, 0.466 mmol), TEA (0.15 mL) and (1S,3S)-1-(aminomethyl)-3-methylcyclohexanol (0.0532 g, 0.358 mmol) to give 4-chloro-N-(((1S,3S)-1-hydroxy-3-methylcyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.036 g, 21.0%) as a light yellow solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.78 (s, 1H), 7.76 (d, J = 6.0Hz, 1H), 7.58 (d, J = 8.5Hz, 1H), 7.18 (t, J = 7.5Hz, 1H), 7.14 (d, J = 7.5Hz, 1 H), 4.33 (m, 1H), 4.27 (s, 1H), 4.23-4.13 (m, 2H), 3.75 (dd, J=7.0, 15.0Hz, 1H), 3.62 (dd, J=7.0, 15.0Hz, 1H), 3.30 (s, 1H), 3.21 (d, J=6.0Hz, 2H), 2.00-1.93 (m, 1H), 1.82-1.76 (m, 2H), 1.60-1.52 (m, 5H), 1.45 ( d, J＝10.5Hz, 1H), 1.25-1.19(m, 1H), 0.95-0.91(m, 1H), 0.83-0.78(m, 3H), 0.80-0.74(m, 1H)ppm; [M+H] ^+405.1 .

Example 146: 4-Chloro-N-((3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (138)

The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-indole-3-carboxylic acid (500.00 mg; 1.79 mmol; 1.00 eq.), EDC (411.20 mg; 2.15 mmol; 1.20 eq.), triethylamine (0.50 ml; 3.58 mmol; 2.00 eq.), and aminomethyl-3,3-difluoro-5-methyl-cyclohexanol (352.37 mg; 1.97 mmol; 1.10 eq.) to obtain 4-chloro-N-((3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (82, 10%). [M+H] ⁺ 441.

Example 147: Preparation of 4-chloro-N-((3,3-difluoro-5-(trifluoromethyl)cyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (141)

The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (0.060 g, 0.214 mmol), (3,3-difluoro-5-(trifluoromethyl)cyclo-hexyl)methanamine (0.0467 g, 0.214 mmol), HATU (0.122 g, 0.322 mmol) and TEA (0.065 g, 0.64 mmol) to give 4-chloro-N-((3,3-difluoro-5-(trifluoromethyl)cyclo-hexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (0.022 g, 21.5%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.20-8.15(m, 1H), 7.72(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.19-7.13(m, 2H), 4.36-4.27(m, 1H), 4.23-4.11(m, 2H), 3.77-3.68(m, 1H), 3.64-3.60(m, 1H), 3.28-3.20(m, 2H), 2.78-2.64(m, 1H), 2.33-2.15(m, 2H), 2.09-1.50(m, 8H), 1.29-1.09(m, 1H)ppm; [M+H] ^+479.1 .

Example 148: 4-Chloro-N-((1-hydroxy-3-(trifluoromethyl)cyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (136)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-indole-3-carboxylic acid (200.00 mg; 0.72 mmol; 1.00 eq.), 1-aminomethyl-3-trifluoromethyl-cyclohexanol hydrochloride (192.13 mg; 0.82 mmol; 1.15 eq.), EDC (178.19 mg; 0.93 mmol; 1.30 eq.), benzotriazol-1-ol (125.60 mg; 0.93 mmol; 1.30 eq.) and ethyl-diisopropyl-amine (0.35 ml; 2.15 mmol; 3.00 eq.) in N,N-dimethyl-formamide (3.00 ml).

¹ H NMR (400 MHz, chloroform-d) δ 7.76 (s, 1H), 7.42–7.04 (m, 3H), 4.33–3.92 (m, 4H), 3.91–3.32 (m, 5H), 2.27 (q, J=10.1, 9.4 Hz, 1H), 2.07 (d, J=12.9 Hz, 1H), 2.03–1.64 (m, 5H), 1.63–1.00 (m, 5H). [M+H] ⁺ 459.

Example 149: Preparation of 4-chloro-N-((3-ethyl-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxamide (137)

The title compound was synthesized according to the procedure described in Example 2 using a mixture of 4-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-indole-3-carboxylic acid (50.00 mg; 0.18 mmol; 1.00 eq.), 1-(aminomethyl)-3-ethylcyclohexanol (33.19 mg; 0.23 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (45.34 mg; 0.24 mmol; 1.20 eq.), benzotriazol-1-ol (31.96 mg; 0.24 mmol; 1.20 eq.) and DIPEA (0.093 g, 0.72 mmol) in DMF (2.0 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 7.81(1H), 7.66(s, 1H), 7.58(1H), 7.19(2H), 4.35(m, 1H), 4.24(1H), 4.17(m, 1H), 3. 76(1H), 3.63(1H), 3.39(1H), 1.96(m, 1H), 1.79(2H), 1.37(2H), 1.13(4H), 0.83(2H). m/z: 419[M+H].

Example 150: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxamide (147)

Step 1: Preparation of (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate

To a solution of (tetrahydrofuran-3-yl)methanol (5.0 g, 49.0 mmol) in pyridine (30 mL) was slowly added TsCl (11.2 g, 58.8 mmol) with stirring at 0°C. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous citric acid (100 mL x 5) and saturated aqueous _NaHCO₃ (100 mL x 3), dried _{over Na₂SO₄} , filtered, and concentrated in vacuo. The resulting product was purified by silica gel column chromatography (0-15% ethyl acetate in petroleum ether) to afford (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (8.7 g, 69%) as a colorless oil.

Step 2: Preparation of 1-(4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone

A mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (2.48 g, 10.0 mmol), (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (3.07 g, 12.0 mmol) and K ₂ CO ₃ (4.14 g, 30.0 mmol) in DMF (40 mL) was stirred overnight at 120° C. The resulting mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous NaHCO ₃ (100 mL×5), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford 1-(4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (3.3 g, 100%) as a yellow oil.

Step 3: Preparation of 4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxylic acid

A mixture of 1-(4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (3.5 g, 10.6 mmol) and NaOH (30 mL, 2 M) in hexanol (30 mL) was stirred at 80°C for 2 hours. The resulting mixture was concentrated in vacuo, extracted with ethyl acetate (30 mL), adjusted to pH 4-5, and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL x 3), dried _{over Na2SO4} , filtered, and concentrated in vacuo to afford the title compound (2.76 g, 90%) as a yellow solid.

Step 4: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxylic acid (0.140 g, 0.5 mmol), 1-(aminomethyl)-4,4-difluorocyclohexanol hydrochloride (0.101 g, 0.5 mmol), EDCI (0.144 g, 0.75 mmol), HOBt (0.101 g, 0.75 mmol), and TEA (0.253 g, 2.5 mmol) in anhydrous THF (10.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NaHCO ₃ solution (50 mL) and extracted with ethyl acetate/THF (20 mL x 3). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to dryness. The residue was purified by recrystallization from ethyl acetate/petroleum ether to give 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxamide (0.120 g, 56%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.01-7.99(m, 1H), 7.85(s, 1H), 7.61-7.59(m, 1H), 7.22-7.15(m, 2H), 4.74(s, 1H), 4.22-4.20(m, 2H), 3.85-3.82(m, 1H), [M+H] ^+427.1 .

Example 151: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxamide (148)

The title compound was synthesized according to the procedure described in Example 33 using (tetrahydrofuran-3-yl)methanol (0.094 g, 0.92 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.150 g, 0.56 mmol) and CMTP (0.433 g, 1.84 mmol) to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxamide (0.035 g, 20%) as a white solid.

¹ HNMR (500 MHz, DMSO-d ₆ )δ8.12 (t, J=6.0Hz, 1H), 7.77 (s, 1H), 7.58 (d, J=6.5Hz, 1H), 7.19 (t, J=8 .0Hz, 1H), 7.14 (d, J=7.5Hz, 1H), 4.20-4.19 (m, 2H), 3.86-3.82 (m, 1H), 3 .67-3.62(m, 2H), 3.48-3.45(m, 1H), 3.15(t, J=6.5Hz, 2H), 2.80-2.71(m , 1H), 2.04-2.02(m, 2H), 1.92-1.59(m, 7H), 1.29-1.21(m, 2H)ppm; [M+H] ^+411.1 .

Example 152: Preparation of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indole-3-carboxamide (146)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), (tetrahydrofuran-3-yl)methanol (31.26 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.22(1H), 8.01(s, 1H), 7.58(1H), 7.20(2H), 5.80(1H), 5.05(m, 2H), 4.94(2H), 4. 65(s, 1H), 3.43(1H), 3.23(1H), 2.02-1.96(m, 3H), 1.77(2H), 1.59(2H), 1.51(1H). m/z: 427[M+H].

Example 153: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide (166)

Step 1: Preparation of (tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (tetrahydro-2H-pyran-2-yl)methanol (2.32 g, 20.0 mmol) in pyridine (15 mL) was added dropwise a solution of TsCl (4.58 g, 24.0 mmol) in pyridine (10 mL) at 0°C over 30 minutes. After stirring overnight at room temperature, the reaction mixture was quenched with 10% aqueous citric acid and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried _{over Na₂SO₄} , filtered, and concentrated to a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain (tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (3.72 g, 68.7%) as a white solid.

Step 2: Preparation of 1-(4-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone

To a solution of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (2.0 g, 8.1 mmol) in DMF (20 mL) was added (tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (2.6 g, 9.7 mmol) and _K₂CO₃ (3.4 g, 24.6 mmol) _with stirring at room temperature. The resulting reaction mixture was stirred at 120°C overnight, quenched with water, and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over _Na₂SO₄ , filtered, and concentrated to afford 1-(4-chloro- ₁ -((tetrahydro-2H-pyran-2-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (2.2 g, 81%) as a red oil.

Step 3: Preparation of 4-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxylic acid

To a stirred solution of 1-(4-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone (2.2 g, 6.4 mmol) in hexanol (20 mL) was added 10% aqueous NaOH (20 mL). The resulting reaction mixture was stirred at 90°C for 4 hours, adjusted to pH 4-5, and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (20 mL x ₃ ), dried over _Na₂SO₄ , and filtered. The filtrate was concentrated under vacuum to afford 4-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxylic acid (1.6 g, 87%) as a red oil.

Step 4: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide (0.200 g, 0.68 mmol), 1-(aminomethyl)-4,4-difluorocyclohexanol (0.113 g, 0.68 mmol), HOBt (0.138 g, 1.0 mmol), EDCI (0.196 g, 1.0 mmol) and triethylamine (0.345 g, 3.4 mmol) in DCM (15 mL) was stirred at room temperature overnight and diluted with DCM (20 mL). The organic layer was washed with brine (10 mL), dried _{over Na2SO4} , filtered, and concentrated to a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide (0.080 g, 27%) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ7.91 (s, 1H), 7.35 (d, J=8.0Hz, 1H), 7.23 (d, J=7.0Hz, 1H), 7.18 (t, J =8.0Hz, 2H), 4.16-4.08(m, 2H), 3.96-3.93(m, 1H), 3.64-3.61(m, 1H), 3. 55(d, J=5.5Hz, 2H), 3.35-3.30(m, 1H), 2.24-2.12(m, 2H), 1.97-1.93(m , 2H), 1.87-1.84 (m, 4H) 1.47-1.42 (m, 5H), 1.33-1.23 (m, 2H), ppm; [M+H] ^+441.2 .

Example 154: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide (167)

The title compound was synthesized according to the procedure described in Example 33 using (tetrahydro-2H-pyran-2-yl)methanol (0.070 g, 0.61 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.100 g, 0.31 mmol) and cyanomethylenetributylphosphorane (0.296 g, 1.23 mmol) to give 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide (0.070 g, 54%) as a white solid.

1H NMR (500 MHz, DMSO-d ₆ )δ8.10 (t, J=6.0Hz, 1H), 7.66 (s, 1H), 7.55 (d, J=8.5Hz, 1H), 7.18 (t, J=7.5Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 4.26-4.17 (m, 2H), 3.84-3.82 (m, 1H) , 3.62-3.60(m, 1H), 3.30-3.23(m, 1H), 3.18-3.14(m, 2H), 2.04-2.00(m , 2H), 1.85-1.61(m, 7H), 1.46-1.39(m, 3H), 1.29-1.17(m, 3H)ppm; [M+H] ^+424.2 .

Example 155: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxamide (168)

The title compound was synthesized according to the procedure described in Example 33 using (tetrahydro-2H-pyran-4-yl)methanol (0.142 g, 1.22 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.200 g, 0.61 mmol) and cyanomethylenetributylphosphorane (0.747 g, 3.06 mmol) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole-3-carboxamide (0.048 g, 18%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.08 (t, J=6.0Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 7.12 (d, J=7.0Hz, 1H), 4.10 (d, J=7.0Hz, 2H) , 3.83-3.80 (m, 2H), 3.22-3.18 (m, 2H), 3.14 (t, J=6.5Hz, 2H), 2.07-2.00 (m, 3H), 1.84-1.68 (m, 5H), 1.39-1.19 (m, 6H)ppm; [M+H] ^+425.1 .

Example 156: Preparation of 1-((1,4-dioxan-2-yl)methyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (150)

Step 1: Preparation of 2-(iodomethyl)-1,4-dioxane

To a solution of 2-(allyloxy)ethanol (1.02 g, 10 mmol) in acetonitrile (10 mL) at room temperature was added iodine (3.81 g, 15 mmol) followed by _NaHCO₃ (1.26 g, 15 mmol). After stirring at room temperature for 20 hours, the resulting reaction mixture was quenched with water and extracted with ethyl acetate ( ₆₀ mL). The organic extract was washed with saturated _{aqueous Na₂S₂O₃} and brine, dried over _MgSO₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 2:1) to obtain 2-(iodomethyl)-1,4-dioxane (1.6 g, 70%) as a light yellow oil.

Step 2: Preparation of 1-((1,4-dioxan-2-yl)methyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

To a solution of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.200 g, 0.613 mmol) in DMF (4 ml) was added 2-(iodomethyl)-1,4-dioxane (0.210 g, 0.920 mmol) and _{CsCO (} 0.599 g, 1.839 mmol). After stirring at 80°C overnight, the reaction mixture was diluted with ethyl acetate (30 mL) and filtered through a pad of Celite. The organic phase was washed with water (3 x 20 mL), dried _{over NaSO} , and vacuum filtered. The residue was purified by preparative HPLC to afford 1-((1,4-dioxan-2-yl)methyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.105 g, 40%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ )δ8.12 (t, J=6.0Hz, 1H), 7.76 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.20-7.13 (m, 2H), 4.30-4.17 (m, 2H), 3.86-3.79 (m, 2H), 3.71 (d, J=10.5Hz, 1H), 3. 62(d, J=10.5Hz, 1H), 3.52-3.42(m, 2H), 3.30-3.24(m, 1H), 3.16-3.14(m , 2H), 2.04-2.01(m, 2H), 1.84-1.69(m, 5H), 1.28-1.20(m, 2H)ppm; [M+H] ^+427.1 .

Example 157: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((4-methylmorpholin-2-yl)methyl)-1H-indole-3-carboxamide (183)

The title compound was synthesized according to the procedure described in Example 33 using 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.100 g, 0.30 mmol), (4-methylmorpholin-2-yl)methanol (0.098 g, 0.74 mmol) and CMTP (0.286 g, 1.19 mmol) to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((4-methylmorpholin-2-yl)methyl)-1H-indole-3-carboxamide (0.056 g, 38%) as a light yellow solid.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ8.12 (t, J=6.0Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.20-7.12 (m, 2H), 4.29-4.24 (m, 2H), 3.76 (d, J=7.0Hz, 2H), 3.43-3.40 (m, 1H) 3.15 (t, J=6.0Hz, 2H), 2.73 (d, J=10.5Hz, 1H), 2.56 (d, J=11.5Hz, 1H), 2.16 (s , 3H), 2.03-1.93(m, 3H), 1.85-1.66(m, 6H), 1.28-1.19(m, 2H)ppm; [M+Na] ^+440.2 .

Example 158: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(1-methylazetidin-3-yl)-1H-indole-3-carboxamide (119)

Step 1: Preparation of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone

To a solution of 4-chloro-1H-indole (5.00 g, 32.98 mmol) in DMF (40 mL) at 0°C was added trifluoroacetic anhydride (6.88 mL, 49.47 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 hours, quenched with water (50 mL), and extracted with DCM (200 mL). The separated organic layer _was dried over anhydrous _Na₂SO₄ , filtered, and concentrated to afford 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (8.00 g, 95%) as a brown oil, which was used directly in the next step without purification. LCMS: m/z = 248 (M+H) ^⁺ .

Step 2: Preparation of tert-butyl 3-(4-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)azetidine-1-carboxylate

A mixture of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (8.00 g, 32.31 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (10.06 g, 35.54 mmol), and potassium carbonate ( _13.40 g, 96.93 mmol) in DMF (30 mL) was stirred at 100°C overnight. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The organic layers were combined, dried over anhydrous _Na₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain tert-butyl 3-(4-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)azetidine-1-carboxylate (9.60 g, 80%) as a yellow solid. LCMS: m/z = 403.1 (M+H) ⁺ .

Step 3: Preparation of 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-chloro-1H-indole-3-carboxylic acid

To a solution of tert-butyl 3-(4-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)azetidine-1-carboxylate (9.00 g, 22.34 mmol) in ethanol (160 mL) was added aqueous sodium hydroxide solution (80 mL, 10%) with stirring. After stirring at 100°C for 1 hour, the reaction mixture was concentrated in vacuo to remove the ethanol. The pH of the aqueous solution was adjusted to 6 with concentrated hydrochloric acid and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over _{anhydrous Na₂SO₄} , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-chloro-1H-indole-3-carboxylic acid (7.00 g, 82%) as a yellow oil. LCMS: m/z = 351.1 (M+H) ^⁺ .

Step 4: Preparation of tert-butyl 3-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate

To a solution of 1-(1-(tert-butoxycarbonyl)azetidine-3-yl)-4-chloro-1H-indole-3-carboxylic acid (1.20 g, 3.42 mmol), EDCI (0.852 g, 4.44 mmol) and HOBt (0.600 g, 4.44 mmol) in acetonitrile (30 mL) was added triethylamine (1.03 g, 10.26 mmol) and (4,4-difluorocyclohexyl)methylamine (0.510 g, 3.42 mmol) with stirring. The reaction mixture was stirred at room temperature overnight, quenched with water (50 mL), and extracted with DCM (70 mL x 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain tert-butyl 3-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (1.39 g, 88%) as a yellow solid. LCMS: m/z = 482.1 (M+1).

Step 5: Preparation of 1-(azetidin-3-yl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

To a solution of tert-butyl 3-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (1.39 g, 2.88 mmol) in DCM (20 mL) was added trifluoroacetic acid (4.0 mL) with stirring at 0°C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with water (30 mL), and the pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. The system was extracted with DCM (30 mL x 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to obtain 1-(azetidin-3-yl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (1.00 g, 91%) as a yellow solid. LCMS: m/z = 382.1 (M+H) ⁺ .

Step 6: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(1-methylazetidin-3-yl)-1H-indole-3-carboxamide

To a solution of 1-(azetidine-3-yl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.200g, 0.52mmol) in DCM (20mL) was added formaldehyde (0.5mL) while stirring, and the mixture was stirred at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride. The resulting reaction mixture was stirred at room temperature for 0.5 hour, quenched with water (30mL), and extracted with DCM (50mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM:methanol=10:1) and recrystallization (hexane:ethyl acetate=10:1) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(1-methylazetidin-3-yl)-1H-indole-3-carboxamide (0.045 g, 22%) as a white solid.

¹ HNMR (400MHz, DMSO-d ₆ )δ8.16 (t, J=6.0Hz, 1H), 7.97 (s, 1H), 7.55 (d, J=8.0Hz, 1H), 7.19-7.14 (m, 2H), 5.15-5.10 (m, 1H), 3.77 (t, J=7.5Hz, 2H), [M+H] ^+396.1 .

Example 159: Preparation of 4-chloro-1-(1-cyclopropylazetidin-3-yl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (171)

A solution of 1-(azetidin-3-yl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.400 g, 1.05 mmol), bromocyclopropane (0.383 g, 3.14 mol), potassium carbonate (0.434 g, 3.14 mmol) and sodium iodide (0.156 g, 1.04 mmol) in DMF (3 mL) was stirred at 110 ° C overnight. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (60 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:2) to obtain 4-chloro-1-(1-cyclopropylazetidin-3-yl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.042 g, 10%) as a white solid.

¹ HNMR (500MHz, DMSO-d ₆ ,) δ8.16 (t, J=4.0Hz, 1H), 7.98 (s, 1H), 7.57 (d, J=7.5Hz, 1H), 7.20-7.15 (m, 2H), 5.83-5.75 (m, 1H), 5.25-5.11 (m, 3H), 3.79 ( t, J=7.0Hz, 2H), 3.37-3.36 (m, 2H), 3.16 (t, J=6.5Hz, 4H), 2.08-1.98 (m, 2H), 1.86-1.66 (m, 5H), 1.29-1.21 (m, 2H)ppm; [M+H] ^+422.1 .

Example 160: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(1-methylazetidin-3-yl)-1H-indole-3-carboxamide (118)

Step 1: Preparation of tert-butyl 3-(4-chloro-3-((4,4-difluoro-1-hydroxycyclohexyl)methyl-carbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate

A mixture of 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-chloro-1H-indole-3-carboxylic acid (0.150 g, 0.43 mmol), HATU (0.243 g, 0.64 mmol), DIPEA (0.2 mL), and 1-(aminomethyl)-4,4-difluorocyclohexanol (0.106 g, 0.64 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and extracted with DCM (150 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 3-(4-chloro-3-((4,4-difluoro-1-hydroxycyclohexyl)methyl-carbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (0.180 g, 86%) as a yellow oil.

Step 2: Preparation of 1-(azetidin-3-yl)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide

To a solution of tert-butyl 3-(4-chloro-3-((4,4-difluoro-1-hydroxycyclohexyl)methyl-carbamoyl)-1H-indol-1-yl)azetidine-1-carboxylate (0.180 g, 0.36 mmol) in DCM (20 mL) was added TFA (4.0 mL) at 0°C. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL) and the pH of the organic layer was adjusted to 8 with saturated _NaHCO3 solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated to afford 1-(azetidin-3-yl)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (0.160 g, 95%) as a yellow oil.

Step 3: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(1-methylazetidin-3-yl)-1H-indole-3-carboxamide

To a solution of 1-(azetidin-3-yl)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (0.160 g, 0.40 mmol) in DCM (20 mL) was added HCHO (0.5 mL, 37% aqueous solution). After stirring at room temperature for 1 hour, NaBH(OAc) ₃ (0.333 g, 1.57 mmol) was added. The resulting reaction mixture was stirred at room temperature for 0.5 hour, quenched with water (30 mL), and extracted with DCM (150 mL). The separated organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC to obtain 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(1-methylazetidin-3-yl)-1H-indole-3-carboxamide (0.22 g, 14%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.06-8.03 (m, 2H), 7.57 (d, J=7.5Hz, 1H), 7.21-7.16 (m, 2H), 5.17-5.12 (m, 1H), 4.75 (s, 1H), 3.80 (t, J=7 .5Hz, 2H), 3.38-3.35(m, 2H), 3.33-3.32(m, 2H), 2.36(s, 3H), 2.06-1.89(m, 4H), 1.67-1.65(m, 4H)ppm; [M+H] ^+412.1 .

Example 161: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(2-azaspiro[3.3]hept-6-yl)-1H-indole-3-carboxamide (172)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (71.29 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.88(s, 1H), 8.10(1H), 7.92(s, 1H), 7.50(1H), 7.15-7.19(m, 2H), 4.91(m, 2H), 4.16(2H), 4.00(2H), 3.1 4(2H), 2.85(2H), 2.68(2H), 2.03(2H), 1.85(2H), 1.71(m, 1H), 1.60(1H), 1.37(1H), 1.25(m, 1H), 0.93(2H). m/z: 422[M+H].

Example 162: (S)-1-(azetidin-2-ylmethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxylate

Preparation of amine (122)

Step 1: Preparation of (S)-tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)azetidine-1-carboxylate

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.500 g, 1.53 mmol), (S)-2-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester (0.574 g, 3.06 mmol) and CMTP (1.50 g, 6.12 mmol) in anhydrous toluene (2 mL) was stirred at 110 ° C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain (S)-tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)azetidine-1-carboxylate (0.600 g, 80%) as a white solid. LCMS: [M+H] ^496.1 .

Step 2: Preparation of (S)-1-(azetidin-2-ylmethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

To a solution of (S)-tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)azetidine-1-carboxylate (0.600 g, 1.20 mmol) in DCM (15 mL) was added trifluoroacetic acid (3 mL) at 0°C, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL), the pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution, and then extracted with DCM (20 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol=1:10) to obtain (S)-1-(azetidin-2-ylmethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.475 g, 91%) as a white solid.

¹ HNMR (500MHz, DMSO-d ₆ ,) δ8.07 (t, J=5.5Hz, 1H), 7.73 (s, 1H), 7.57 (d, J=8.5Hz, 1H), 7.18-7.11 (m, 2H), 4.27-4.19 (m, 2H), 4.13-4.08 (m, 1H), 3.48-3.39 ( [M+H] ^+396.3 .

Example 163: Preparation of (S)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methylazetidin-2-yl)methyl)-1H-indole-3-carboxamide (151)

To a solution of (S)-1-(azetidin-2-ylmethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.120 g, 0.30 mmol) in DCM (2 mL) was added formaldehyde (0.4 mL) while stirring. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.190 g, 0.90 mmol) was added to the mixture. The resulting reaction mixture was stirred at room temperature for 0.5 hours, quenched with water (10 mL), and extracted with DCM (50 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol=1:10) to obtain (S)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methylazetidin-2-yl)methyl)-1H-indole-3-carboxamide (0.053 g, 42%) as a white solid.

¹ HNMR (500MHz, DMSO-d ₆ )δ8.07 (t, J=5.5Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 7.13 (d, J=7.5Hz, 1H), 4.25 (d, J=5.0Hz, 2H), 3.27-3 .21 (m, 1H), 3.20-3.14 (m, 3H), 2.67-2.63 (m, 1H), 2.04-1.99 (m, 5H), 1.94-1.89 (m, 1H), 1.85-1.70 (m, 6H), 1.29-1.21 (m, 2H)ppm; [M+H] ⁺ 410.2.

Example 164: Preparation of (R)-1-(azetidin-2-ylmethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (123)

The title compound was synthesized according to the procedure described in Example 162 using 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (85.00 mg; 0.26 mmol; 1.00 eq.), (R)-2-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (97.41 mg; 0.52 mmol; 2.00 eq.) and (CMTP) (0.27 ml; 1.04 mmol; 4.00 eq.) to give (R)-1-(azetidin-2-ylmethyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (70 mg, 68%). [M+H] ⁺ 396.

Example 165: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((2-methylazetidin-2-yl)methyl)-1H-indole-3-carboxamide (152)

The title compound was synthesized using 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (200.00 mg; 0.61 mmol; 1.00 eq.), 2-hydroxymethyl-2-methyl-azetidine-1-carboxylic acid tert-butyl ester (246.37 mg; 1.22 mmol; 2.00 eq.), and (tributyl-λ5-phosphinilidene)-acetonitrile (CMTP) (0.48 ml; 1.84 mmol; 3.00 eq.) according to the procedure described in Example 162. The boc-protected product was treated with a solution of TFA (5 ml) in DCM, and the crude product was purified on a silica gel column to obtain the title compound.

¹ H NMR (400 MHz, chloroform-d) δ 8.00 (s, 1H), 7.41 (dd, J = 7.9, 1.2 Hz, 1H), 7.20 (dq, J = 15.6, 8.3, 7.8 Hz, 2H), 6.92 (t, J = 6.1 Hz, 1H), 4.36 (d, J = 14.6 Hz, 1H), 4.13 (d, J = 14. 7Hz, 1H), 3.66 (q, J＝8.4Hz, 1H), 3.48–3.25 (m, 4H), 2.39 (dt, J＝11.2, 8.6Hz, 1H ), 2.23–1.99(m, 3H), 1.98–1.83(m, 2H), 1.82–1.56(m, 4H), 1.50–1.26(m, 4H). [M+H] ⁺ 410.

Example 166: Preparation of (S)-1-((1-acetylazetidin-2-yl)methyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (181)

To a solution of 1-(S)-1-azetidin-2-ylmethyl-4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (100.00 mg; 0.25 mmol; 1.00 eq.) in dichloromethane (5.00 ml) was added ethyl-diisopropyl-amine (0.25 ml; 1.52 mmol; 6.00 eq.) and acetyl chloride (0.05 ml; 0.76 mmol; 3.00 eq.). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the crude product was purified by Biotage cartridge (10 g) with an ethyl acetate-hexane gradient to afford the title compound as a white solid (100 mg, 90%).

1H NMR (400 MHz, chloroform-d) δ 7.80 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.21 (dt, J = 15.7, 7.7 Hz, 2H), 6.87 (t, J = 6.2 Hz, 1H), 4.73 (H, J = 5.1 Hz, 1H), 4.65–4.44 (m, 2H), 3.91 (td, J = 8. 6, 6.1Hz, 2H), 3.69 (td, J=8.8, 5.8Hz, 1H), 3.42 (t, J=6.5Hz, 2H), 2.37–2.22 (m, 1H), 2. 20–2.07(m, 3H), 2.04–1.87(m, 3H), 1.84(s, 2H), 1.81–1.63(m, 2H), 1.61–1.34(m, 2H). [M+H] ⁺ 438.4.

Example 167: Preparation of (S)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-isopropylazetidin-2-yl)methyl)-1H-indole-3-carboxamide (191)

The title compound was synthesized using 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (75.00 mg; 0.23 mmol; 1.00 eq.), ((S)-1-isopropyl-azetidin-2-yl)-methanol (59.31 mg; 0.46 mmol; 2.00 eq.), and (tributyl-λ-5-phosphinidylidene)-acetonitrile (CMTP) (0.24 ml; 0.92 mmol; 4.00 eq.) according to the procedure described in Example 33. [M+H] ⁺ 438.

Example 168: Preparation of 1-(azetidin-2-ylmethyl)-4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (124)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 2-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (57.36 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.18(1H), 7.88(2H), 7.65(1H), 7.20(2H), 4.69(s, 1H), 4.50(2H), 3.73(1H), 3 .57(1H), 3.41(2H), 3.23(2H), 2.29(m, 2H), 2.03(m, 3H), 1.75(2H), 1.59(2H). m/z: 412[M+H].

Example 169: Preparation of 1-(azetidin-4-ylmethyl)-4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (125)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 3-(hydroxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (57.31 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.01(1H), 7.88(1H), 7.65(1H), 7.20(2H), 4.50(2H), 3.89(2H), 3.73(2H), 3.41(1H), 3.23(2H), 2.98(m, 3H), 1.75(2H), 1.59(3H). m/z: 412[M+H].

Example 170: Preparation of (S)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (153)

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.440 g, 1.35 mmol), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.543 g, 2.70 mmol) and CMTP (1.30 g, 5.40 mmol) in anhydrous toluene (4 mL) was stirred at 110° C. under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo to a residue. A mixture of the residue in DCM (10 ml) and TFA (6 ml) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, diluted with water, adjusted to pH 9, and extracted with DCM (60 mL x 3). The organic layers were combined, concentrated in vacuo, and purified by preparative HPLC to obtain the desired compound as a white solid (0.410 g, 74%).

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.06 (t, J=5.8Hz, 1H), 7.74 (s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.18-7.12 (m, 2H), 4.13-4.04 (m, 2H), 3.41-3.38 ( m, 1H), 3.17-3.15 (m, 2H), 2.83-2.76 (m, 2H), 2.04-2.02 (m, 2H), 1.75-1.59 (m, 8H), 1.36-1.24 (m, 3H)ppm; [M+H] ^+410.1 .

Example 171: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (154)

The title compound was synthesized using a mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.400 g, 1.23 mmol), (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.493 g, 2.45 mmol) and CMTP (1.19 g, 4.92 mmol) in anhydrous toluene (4 mL) according to the procedure described in Example 170, followed by treatment with TFA in DCM to obtain the compound as a white solid (0.376 g, 76%).

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.06 (t, J=5.8Hz, 1H), 7.74 (s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.18-7.12 (m, 2H), 4.14-4.06 (m, 2H), 3.41-3.40 (m, 1H), 3.17-3.14 (m, 2H), 2.84-2.77 (m, 2H), 2.04-2.02 (m, 2H) 1.76-1.59 (m, 8H) 1.36-1.24 (m, 3H)ppm; [M+H] ^+410.1 .

Example 172: Preparation of 4-chloro-N-((3,3-difluoro-5-methylcyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (157)

Step 1: Preparation of 4-chloro-N-((3,3-difluoro-5-methylcyclohexyl)methyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-1H-indole-3-carboxylic acid (0.300 g, 1.5 mmol), (3,3-difluoro-5-methylcyclohexyl)methanamine (0.245 g, 1.5 mmol), HATU (0.684 g, 1.8 mmol), and DIPEA (0.387 g, 3.0 mmol) in DMF (15 mL) was stirred at room temperature for 4 hours. The mixture was poured into water (15 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 4-chloro-N-((3,3-difluoro-5-methyl-cyclohexyl)methyl)-1H-indole-3-carboxamide (0.110 g, 22%) as a white solid.

Step 2: Preparation of tert-butyl 2-((4-chloro-3-((3,3-difluoro-5-methylcyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate

A solution of 4-chloro-N-((3,3-difluoro-5-methylcyclohexyl)methyl)-1H-indole-3-carboxamide (0.110 g, 0.32 mmol), tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.200 g, 1.0 mmol), and cyanomethylenetributylphosphorane (CMTP) (0.482 g, 2.0 mmol) in toluene (2 mL) was stirred at 110° C. under a nitrogen atmosphere for 4 hours. The mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL×3), dried over Na ₂ SO ₄ , filtered, and concentrated to a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain tert-butyl 2-((4-chloro-3-((3,3-difluoro-5-methylcyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (0.100 g, 60%) as a white solid.

Step 3: Preparation of 4-chloro-N-((3,3-difluoro-5-methylcyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide

To a solution of 4-chloro-N-((3,3-difluoro-5-methylcyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (0.100 g, 0.19 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The volume was concentrated to approximately 2 mL under vacuum. The residue was partitioned between saturated aqueous _NaHCO₃ solution (10 mL) and DCM (30 mL). The organic layer was dried over _{anhydrous Na₂SO₄} , concentrated, and purified by preparative HPLC to give 4-chloro-N-((3,3-difluoro-5-methylcyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (0.050 g, 62%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.08 (t, J=6.0Hz, 1H), 7.75 (d, J=3.5Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.17 (t, J=7.5H z, 1H), 7.13 (d, J=7.5Hz, 1H), 4.16-4.12 (m, 1H), 4.07-4.02 (m, 1H), 3.4–3.21 (m, 2H), 3 .15–3.09(m, 1H), 2.85–2.81(m, 1H), 2.79–2.74(m, 1H), 2.16(s, 1H), 2.09–1.97(m, 3H) , 1.79–1.71(m, 3H), 1.69–1.53(m, 3H), 1.40–1.31(m, 2H), 0.99–0.96(m, 3H)ppm; [M+H] ^+424.1 .

Example 173: Preparation of 4-chloro-N-((3,3-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (156)

The title compound was synthesized according to the procedure described in Example 172 using 4-chloro-1H-indole-3-carboxylic acid and the appropriate amine.

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.08 (t, J=6.0Hz, 1H), 7.76 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 7 .13(d, J=7.0Hz, 1H), 4.16-4.12(m, 1H), 4.06-4.02(m, 1H), 3.41–3.37(m, 1H), 3.24–3 .20 (m, 1H), 3.17–3.12 (m, 1H), 2.85–2.80 (m, 1H), 2.79–2.74 (m, 1H), 2.16 (d, J=7.5Hz , 1H), 1.99 (s, 1H), 1.82–1.63 (m, 6H), 1.61–1.33 (m, 4H), 1.09–1.02 (m, 1H)ppm; [M+H] ^+410.1 .

Example 174. 4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (155)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (51.56 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphinilide)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.18(1H), 7.88(2H), 7.65(1H), 7.20(2H), 4.71(s, 1H), 4.35(2H), 3.66 (1H), 3.41(2H), 3.03(1H), 2.95(1H), 2.03(m, 3H), 1.75(3H), 1.59(4H). m/z: 426[M+H].

Example 175: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (158)

Step 1: Preparation of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a mixture of pyrrolidin-2-ylmethanol (0.500 g, 4.95 mmol) and di-tert-butyl dicarbonate (2.16 g, 9.89 mmol) in DCM (10 mL) was added triethylamine (0.751 g, 7.42 mmol) with stirring. The system was stirred at room temperature overnight. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.900 g, 90%) as a light yellow oil.

Step 2: Preparation of tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.366 g, 1.82 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.198 g, 0.61 mmol), and CMTP (0.588 g, 2.44 mmol) in toluene (4 mL) was placed in a sealed test tube and stirred at 110°C under a nitrogen atmosphere for 4 hours. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (0.800 g, crude product) as a light yellow solid. LCMS: [M+H] ^510.1 .

Step 3: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide

To a stirred solution of tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (0.800 g, crude product) in DCM (10 mL) was added trifluoroacetic acid (1.5 mL) dropwise. The resulting solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was redissolved in DCM (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL x 2), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol = 20:1) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (0.100 g, 32% (two steps)) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ )δ8.07 (t, J=6.0Hz, 1H), 7.75 (s, 1H), 7.57 (d, J=7.5Hz, 1H), 7.17 (t, J=7 .5Hz, 1H), 7.13 (d, J=7.5Hz, 1H), 4.19-4.15 (m, 1H), 4.10-4.05 (m, 1H), 3 .44-3.42(m, 2H), 3.16(t, J=6.0Hz, 2H), 2.87-2.78(m, 2H), 2.03-2.02(m , 2H), 1.85-1.61(m, 8H), 1.41-1.37(m, 1H), 1.29-1.24(m, 2H)ppm; [M+H] ^+410.1 .

Example 176: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (170)

To a solution of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (0.060 g, 0.147 mmol) in DCM (10 mL) was added formaldehyde (0.120 g, 1.47 mmol, 37% aqueous solution) while stirring. After the mixture was stirred at room temperature for 1 hour, sodium triacetoxyborohydride (0.093 g, 0.44 mmol) was added. The resulting reaction mixture was stirred at room temperature for 0.5 hours, quenched with water (10 mL), and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:methanol=20:1) to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (0.030 g, 48%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.08(t, J＝5.5Hz, 1H), 7.74(s, 1H), 7.54(d, J＝8.0Hz, 1H), 7.18(t, J＝8.0Hz, 1H), 7.13 (d, J=7.5Hz, 1H), 4.31-4.29 (m, 1H), 4.10-4.06 (m, 1H), 3.16 (t, J=6.5Hz, 2H), 2.97(brs, 1H), 2.64-2.59(m, 1H), 2.26(s, 3H), 2.19-2.16(m, 1H), 2.06-2.00(m, 2H ), 1.85-1.70(m, 6H), 1.60(brs, 2H), 1.50-1.47(m, 1H), 1.26-1.24(m, 2H)ppm; [M+H] ^+424.1 .

Example 177: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methyl-5-oxopyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (182)

Step 1: Preparation of (R)-5-oxopyrrolidine-2-carboxylic acid methyl ester

To a mixture of (R)-5-oxopyrrolidine-2-carboxylic acid (10 g, 77 mmol) in methanol (150 mL) was added SOCl₂ ₍ 10 mL) dropwise over 0.5 h at 0°C. After stirring overnight at room temperature, the reaction mixture was concentrated and the residue was partitioned between saturated aqueous _NaHCO₃ (100 mL) and DCM (250 mL). The separated organic layer was dried over _{anhydrous Na₂SO₄} , filtered, and concentrated to afford (R)-5-oxopyrrolidine-2-carboxylic acid methyl ester (9.0 g, 91%) as a yellow oil.

Step 2: Preparation of (R)-1-methyl-5-oxopyrrolidine-2-carboxylic acid methyl ester

To a mixture of (R)-methyl 5-oxopyrrolidine-2-carboxylate (3.5 g, 24.5 mmol) and _K2CO3 (6.8 g, 49 mmol) in _CH3CN (100 _mL ) was added _CH3I (6.1 mL, 114 mmol) dropwise at 0°C. After stirring at 80°C for 72 h, the reaction mixture was concentrated and the residue was partitioned between water (100 mL) and DCM (350 mL). The separated organic layer was dried over _{anhydrous Na2SO4} , filtered, and concentrated to afford (R)-methyl 1-methyl-5-oxopyrrolidine-2-carboxylate (3.2 g, 84%) as a yellow oil.

Step 3: Preparation of (R)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one

To a solution of (R)-methyl 1-methyl-5-oxopyrrolidine-2-carboxylate (2.5 g, 16 mmol) in methanol (50 mL) was added _NaBH₄ (1.2 g, 32 mmol) portionwise at 0°C. After stirring at room temperature for 5 hours, the reaction mixture was concentrated and the residue was partitioned between water (50 mL) and DCM (150 mL). The separated organic layer was dried _over anhydrous _Na₂SO₄ , filtered, concentrated, and purified by silica gel column chromatography (methanol:DCM = 1:20) to afford (R)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (1.50 g, 72%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ,) δ 3.86 (m, 1H), 3.62-3.57 (m, 2H), 3.03-2.84 (m, 4H), 2.50-2.43 (m, 1H), 2.34-2.28 (m, 1H), 2.16-2.08 (m, 1H), 2.02-1.95 (m, 1H) ppm. Step 4: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methyl-5-oxopyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide

A mixture of (R)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (0.120 g, 0.92 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.150 g, 0.46 mmol), and cyanomethylenetributylphosphorane (CMTP) (0.443 g, 1.84 mmol) in toluene (2 mL) was stirred at 110° C. for 4 hours. After cooling to room temperature, the mixture was partitioned between water (30 mL) and ethyl acetate (100 mL). The separated organic layer was dried _over anhydrous _Na2SO4 , filtered, concentrated, and purified by preparative HPLC to obtain (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-methyl-5-oxopyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (0.082 g, 41%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.12 (t, J=5.5Hz, 1H), 7.76 (s, 1H), 7.63 (d, J=8.0Hz, 1H), 7.23-7.15 (m, 2H), 4.52-4.48 (m, 1H), 4.30-4.26 (m, 1H), 3.98-3.93 (m, 1H), 3.17-3.15 (t, J=6.5Hz, 2H), 2.67 (s, 3H), 2.22-2.15 (m, 1H), 2.08-1.91 (m, 4H), 1.86-1.65 (m, 6H), 1.29-1.21 (m, 2H)ppm.

Example 178: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (162)

Step 1: Preparation of (R)-5-(hydroxymethyl)pyrrolidin-2-one

To a solution of (R)-methyl 5-oxopyrrolidine-2-carboxylate (6.0 g, 42 mmol) in methanol (80 mL) at 0°C was added _NaBH₄ (3.2 g, 84 mmol) portionwise. After stirring at room temperature for 5 hours, the reaction mixture was concentrated, and the residue was partitioned between water (50 mL) and DCM (150 mL ₎ . The separated organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol:DCM = 1:10) to obtain (R)-5-(hydroxymethyl)pyrrolidin-2-one (3.2 g, 73%) as a white solid.

Step 2: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide

A solution of (R)-5-(hydroxymethyl)pyrrolidin-2-one (0.115 g, 1.0 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.163 g, 0.5 mmol), and CMTP (0.482 g, 2.0 mmol) in toluene (2 mL) was stirred at 110°C for 4 hours. After cooling to room temperature, the mixture was partitioned between water (30 mL) and ethyl acetate (100 mL). The separated organic layer was dried over _{anhydrous Na₂SO₄} , filtered, concentrated, and purified by preparative HPLC to afford (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (0.057 g, 22%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.09-8.06 (t, J=6.0Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.0Hz, 1H), 7.21-7.14 (m, 2H), 4.25 (d, J=5.5Hz, 2 [M+H] ^+424.1 .

Example 179: Preparation of (S)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (169)

Step 1: Preparation of tert-butyl (S)-2-(tosyloxymethyl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.02 g, 20.0 mmol) in pyridine (30 mL) was slowly added TsCl (4.58 g, 24.0 mmol) with stirring at 0°C. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (150 mL), washed with saturated aqueous citric acid (100 mL x 5) and saturated aqueous _NaHCO₃ (100 mL x 3), dried _{over Na₂SO₄} , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-15% ethyl acetate in petroleum ether) to afford (S)-tert-butyl 2-(tosyloxymethyl)pyrrolidine-1-carboxylate (5.2 g, 73%) as a colorless oil.

Step 2: Preparation of (S)-tert-butyl 2-((4-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate

A solution of 1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (1.24 g, 5.0 mmol), (S)-tert-butyl 2-(tosyloxymethyl)pyrrolidine-1-carboxylate (5.3 g, 15.0 mmol) and K ₂ CO ₃ (8.15 g, 25.0 mmol) in DMF (40 mL) was stirred overnight at 80° C. The resulting mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous NaHCO ₃ solution (100 mL×5), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to afford (S)-tert-butyl 2-((4-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (1.5 g, 70%) as a white solid.

Step 3: Preparation of (S)-1-((1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-chloro-1H-indole-3-carboxylic acid

A solution of (S)-tert-butyl 2-((4-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (1.4 g, 3.25 mmol) and NaOH (15 mL, 2 M solution in water) in hexanol (30 mL) was stirred at 80°C for 2 hours. The resulting mixture was concentrated in vacuo to remove the hexanol. The aqueous layer was washed with ethyl acetate (30 mL), adjusted to pH 4-5, and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine ( ₅₀ mL x 3), dried over _Na₂SO₄ , filtered, and concentrated in vacuo to afford (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-chloro-1H-indole-3-carboxylic acid (1.17 g, 95%) as a white solid.

Step 4: Preparation of (S)-tert-butyl 2-((4-chloro-3-((4,4-difluoro-1-hydroxycyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate

A mixture of (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-chloro-1H-indole-3-carboxylic acid (0.189 g, 0.5 mmol), 1-(aminomethyl)-4,4-difluorocyclohexanol hydrochloride (0.101 g, 0.5 mmol), EDCI (0.144 g, 0.75 mmol), HOBt (0.101 g, 0.75 mmol), and TEA (0.253 g, 2.5 mmol) in anhydrous THF (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with saturated _NaHCO₃ solution (50 mL) and extracted with ethyl acetate/THF (50 mL x 3). The organic layers were combined, washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate/petroleum ether to give (S)-tert-butyl 2-((4-chloro-3-((4,4-difluoro-1-hydroxycyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (0.172 g, 65%) as a white solid.

Step 5: Preparation of (S)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide

A mixture of (S)-tert-butyl 2-((4-chloro-3-((4,4-difluoro-1-hydroxycyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)pyrrolidine-1-carboxylate (0.140 g, 0.265 mmol) and TFA (6 mL) in DCM (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to a residue. A mixture of this residue and HCHO (0.065 g, 0.795 mmol, 37% solution in water) in DCM (10 mL) was stirred at room temperature for 3 minutes, then _NaBH3CN (0.050 g, 0.795 mmol) was added. The resulting reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo, diluted with aqueous _NaHCO3 solution (30 mL), and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, concentrated in vacuo, and purified by preparative HPLC to afford (S)-4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (0.070 g, 60%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.96-7.94(m, 1H), 7.81(s, 1H), 7.57-7.55(m, 1H), 7.21-7.14(m, 2H), 4.75(s, 1H), 4.33-4.29(m, 1H), 4.12-4.07(m, 1 [M+H] ^+440.1 .

Example 180: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-isopropylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (196)

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (0.100 g, 0.24 mmol), acetone (2.0 mL), _NaBH₃CN (0.050 g, 0.72 mmol), and 4A molecular sieves (0.050 g) in methanol (2.0 mL) was stirred at 55°C overnight. The reaction mixture was cooled to room temperature, saturated aqueous _NaHCO₃ (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined, dried over _MgSO₄ , concentrated, and purified by preparative HPLC to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((1-isopropylpyrrolidin-2-yl)methyl)-1H-indole-3-carboxamide (0.060 g, 55%) as a white solid.

1H NMR (500 MHz, DMSO-d ₆ )δ8.06(t, J＝6.0Hz, 1H), 7.75(s, 1H), 7.53(d, J＝8.5Hz, 1H), 7.20-7.11( m, 2H), 4.11-3.98 (m, 2H), 3.41 (s, 1H), 3.17-3.14 (m, 3H), 2.82-2.78 (m, 2 H), 2.02-2.01(m, 2H), 1.84-1.69(m, 5H), 1.59-1.55(m, 3H), 1.45(m, 1H), 1.29-1.24(m, 2H), 1.03(d, J＝6.5Hz, 3H), 0.92(d, J＝6.5Hz, 3H)ppm; [M+H] ⁺ 452.2.

Example 181: Preparation of 4-chloro-1-((1-cyclopropylpyrrolidin-2-yl)methyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (197)

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-2-ylmethyl)-1H-indole-3-carboxamide (0.050 g, 0.12 mmol), (1-ethoxycyclopropyloxy)trimethylsilane (0.064 g, 0.36 mmol), _NaBH₃CN (0.015 g, 0.24 mmol), 4A molecular sieves (0.045 g), and _CH₃COOH (0.022 g, 0.36 mmol) in methanol (2.0 mL) was stirred at 55° C. overnight. The reaction mixture was cooled to room temperature, saturated aqueous _NaHCO₃ solution (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined, dried over _MgSO4 , concentrated, and purified by preparative HPLC to give 4-chloro-1-((1-cyclopropylpyrrolidin-2-yl)methyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.015 g, 27%) as a yellow solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.08 (t, J=6.0Hz, 1H), 7.75 (s, 1H), 7.51 (d, J=8.0Hz, 1H), 7.21-7.13 (m, 2H), 4.43-4.38 (m, 1H), 3.99-3.94 (m, 1H), 3.30 (s, 1H) , 3.15(t, J=6.0Hz, 2H), 3.10-3.00(m, 2H), 2.04-2.02(m, 2H), 1.90-1.49(m, 10H), 1.29-1.19(m, 2H), 0.53-0.28(m, 4H)ppm; [M+H] ^+450.1 .

Example 182: Preparation of (S)-4-chloro-1-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (180)

Step 1: Preparation of (S)-tert-butyl 1-2-methyl 4-oxopyrrolidine-1,2-dicarboxylate

To a solution of tert-butyl (2S,4R)-1-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (4.0 g, 16.3 mmol) in DCM (100 mL) was slowly added PCC (7.0 g, 32.6 mmol) with stirring at 0°C. The reaction mixture was stirred at room temperature overnight, then filtered and washed with DCM (50 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain tert-butyl (S)-1-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate (3.15 g, 79%) as a colorless oil.

Step 2: Preparation of (S)-tert-butyl 1-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylate

To a solution of (S)-tert-butyl 1-2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.9 g, 11.9 mmol) in DCM (20 mL) was added dropwise DAST (5.76 g, 35.8 mmol) with stirring at 0°C. After stirring overnight at room temperature, the reaction mixture was quenched with water (10 mL) at 0°C, the pH adjusted to 7-8, and extracted with DCM (50 mL x 3). The organic layer was washed with brine, dried over _Na₂SO₂ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain (S)-tert-butyl 1-2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (2.3 g, 73%) as a colorless oil.

Step 3: Preparation of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol

To a solution of _LiAlH₄ in THF (8.3 mL, 1 M in THF) was added dropwise a solution of (S)-tert-butyl 1-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.2 g, 8.3 mmol) in THF (20 mL) with stirring at 0°C. The reaction mixture was stirred at 0°C for 2 hours, then quenched by the addition of water (0.3 mL), 15% aqueous NaOH (0.3 mL), and water (1.0 mL). The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (0.280 g, 22%) as a colorless oil.

Step 4: Preparation of (S)-4-chloro-1-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

A mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.100 g, 0.31 mmol), (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (0.095 g, 0.62 mmol) and cyanomethylenetributylphosphorane (CMTP) (0.296 g, 1.23 mmol) in anhydrous toluene (4 mL) was stirred at 110° C. under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under vacuum and the residue was purified by preparative HPLC to afford (S)-4-chloro-1-((4,4-difluoro-1-methylpyrrolidin-2-yl)methyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.058 g, 41%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ )δ8.12-8.09(m, 1H), 7.74(s, 1H), 7.56-7.55(m, 1H), 7.22-7.14(m, 2H) , 4.49-4.45(m, 1H), 4.24-4.20(m, 1H), 3.41-3.35(m, 1H), 3.17-3.15(m , 2H), 2.98-2.93(m, 1H), 2.69-2.60(m, 1H), 2.33(s, 3H), 2.30-2.22(m, 1H), 2.08-1.99(m, 3H), 1.86-1.70(m, 5H), 1.29-1.21(m, 2H)ppm; [M+H] ⁺ 460.1.

Example 183: Preparation of 4-chloro-1-[1-(2-fluoro-ethyl)-pyrrolidin-2-ylmethyl]-1H-indole-3-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide (194)

Step 1: Preparation of 4-chloro-1-pyrrolidin-2-ylmethyl-1H-indole-3-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide

To a stirred solution of 4-chloro-1H-indole-3-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide (520 mg, 1.62 mmol, 1.00 eq) in N,N-dimethyl-formamide (10 mL, 19.23 V) were added _K2CO3 (677.45 _mg , 4.85 mmol, 3.00 eq) and 2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (762.58 mg, 1.94 mmol, 1.20 eq), and the reaction mixture was stirred at 130°C for 16 hours. The reaction was confirmed complete by TLC. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude residue was purified by preparative HPLC to obtain 4-chloro-1-pyrrolidin-2-ylmethyl-1H-indole-3-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide (160 mg, 0.39 mmol, 23.9%) as a creamy white solid. [M+H]+: 404.2; LC-MS purity (254 nm): 97.03%; t _R = 3.34 min.

Step 2: Preparation of 4-chloro-1-[1-(2-fluoro-ethyl)-pyrrolidin-2-ylmethyl]-1H-indole-3-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide

To a stirred solution of 4-chloro-1-pyrrolidin-2-ylmethyl-1H-indole-3-carboxylic acid ₍ 1-hydroxy-3-methylcyclohexylmethyl)-amide (150 mg, 0.36 mmol, 1.00 eq) in N,N-dimethyl-formamide (5 ml, 33.33 V) were added _K2CO3 (151.95 mg, 1.09 mmol, 3.00 eq) and 1-bromo-2-fluoro-ethane (51.70 mg, 0.40 mmol, 1.10 eq), and the reaction mixture was heated in a pressure tube at 130°C for 4 hours. The completion of the reaction was confirmed by TLC, and the reaction mixture was cooled to room temperature, filtered through celite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give a crude compound, which was purified by preparative HPLC to give 4-chloro-1-[1-(2-fluoro-ethyl)-pyrrolidin-2-ylmethyl]-1H-indole-3-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide (8 mg, 0.02 mmol, 4.8%) as a brown granular solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.82 (s, 1H), 7.73 (t, J=6.00Hz, 1H), 7.57 (dd, J=7.94, 1.08Hz, 1H), 7.19-7.12 (m, 2H), 4 .52 (s, 1H), 4.40 (d, J=2.44Hz, 1H), 4.22 (d, J=4.76Hz, 2H), 4.10-4.05 (m, 1H), 3.18 (t, J=4. 24Hz, 2H), 3.08 (d, J=6.76Hz, 1H), 2.93 (d, J=4.96Hz, 2H), 2.50-2.49 (m, 2H), 2.28 (d, J=6.8 8Hz, 1H), 1.69-1.44 (m, 10H), 1.22 (t, J=3.92Hz, 2H), 0.82 (d, J=6.60Hz, 3H), [M+H]+450.2.

Example 184: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-3-yl)-1H-indole-3-carboxamide (121)

Step 1: Preparation of tert-butyl 3-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)pyrrolidine-1-carboxylate

A mixture of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.184 g, 0.97 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.160 g, 0.49 mmol), and CMTP (0.825 g, 1.96 mmol) was placed in a sealed tube and stirred at 110°C for 4 hours. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x ₃ ). The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and concentrated in vacuo to obtain tert-butyl 3-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)pyrrolidine-1-carboxylate (0.600 g, crude product) as a light yellow solid.

Step 2: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-3-yl)-1H-indole-3-carboxamide

To a solution of tert-butyl 3-(4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)pyrrolidine-1-carboxylate (0.600 g, crude product) in DCM (10 mL) was added TFA (1.5 mL) with stirring at room temperature. After stirring at room temperature for 1 hour, the reaction was concentrated. The residue was redissolved in DCM (20 mL), washed with saturated aqueous _NaHCO₃ (10 mL x 2), brine (10 _mL ), dried over _Na₂SO₄ , and concentrated to a residue, which was purified by preparative HPLC to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(pyrrolidin-3-yl)-1H-indole-3-carboxamide (0.060 g, 31% (yield over two steps)) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.81-7.75(m, 2H), 7.56(t, J=7.5Hz, 1H), 7.18-7.10(m, 2H), 5.05-5.00(m, 1H), 3.28-3.22(m, 1H), 3 .19-3.15(m, 2H), 3.02-2.88(m, 4H), 2.34-2.26(m, 1H), 2.07-1.65(m, 8H), 1.34-1.26(m, 2H)ppm; [M+H] ⁺ 396.1.

Example 185: Preparation of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(pyrrolidin-3-yl)-1H-indole-3-carboxamide (120)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (57.31 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphinilide)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.21(1H), 7.96(2H), 7.65(1H), 7.20(2H), 5.24(s, 1H), 4.35(2H), 3.66 (1H), 3.41(2H), 3.03(1H), 2.95(1H), 2.03(m, 3H), 1.75(3H), 1.59(4H). m/z: 412[M+H].

Example 186. 4-Chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1-(pyrrolidin-3-ylmethyl)-1H-indole-3-carboxamide (159)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-N-((3,3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-carboxamide (70.00 mg; 0.28 mmol; 1.00 eq.), 3-(hydroxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (61.65 mg; 0.31 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL) and heated at 110° C. for 4 hours.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.18(1H), 7.88(2H), 7.65(1H), 7.20(2H), 4.71(s, 1H), 4.35(2H), 3.66 (1H), 3.41(2H), 3.03(1H), 2.95(1H), 2.03(m, 3H), 1.75(3H), 1.59(4H). m/z: 426[M+H].

Example 187: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((2-oxooxazolidin-5-yl)methyl)-1H-indole-3-carboxamide (126)

Step 1: Preparation of (S)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxiran-2-ylmethyl)-1H-indole-3-carboxamide

To a solution of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.300 g, 0.92 mmol) in THF (30 mL) was added NaHMDS (0.93 mL, 0.93 mmol, 1 M solution in THF) at -78°C. The reaction mixture was stirred at -78°C for 20 minutes and then at room temperature for 1 hour. (R)-2-(Chloromethyl)oxirane (171 mg, 1.86 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was quenched with ice water and extracted with ethyl acetate (30 mL x 3 ₎ . The separated organic layer was dried over _Na₂SO₄ , filtered, and concentrated. The resulting residue (0.300 g, 84%) was used directly in the next step without purification.

Step 2: Preparation of (R)-1-(3-amino-2-hydroxypropyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide

A solution of (S)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(oxiran-2-ylmethyl)-1H-indole-3-carboxamide (0.300 g, 0.78 mmol) and _NH4OH (8 mL) in methanol/hexanol (1/1 mL) was placed in a sealed tube and stirred at 80°C for 18 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by preparative HPLC to give (R)-1-(3-amino-2-hydroxypropyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.150 g, 48%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ8.07 (t, J=5.5Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.56-7.49 (m, 1H), 7.19-7.12 (m, 2H), 5.04 (s, 1H), 4.33-4.26 (m, 1H), 4.08-4.04 (m, 1H), 3. 81-3.70(m, 1H), 3.17-3.10(m, 2H), 3.06-3.00(m, 2H), 2.58-2.53(m, 2 H), 2.04-2.00(m, 2H), 1.85-1.70(m, 5H), 1.29-1.21(m, 2H)ppm; [M+H] ^+400.1 .

Step 3: Preparation of (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((2-oxooxazolidin-5-yl)methyl)-1H-indole-3-carboxamide

A mixture of (R)-1-(3-amino-2-hydroxypropyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.050 g, 0.13 mmol) and CDI (0.081 g, 0.5 mmol) in anhydrous THF (5.0 mL) was refluxed overnight, poured into water (15 mL), and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried _{over Na2SO4} , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to afford (R)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((2-oxooxazolidin-5-yl)methyl)-1H-indole-3-carboxamide (0.020 g, 37%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.15-8.14 (m, 1H), 7.72 (s, 1H), 7.60 (d, J=8.5Hz, 1H), 7.21-7.14 (m, 2H), 4.93-4.88 (m, 1H), 4.53-4.45 (m, 2H), 3.60 (t, J＝9.0Hz, 1H), 3.25-3.22(m, 1H), 3.15(t, J＝6.5Hz, 2H), 2.08-2.01(m, 3H), 1.84-1.69(m, 5H), 1.28-1.20(m, 2H), ppm; [M+H] ^+425.8 .

Example 188: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(piperidin-2-ylmethyl)-1H-indole-3-carboxamide) (173)

Step 1: Preparation of tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate

A mixture of piperidin-2-ylmethanol (2.0 g, 16.4 mmol), di-tert-butyl dicarbonate (7.6 g, 34.8 mmol), and triethylamine (5.28 g, 52.2 mmol, 7.2 mL) in DCM (20 mL) was stirred at room temperature overnight, quenched with water (20 mL), and extracted with ethyl acetate (50 mL x ₃ ). The organic layers were combined, washed with brine, dried over _Na₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (2.3 g, 61%) as a white solid.

Step 2: Preparation of tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate

A mixture of tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (0.528 g, 2.45 mmol), 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.160 g, 0.49 mmol) and CMTP (0.472 g, 1.96 mmol) in toluene was stirred at 110 ° C for 4 hours. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to obtain tert-butyl 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate (0.800 g, crude product) as a light yellow solid.

Step 3: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(piperidin-2-ylmethyl)-1H-indole-3-carboxamide

To a solution of 2-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate (0.800 g, crude product) in DCM (6 mL) was added TFA (1.5 mL) with stirring at room temperature. After stirring at room temperature for 1 hour, the reaction was concentrated and the residue was redissolved in DCM (20 mL), washed with saturated aqueous _NaHCO₃ (10 mL x 2), brine (10 mL), dried _{over Na₂SO₄} , and concentrated to a residue. The residue was purified by preparative HPLC to afford 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(piperidin-2-ylmethyl)-1H-indole-3-carboxamide (0.036 g, 15% (yield over two steps)) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.09 (t, J=6.0Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.19-7.12 (m, 2H), 4.10 (d, J=6.5Hz, 2H), 3.15 (t, J=6.0Hz, 2H), 2.91 (d, J= [M+H] ⁺ 424.1.

Example 189: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(piperidin-3-ylmethyl)-1H-indole-3-carboxamide (174)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (39.53 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.10(1H), 7.92(s, 1H), 7.50(1H), 7.15-7.19(m, 2H), 4.08(2H), 3.15(2H), 2.91(2H), 2. 35(2H), 2.03(2H), 1.85(2H), 1.71(m, 1H), 1.60(1H), 1.37(1H), 1.25(m, 1H), 0.87(4H). m/z: 424[M+H].

Example 190: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(piperidin-4-ylmethyl)-1H-indole-3-carboxamide (175)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-indole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (35.93 mg; 0.38 mmol; 2.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (147.72 mg; 0.61 mmol; 4.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.10(1H), 7.92(s, 1H), 7.50(1H), 7.15-7.19(m, 2H), 4.08(2H), 3.15(2H), 2.91(2H), 2. 35(2H), 2.03(2H), 1.85(2H), 1.71(m, 1H), 1.60(1H), 1.37(1H), 1.25(m, 1H), 0.87(4H). m/z: 424[M+H].

Example 191: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(morpholin-3-ylmethyl)-1H-indole-3-carboxamide (164)

Step 1: Preparation of tert-butyl 3-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)morpholine-4-carboxylate

To a mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.200 g, 0.61 mmol) and tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (0.266 g, 1.22 mmol) in anhydrous toluene (2 mL) was added CMTP (0.591 g, 2.45 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 110°C for 4 hours, concentrated to dryness, and redissolved in ethyl acetate (10 mL). The organic layer was washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated in vacuo to a residue that was used in the next step without purification.

Step 2: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(morpholin-3-ylmethyl)-1H-indole-3-carboxamide

To a mixture of tert-butyl 3-((4-chloro-3-((4,4-difluorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)morpholine-4-carboxylate (0.095 mg, 0.18 mmol) in DCM (10 mL) was added TFA (6 mL). The mixture was stirred at room temperature for 5 hours, washed with saturated _NaHCO3 aqueous solution, and extracted with DCM (10 mL x ₃ ). The organic layer was washed with brine, dried over _Na2SO4 , filtered, and concentrated. The residue was purified by preparative HPLC to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(morpholin-3-ylmethyl)-1H-indole-3-carboxamide (0.020 g, 26%) as a light yellow solid.

¹ H NMR (500MHz, CDCl3): δ7.81 (s, 1H), 7.35 (d, J=7.5Hz, 1H), 7.24 (d, J=7.0Hz, 1H), 7.20 ( t, J=8.0Hz, 1H), 6.81 (s, 1H), 4.15-4.03 (m, 2H), 3.83-3.76 (m, 2H), 3.59-3.54 (m, 1H), 3.41 (t, J=6.5Hz, 2H), 3.35 (t, J=9.0Hz, 1H), 3.31-3.23 (m, 1H), 2.89-2.80 (m, 2H), 2.1 3-2.08 (m, 2H), 1.90 (d, J=13.5Hz, 2H), 1.80-1.67 (m, 4H), 1.44-1.36 (m, 2H)ppm; [M+H] ^+426.1 .

Example 192: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((4-methylmorpholin-3-yl)methyl)-1H-indole-3-carboxamide (184)

Step 1: Preparation of morpholin-3-ylmethanol

To a mixture of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.0 g, 4.6 mmol) in DCM (30 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous _NaHCO₃ , and extracted with DCM (30 mL x ₃ ). The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and concentrated in vacuo to a residue that was used in the next step without purification.

Step 2: Preparation of (4-methylmorpholin-3-yl)methanol

To a mixture of morpholin-3-ylmethanol (0.540 g, 4.6 mmol) in _CH₃OH (20 mL) was added HCHO (1.86 g, 23 mmol, 37% solution in water) and Pd/C (0.200 g). The mixture was stirred at room temperature under a hydrogen atmosphere (1.0 atm) overnight, then filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (CH₃OH:DCM = 1:15) to obtain (4-methylmorpholin-3-yl)methanol (0.130 g, 22%) as a yellow oil.

Step 3: Preparation of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((4-methylmorpholin-3-yl)methyl)-1H-indole-3-carboxamide

To a mixture of 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3-carboxamide (0.134 g, 0.41 mmol) and (4-methylmorpholin-3-yl)methanol (0.054 g, 0.41 mmol) in anhydrous toluene (2 mL) was added CMTP (0.200 g, 0.82 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 110 ° C for 4 hours, concentrated to dryness, and redissolved in ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-((4-methylmorpholin-3-yl)methyl)-1H-indole-3-carboxamide (0.070 g, 39%) as a white solid.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.13 (t, J=6.0Hz, 1H), 7.70 (s, 1H), 7.52 (d, J=8.0Hz, 1H), 7.22-7.14 (m, 2H) , 4.55-4.51(m, 1H), 4.15-4.10(m, 1H), 3.65(t, J=6.5Hz, 1H), 3.50(m, 2H), 3.3 5-3.20 (m, 1H), 3.17-3.12 (m, 3H), 2.75-2.72 (m, 1H), 2.55-2.41 (m, 3H), 2.26- 2.21(m, 1H), 2.04-1.99(m, 2H), 1.85-1.69(m, 5H), 1.29-1.21(m, 2H)ppm; [M+H] ^+440.1 .

Example 193: Preparation of 4-chloro-1-(2-methoxy-ethyl)-1H-indole-3-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-amide (230)

Using 4-chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (200 mg, 0.68 mmol, 1.00 eq), (4,4-difluoro-cyclohexyl)-methylamine hydrochloride (192 mg, 1.02 mmol, 1.50 eq), triethylamine (0.29 mL, 2.03 mmol, 3.00 eq), benzotriazole-1-ol (165 mg, 1.02 mmol, From the mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide (130 mg, 0.34 mmol, 51.6%), a mixture of 4-chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide was prepared in dry THF (10 mL, 50 V) to give the title compound according to the procedure described in Example 2.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.24 (d, J=5.12Hz, 1H), 8.19 (t, J=6.00Hz, 1H), 7.95 (s, 1H), 7.27 (d, J=5.12Hz, 1H), 4.45 (t, J=5.36Hz, 2H), 3.72 (t, J=5.32Hz, 2H), 3.23(s, 3H), 3.15(t, J=6.32Hz, 2H), 2.03-2.00(m, 2H), 1.84-1.81(m, 3H), 1.77-1.69(m, 2H), 1.28-1.19(m, 2H); [M+H]+386.2.

Example 194: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (223)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), 2-methoxy-ethanol (19.28 mg; 0.22 mmol; 1.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (105.32 mg; 0.44 mmol; 3.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.26(1H), 8.09(m, 1H), 8.05(1H), 7.31(s, 1H), 4.77(m, 1H), 4.47(2H), 3.74(2H), 2.62(3H), 2.09-1.91(3H), 1.65(3H). m/z: 402[M+H].

Example 195: Preparation of 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (209)

The reaction mixture was prepared by mixing 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.20 g, 0.76 mmol, 1.00 eq), triethylamine (0.32 mL, 2.27 mmol, 3.00 eq), 1-aminomethyl-4,4-difluoro-cyclohexanol (0.15 g, 0.91 mmol, 1.20 eq), EDC (0.29 g, 1.51 mmol, 2.00 eq.) and A mixture of benzotriazole-1-ol (0.18 g, 1.13 mmol, 1.50 eq) in dry THF (5 mL, 25 V) was used to synthesize the title compound according to the procedure described in Example 2 to obtain 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (0.17 g, 0.42 mmol, 55.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.22-8.21(m, 1H), 8.05-8.01(m, 2H), 7.67(s, 1H), 7.29-7.27(m, 2H), 4.94(s, 2H) ), 4.74(s, 1H), 3.32(s, 2H), 2.07-1.87(m, 4H), 1.64-1.62(m, 4H)ppm; [M+H]+401.2.

Example 196: Preparation of 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide (210)

The reaction mixture was stirred at 0 ° C using 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.15 g, 0.57 mmol, 1.00 eq) and C-(4,4-difluoro-cyclohexyl)-methylamine (0.10 g, 0.68 mmol, 1.20 eq), triethylamine (0.24 mL, 1.70 mmol, 3.00 eq), EDC (0.22 g, 1.13 mmol, 2.00 eq) at room temperature. A mixture of 4-nitro-1-oxo-2-nitropropane-1-ol (0.14 g, 0.85 mmol, 1.50 eq) and benzotriazole-1-ol (0.14 g, 0.85 mmol, 1.50 eq) in dry THF (7.50 mL, 50 V) was used to synthesize the title compound according to the procedure described in Example 2 to obtain 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide (0.05 g, 0.12 mmol, 21.3%) as a creamy white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.21-8.19 (m, 2H), 7.93 (s, 1H), 7.67 (s, 1H), 7.28-7.26 (m, 2H), 4.93 (t, J=6.0Hz, 2H), 3.13-3.15 (m, 2H), 2.02-2.00 (m, 2H), 1.84-1.81 (m, 3H), 1.77-1.69 (m, 2H), 1.28-1.19 (m, 2H)ppm; [M+H]+385.2.

Example 197: Preparation of 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (214)

The reaction mixture was prepared by mixing 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.15 g, 0.57 mmol, 1.00 eq), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (0.10 g, 0.68 mmol, 1.20 eq), triethylamine (0.24 mL, 1.70 mmol, 3.00 eq), (0.22 g, 1.13 mmol, 2.00 eq) and benzo[1-carbamoylmethyl]-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.15 g, 0.57 mmol, 1.00 eq), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (0.10 g, 0.68 mmol, 1.20 eq), triethylamine (0.24 mL, 1.70 mmol, 3.00 eq), A mixture of triazol-1-ol (0.14 g, 0.85 mmol, 1.50 eq) in dry THF (3 mL, 20 V) was used to synthesize the title compound according to the procedure described in Example 2 to obtain 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (0.17 g, 0.44 mmol, 77.2%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.21 (d, J=5.2Hz, 1H), 7.91 (s, 1H), 7.67 (t, J=Hz, 1H), 7.29 (s, 1H), 4.94 (d, J=Hz, 2H), 4.27 (s, 2H), 3.20 (s, 1H), 1. 70-1.43 (m, 6H), 1.23-1.17 (m, 1H), 0.94 (t, J=12.4Hz, 1H), 0.82 (d, J=6.8Hz, 3H), 0.76-0.70 (m, 1H)ppm; [M+H]+379.2.

Example 198: Preparation of 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (213)

1-Carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.15 g, 0.57 mmol, 1.00 eq), (1S,3S)-1-aminomethyl-3-methyl-cyclohexanol (0.10 g, 0.68 mmol, 1.20 eq), triethylamine (0.24 mL, 1.70 mmol, 3 eq), EDC (0.22 g From the mixture of 4-nitro-1-oxo-2-nitropropane (4-nitro-1-oxo-2-nitropropane) (1.13 mmol, 2.00 eq) and benzotriazole-1-ol (0.14 g, 0.85 mmol, 1.50 eq) in dry THF (7.5 mL, 50 V), the title compound was synthesized according to the procedure described in Example 2 to obtain 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (0.04 g, 0.09 mmol, 15.6%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.22-8.20 (m, 1H), 8.01 (s, 1H), 7.87-7.84 (m, 1H), 7.66 (s, 1H), 7.29-7.27 (m, 2H), 4.93 (s, 2H), 4.26 (s, 1H), 3.21-3 .19(m, 2H), 1.71(s, 1H), 1.60-1.43(m, 5H), 1.23-1.17(m, 1H), 0.97-0.87(m, 4H), 0.76-0.67(m, 1H)ppm; [M+H]+379.2.

Example 199: Preparation of 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide (212)

The reaction mixture was stirred at 4 ℃ for 1 h. The reaction mixture was stirred at 4 ℃ for 1 h. The reaction mixture was stirred at 4 ℃ for 2 h. 1-aminoformylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.15 g, 0.57 mmol, 1.00 eq), triethylamine (0.24 l, 1.70 mmol, 3.00 eq) and C-(3,3-difluoro-cyclohexyl)-methylamine hydrochloride (0.13 g, 0.68 mmol, 1.20 eq), EDC (0.22 g, 1.13 mmol, 2.0 A mixture of 4-nitro-1-oxo-2-nitropropane (0.04 mmol, 0.1 eq) and benzotriazole-1-ol (0.14 g, 0.85 mmol, 1.50 eq) in dry THF (10 mL) was prepared and the title compound was synthesized according to the procedure described in Example 2 to obtain 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide (0.06 g, 0.14 mmol, 24.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.21-8.20(m, 2H), 7.95(s, 1H), 7.67(s, 1H), 7.28-7.26(m, 2H), 4.93(s, 2 H), 3.24-3.10(m, 2H), 1.80-1.22(m, 6H), 1.09-1.06(m, 1H)ppm; [M+H]+385.2.

Example 200: Preparation of 1-carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide (211)

1-Carbamoylmethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.20 g, 0.76 mmol, 1.00 eq), triethylamine (0.24 mL, 1.70 mmol, 3.00 eq), 1-aminomethyl-3,3-difluorocyclohexanol hydrochloride (0.18 g, 0.9 mmol, 1.20 eq), EDC (0.29 g, 1.52 mmol, 2.00 eq) were used to prepare a 1-aminomethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ester. The title compound was synthesized from a mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide (0.04 g, 0.11 mmol, 13%) in THF (10 mL).

^1H NMR (400 MHz, DMSO- _d6 ): δ 8.22-8.21 (m, 1H), 8.04 (s, 1H), 8.00-7.97 (m, 1H), 7.67 (s, 1H), 7.30-7.27 (m, 2H), 4.94 (s, 2H), 4.69 (s, 1H), 3.41-0.36 (m, 1H), 3.24-3.19 (m, 1H), 2.01-1.89 (m, 3H), 1.75-1.73 (m, 2H), 1.57-1.51 (m, 3H) ppm; [M+H]+ 401.2; LC-MS purity (254 nm): 96.9%; _tR =2.49 min; HPLC purity (254 nm): 98.2%; t _R =2.57 min.

Example 201: Preparation of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide (228)

Step 1: Preparation of methyl 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (500.00 mg; 2.33 mmol; 1.00 eq.) in dry DMF (15 mL, 30 V) and cesium carbonate (1531.67 mg, 4.65 mmol, 2.00 eq) was added dropwise 3-bromo-oxetane (487.86 mg, 3.49 mmol, 1.50 eq) at 0°C and stirred at 80°C for 18 hours. After TLC confirmed the completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using 25% ethyl acetate in petroleum ether as eluent to obtain methyl 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (350 mg, 1.23 mmol, 53.1%) as a creamy white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.70 (s, 1H), 8.30 (d, J=5.12 Hz, 1H), 7.41 (d, J=5.12 Hz, 1H), 5.99-5.92 (m, 1H), 5.06-4.97 (m, 4H), 3.81 (s, 3H) ppm.

Step 2: Preparation of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

To a solution of methyl 4-chloro-1-oxetane-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (350 mg, 1.23 mmol, 1.00 eq) in dry THF (2.00 mL, 26.67 V), methanol (2.00 mL, 26.67 V) and water (1.00 mL, 13.33 V) was added lithium hydroxide monohydrate (22.62 mg, 0.53 mmol, 2.00 eq) and stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated, water was added, and the mixture was acidified with 1.5 N HCl. The solid formed was filtered, washed with water, and dried to obtain 4-chloro-1-oxetane-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (250 mg, 0.97 mmol, 78.7%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ12.33 (brs, 1H), 8.61 (s, 1H), 8.27 (d, J=5.12Hz, 1H), 7.37 (d, J=5.16Hz, 1H), 5.98-5.91 (m, 1H), 5.06-5.03 (m, 2H), 5.00-4.97 (m, 2H)ppm.

Example 202: Preparation of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide

The reaction mixture was prepared by mixing 4-chloro-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (200 mg, 0.68 mmol, 1.00 eq), (4,4-difluoro-cyclohexyl)-methylamine hydrochloride (192 mg, 1.02 mmol, 1.50 eq), triethylamine (0.29 mL, 2.03 mmol, 3.00 eq), benzotriazole-1-ol (165 mg, 1.02 mmol, 1. To the mixture of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide (120 mg, 0.30 mmol, 58.5%) in dry THF (10 mL, 50 V), the title compound was synthesized according to the procedure described in Example 2 to obtain 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide (120 mg, 0.30 mmol, 58.5%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.44 (s, 1H), 8.25 (d, J=5.16 Hz, 1H), 8.14 (t, J=6.12 Hz, 1H), 7.32 (d, J=5.12 Hz, 1H), 5.98 (t, J=6.92 Hz, 1H), 5.05-4.97 (m, 4H), 4.71 (s, 1H), 3.31 (s, 2H), 2.07-1.88 (m, 4H), 1.65 (s, 4H), ppm; [M+H]+ 400.2; LC-MS purity (254 nm): 98.1%; t _R =3.15 min; HPLC purity (254 nm): 97.7%; t _R =3.17 min.

Example 203: Preparation of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methylcyclohexylmethyl)-amide (221)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (100 mg, 0.38 mmol, 1.00 eq), triethylamine (0.16 mL, 1.13 mmol, 3.00 eq), HATU (295.16 mg, 0.75 mmol, 2.00 eq) and (1S,3S)-1-aminomethyl-3-methyl-cyclohexanol (66.33 mg, 0.45 mmol, 1.20 eq) in dry DMF (5 mL, 50 V) to afford 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methylcyclohexylmethyl)-amide (30 mg, 0.08 mmol, 20.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.44 (s, 1H), 8.25 (d, J=5.16Hz, 1H), 7.99 (t, J=6.24Hz, 1H), 7.31 (dd, J=1.1 6, 5.10Hz, 1H), 6.00-5.97 (m, 1H), 5.05-4.98 (m, 4H), 4.24 (s, 1H), 3.21 (d, J=5.8 4Hz, 2H), 1.72-1.71(m, 1H), 1.61-1.56(m, 4H), 1.46-1.44(m, 1H), 1.24-1.22(m, 1H), 0.98-0.92(m, 1H), 0.82(d, J=6.44Hz, 3H), 0.77-0.74(m, 1H); [M+H]+378.2.

Example 204: Preparation of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methylcyclohexylmethyl)-amide (222)

The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (100 mg, 0.38 mmol, 1.00 eq), triethylamine (0.16 mL, 1.13 mmol, 3.00 eq), HATU (295.16 mg, 0.75 mmol, 2.00 eq) and (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (65.39 mg, 0.45 mmol, 1.20 eq) in dry DMF (5 mL, 50 V) to afford 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methylcyclohexylmethyl)-amide (30 mg, 0.08 mmol, 20.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.44 (s, 1H), 8.24 (d, J = 5.12Hz, 1H), 7.98 (t, J = 6.08Hz, 1H), 7.31 (d, J = 5.12Hz, 1H) ), 6.02-5.95 (m, 1H), 5.05-4.98 (m, 4H), 4.23 (s, 1H), 3.20 (d, J=6.16Hz, 2H), 1.72-1.7 1 (m, 1H), 1.70-1.60 (m, 4H), 1.58-1.55 (m, 1H), 1.25-1.22 (m, 1H), 0.98-0.92 (m, 1H), 0.82 (d, J=6.44 Hz, 3H), 0.77-0.74 (m, 1H) ppm; [M+H]+378.2; LC-MS purity (220 nm): 97.8%; _tR =3.53 min; HPLC purity (254 nm): 99.5%; _tR =3.52 min.

Example 205: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-(oxetan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (224)

The title compound was synthesized according to the procedure described in Example 33 using 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), oxetan-3-ylmethanol (20.18 mg; 0.22 mmol; 1.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (105.32 mg; 0.44 mmol; 3.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.26(1H), 8.09(m, 1H), 8.05(1H), 7.31(s, 1H), 4.77(m, 1H), 4.47(2H), 3.74(2H), 2.62(3H), 2.09-1.91(3H), 1.65(3H). m/z: 414[M+H].

Example 206: Preparation of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (227)

The title compound was synthesized as a white solid (130 mg, 0.30 mmol, 58.2%) according to the procedure described in Example 2 using a mixture of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (150 mg, 0.51 mmol, 1.00 eq), (4,4-difluoro-cyclohexyl)-methylamine hydrochloride (96 mg, 0.51 mmol, 1.00 eq), benzotriazol-1-ol (124.57 mg, 0.77 mmol, 1.50 eq) and (3-dimethylamino-propyl)-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol, 1.50 eq) in dry THF (25 mL, 166.67 V).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.23 (d, J=5.12Hz, 1H), 8.18 (t, J=5.88Hz, 1H), 7.95 (s, 1H), 7.27 (d, J=5 .12Hz, 1H), 4.35-4.21(m, 3H), 3.79-3.75(m, 1H), 3.65-3.59(m, 1H), 3.15(t, J = 6.40 Hz, 2H), 2.03-2.00 (m, 2H), 1.95-1.90 (m, 1H), 1.82-1.69 (m, 7H), 1.59-1.55 (m, 1H), 1.25-1.23 (m, 2H) ppm; [M+H]+ 412.0; LC-MS purity (220 nm): 93.6%; _tR = 4.18 min; HPLC purity (254 nm): 93.4%; _tR = 4.15 min.

Example 207: Preparation of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (218)

The reaction mixture was stirred at 40 ℃ for 2 h using 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (75 mg, 0.25 mmol, 1.00 eq), (1S,3S)-1-aminomethyl-3-methyl-cyclohexanol (55.96 mg, 0.38 mmol, 1.50 eq), benzotriazole-1-ol (62.05 mg, 0.38 mmol, 1.50 eq) and (3-dimethylamino-propyl)-ethylcarbodiimide hydrochloride. A mixture of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30.00 mg, 0.07 mmol, 29.0%) was prepared from a mixture of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30.00 mg, 0.07 mmol, 29.0%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.24 (d, J=5.12Hz, 1H), 8.02 (s, 1H), 7.89 (t, J=6.08Hz, 1H), 7.28 (d, J=5.08Hz, 1H), 4.38-4.2 1(m, 4H), 3.79-3.75(m, 1H), 3.65-3.61(m, 1H), 3.19(d, J=6.12Hz, 2H), 1.94-1.90(m, 1H), 1.81-1 0.05 (m, 4H), 0.09 (m, 1H), 0.14 (m, 5H), 0.12 (m, 1H), 0.17 (m, 2H), 0.19 (m, 3H), 0.91 (m, 1H), 0.96 (m, 2H), 0.14 (m, 1H), 0.96 (m, 1H), 0.16 (m, 1H), 0.94 (m, 2H), 0.08 (m, 3H), 0.70 (m, 1H), 0.96 (m, 1H), 0.96 (m, 2H), 0.14 (m, 1H), 0.96 (m, 1H), 0.96 (m, 1H), 0.94 (m, 2H), 0.08 (m, 1H), 0.76 (m, 1H), ppm; [M+H]+406.2; LC-MS purity (220 nm): 94.1%; _tR = 3.91 min; HPLC purity (254 nm): 95.6%; _tR = 3.88 min.

Example 208: Preparation of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (220)

Using 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (75 mg, 0.25 mmol, 1.00 eq), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (55.17 mg, 0.38 mmol, 1.50 eq), benzotriazol-1-ol (62.05 mg, 0.38 mmol, 1.50 eq) and (3-dimethylamino-propyl)-ethylcarbodiimide salt To the mixture of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 29.0%) was prepared from a mixture of 4-chloro-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 29.0%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.24 (d, J=5.08Hz, 1H), 8.02 (s, 1H), 7.87 (t, J=6.04Hz, 1H), 7.28 (d, J=5.12Hz, 1H), 4.35-4.27 (m, 2H), 4.24-4.21(m, 2H), 3.79-3.76(m, 1H), 3.65-3.60(m, 1H), 3.20(d, J=6.08Hz, 2H), 1.95-1.91(m, 1H) ), 1.83-1.79 (m, 1H), 1.77-1.76 (m, 1H), 1.61-1.50 (m, 5H), 1.45-1.43 (m, 1H), 1.21-1.20 (m, 1H), 0.97-0.94 (m, 1H), 0.82 (d, J=6.60 Hz, 1H), 0.76-0.74 (m, 1H), ppm; [M+H]+406.2; LC-MS purity (220 nm): 94.1%; _tR =3.91 min; HPLC purity (254 nm): 96.6%; _tR =3.89 min.

Example 209: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (226)

Step 1: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (500.00 mg; 2.54 mmol; 1.00 eq.), 1-aminomethyl-4,4-difluoro-cyclohexanol hydrochloride (564.13 mg; 2.80 mmol; 1.10 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (585.08 mg; 3.05 mmol; 1.20 eq.), benzotriazole-1-ol ( The title compound was synthesized from a mixture of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (780 mg, 82% yield) using a mixture of 412.40 mg; 3.05 mmol; 1.20 eq.) and ethyldiisopropylamine (986.13 mg; 7.63 mmol; 3.00 eq.) in DMF (10.0 mL) according to the procedure described in Example 2. m/z: 344 (M+H)

Step 2: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), (tetrahydro-furan-2-yl)-methanol (22.28 mg; 0.22 mmol; 1.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (105.32 mg; 0.44 mmol; 3.00 eq.) in toluene (3 mL) to give the desired product (3 mg, 4%).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.26(1H), 8.11(s, 1H), 7.31(1H), 4.74(1H), 3.83(1H), 3.65(1H), 3.53(1H), 2.85(1H), 2.02-1.86(m, 3H), 1.65(3H). m/z: 428[M+H].

Example 210: Preparation of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (230)

The reaction mixture was stirred at 40 ℃ for 1 h using 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (100 mg, 0.34 mmol, 1.00 eq), triethylamine (0.14 mL, 1.02 mmol, 3.00 eq), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (265.66 mg, 0.68 mmol, 2.00 eq) and C A mixture of -(4,4-difluoro-cyclohexyl)-methylamine hydrochloride (75.49 mg, 0.41 mmol, 1.20 eq) in dry DMF (5 mL, 50 V) was used to synthesize the title compound according to the procedure described in Example 5 to obtain 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (50 mg, 0.12 mmol, 34.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.24 (d, J=5.12Hz, 1H), 8.20 (t, J=5.80Hz, 1H), 8.03 (s, 1H), 7.28 (d, J=5.12Hz , 1H), 4.27 (d, J=7.60Hz, 2H), 3.81-3.77 (m, 1H), 3.65-3.59 (m, 2H), 3.51-3.48 (m, 1 H), 3.15 (t, J = 6.32 Hz, 2H), 2.83-2.81 (m, 1H), 2.03-2.00 (m, 2H), 1.90-1.81 (m, 4H), 1.74-1.61 (m, 3H), 1.25-1.22 (m, 2H) ppm; [M+H]+ 412.0; LC-MS purity (220 nm): 97.1%; _tR = 4.00 min; HPLC purity (254 nm): 97.8%; _tR = 3.97 min.

Example 211: Preparation of 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (225)

The title compound was synthesized according to the procedure described in Example 33 using a mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide (50.00 mg; 0.15 mmol; 1.00 eq.), (tetrahydrofuran-3-yl)methanol (22.28 mg; 0.22 mmol; 1.50 eq.) and (tributyl-λ5-phosphino)-acetonitrile (105.32 mg; 0.44 mmol; 3.00 eq.) in toluene (3 mL).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.26(1H), 8.11(s, 1H), 7.31(1H), 4.74(1H), 3.83(1H), 3.65(1H), 3.53(1H), 2.85(1H), 2.02-1.86(m, 3H), 1.65(3H). m/z: 428[M+H].

Example 212: (R)-4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (215)

The racemic 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide was separated using a chiral column to provide the title compound. Mobile phase: hexane:hexanol:DEA = 70:30:0.1; flow rate: 1.0 mL/min; run time: 25 min; column: Chiral PAK AY-H (250 x 4.6 mm, 5 μm).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.26(1H), 8.11(s, 1H), 7.31(1H), 4.74(1H), 3.83(1H), 3.65(1H), 3.53(1H), 2.85(1H), 2.02-1.86(m, 3H), 1.65(3H). m/z: 428[M+H].

Example 213: (S)-4-Chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (216)

The racemic 4-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide was separated by chiral column to afford the title compound. (Isolation: see Example 212).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.26(1H), 8.11(s, 1H), 7.31(1H), 4.74(1H), 3.83(1H), 3.65(1H), 3.53(1H), 2.85(1H), 2.02-1.86(m, 3H), 1.65(3H). m/z: 428[M+H].

Example 214: Preparation of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (219)

Using 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (75 mg, 0.25 mmol, 1.00 eq), (1S,3S)-1-aminomethyl-3-methyl-cyclohexanol (55.96 mg, 0.38 mmol, 1.50 eq), benzotriazol-1-ol (62.05 mg, 0.38 mmol, 1.50 eq) and (3-dimethylamino-propyl)-ethylcarbodiimide salt To the mixture of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 29.0%) was prepared from a mixture of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 29.0%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.25 (d, J=5.12Hz, 1H), 8.10 (s, 1H), 7.93 (t, J=5.92Hz, 1H), 7.28 (d, J=5.12Hz, 1H), 4.27 (d, J=7.60Hz , 2H), 4.23 (s, 1H), 3.81-3.77 (m, 1H), 3.65-3.59 (m, 2H), 3.52-3.49 (m, 1H), 3.19 (d, J=6.12Hz, 2H), 2.83-2 0.05 (m, 5H), 0.09 (m, 1H), 1.24 (m, 1H), 0.91 (m, 1H), 0.82 (d, J = 6.60 Hz, 3H), 0.76 (m, 1H) ppm; [M+H]+ 406.2; LC-MS purity (220 nm): 99.7%; _tR = 3.75 min; HPLC purity (254 nm): 99.4%; _tR = 3.73 min.

Example 215: Preparation of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (217)

Using 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (75 mg, 0.25 mmol, 1.00 eq), (1R,3R)-1-aminomethyl-3-methyl-cyclohexanol (55.17 mg, 0.38 mmol, 1.50 eq), benzotriazol-1-ol (62.05 mg, 0.38 mmol, 1.50 eq) and (3-dimethylamino-propyl)-ethylcarbodiimide salt To the mixture of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 29.0%) was prepared from a mixture of 4-chloro-1-(tetrahydro-furan-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (30 mg, 0.07 mmol, 29.0%) as a cream solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.25 (d, J=5.12Hz, 1H), 8.10 (s, 1H), 7.93 (t, J=6.04Hz, 1H), 7.28 (d, J=5.12Hz, 1H), 4.27 (d, J=7.56Hz , 2H), 4.23 (s, 1H), 3.81-3.77 (m, 1H), 3.65-3.59 (m, 2H), 3.52-3.49 (m, 1H), 3.19 (d, J=6.12Hz, 2H), 2.83-2 0.05 (m, 5H), 0.09 (m, 1H), 1.14 (m, 1H), 0.94 (m, 5H), 0.13 (m, 1H), 0.96 (m, 1H), 0.94 (m, 5H), 0.08 (m, 1H), 0.12 (m, 1H), 0.96 (m, 5H), 0.94 (m, 1H), 0.98 (m, 1H), 0.14 (m, 5H), 0.96 (m, 1H), 0.98 (m, 1H), 0.94 (m, 5H), 0.96 (m, 1H), 0.98 (m, 5H), 0.94 (m, 5H), 0.96 (m, 1H), 0.98 (m, 1H), 0.94 (m, 5H), 0.96 (m, 5H), 0.98 (m, 1H), 0.94 (m, 5H), 0.96 ( _m , 5H), 0.96 (m, 5H), 0.96 (m, 5H), 0.96 (m, _5H ), 0.96

Example 216: Preparation of N-((4,4-difluorocyclohexyl)methyl)-1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxamide (198)

Step 1: Preparation of 2,2,2-trifluoro-1-(1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indol-3-yl)ethanone

To a solution of 1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole (0.800 g, 3.3 mmol) in DMF (10.0 mL) was added TFA (2.1 g, 10 mmol) at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was quenched with _aqueous NaHCO₃. The separated organic layer was dried over _MgSO₄ , filtered, and concentrated in vacuo to afford 2,2,2-trifluoro-1-(1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indol-3-yl)ethanone (0.90 g, 81%) as a yellow oil.

Step 2: Preparation of 1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxylic acid

To a solution of 2,2,2-trifluoro-1-(1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indol-3-yl)ethanone (0.9 g, 2.65 mmol) in hexanol (5.0 mL) was added 15% aqueous NaOH (4.0 mL) at room temperature. The reaction mixture was stirred at 80°C for 16 hours and then cooled to room temperature. The mixture was washed with ether (25 mL x 2) and discarded. The pH of the aqueous layer was adjusted to 3 with 4N HCl and extracted with ethyl acetate. The separated organic layer was dried over _MgSO₄ , filtered, and concentrated in vacuo to afford the product, 1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxylic acid (750 mg, 97%), which was used in the next step without purification.

Step 3: Preparation of N-((4,4-difluorocyclohexyl)methyl)-1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxamide (MSC2495502, FR-210)

A mixture of 1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxylic acid (0.100 g, 0.35 mmol), (4,4-difluorocyclohexyl)methanamine (0.060 g, 0.4 mmol), HOBt (0.100 g, 0.8 mmol), EDCI (0.140 g, 0.8 mmol) and triethylamine (0.100 g, 1.2 mmol) in DMF (3.0 mL) was stirred at room temperature overnight and diluted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (PE:EA=1:1) to give N-((4,4-difluorocyclohexyl)methyl)-1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxamide (0.030 g, 20%) as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ8.14 (d, J=5.5Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.48 (d, J=7.5Hz, 1H), 7.35 (t, J=8.0Hz, 1H), 4.45-4. 43(m, 2H), 3.70-3.30(m, 2H), 3.14(s, 3H), 3.12-3.11(m, 2H), 2.06-2.00(m, 2H), 1.84-1.69(m, 5H), 1.27-1.18(m, 2H)ppm; [M+H]+418.9.

Step 4: Preparation of N-((4,4-difluorocyclohexyl)methyl)-1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxamide

A mixture of N-((4,4-difluorocyclohexyl)methyl)-1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxamide (0.120 g, 0.29 mmol) and pyridine hydrochloride (0.165 g, 1.43 mmol) was stirred at 150 ° C for 16 hours. After cooling to room temperature, the reaction was quenched with NaHCO ₃ and extracted with ethyl acetate. The separated organic layer was dried over MgSO ₄ , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to obtain N-((4,4-difluorocyclohexyl)methyl)-1-(2-hydroxyethyl)-4-(trifluoromethyl)-1H-indole-3-carboxamide (0.035 g, 30%) as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ8.11 (d, J=5.0Hz, 1H), 7.87 (d, J=8.5Hz, 1H), 7.79 (s, 1H), 7.48 (d, J=8.0Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 4.96-4.94 ( m, 1H), 4.32-4.30 (m, 2H), 3.75-3.73 (m, 2H), 3.14-3.11 (m, 2H), 2.03-2.00 (m, 2H), 1.84-1.69 (m, 5H), 1.27-1.18 (m, 2H)ppm; [M+Na]+427.1.

Example 217

IL-1β release assay

Activation of P2X7 by ATP results in rapid transient activation of cells, resulting in Ca ²⁺ influx, followed by conversion of pro-IL-1β to active IL-1β. Mature IL-1β released in THP-1 cell culture medium was detected by sandwich ELISA to measure the functional activity of P2X7 compounds. Cells were maintained in complete growth medium (RPMI 1640 + 10% HI-FCS + 2mM L-glutamine + 1×PS). Every three days, cells were diluted 1/3 to 1/4 and the culture medium was refreshed to a cell density of no more than 500,000 cells/ml (seeding cell density was 1×10 ⁵ cells/ml). Cells were centrifuged at 100g for 3 minutes and THP-1 cells were harvested from 50ml flasks. Cells were resuspended in culture medium supplemented with 0.5μM PMA at a cell density of 2x10 ⁵ cells/ml and incubated. The cells were washed and resuspended in culture medium supplemented with 10 ng/ml LPS at a cell density of 1.5 × ¹⁰ cells/ml and primed at 37°C, 5% _CO₂ for 4 hours. After adding 20 μL of prediluted test compounds, blank reagent, standard reagent, and control reagent, the cells were incubated for an additional 20 minutes at 37°C and stimulated with 0.8 mM BzATP for 30 minutes. The cells were centrifuged, the supernatant collected, and assayed for the presence of mature IL-1β using a dual-strength human IL-1β kit according to the manufacturer's instructions. Tetrahydrobenzodiazepine analogs effectively modulate cellular P2X7 activity, as measured by the levels of the proinflammatory cytokine IL-1β released upon P2X7 receptor activation.

Pore penetration test

HEK293 cells were transfected with the human P2X7 receptor, and the amount of YO PRO fluorescent dye taken up by the cells in the transfected HEK293 cells was measured to determine the pores formed by agonist induction. HEK293 cells overexpressing human P2X7 were harvested by detaching the cells from a T75 cm flask using HQTase reagent. The harvested cells were centrifuged at 1200 rpm for 5 minutes at room temperature. Cell viability was determined using Trypan Blue dye, and 50 μl of cells were plated at 10,000 cells/well in 384W BD polylysine-coated well plates and incubated overnight at 37°C. After overnight incubation, the culture medium was replaced with 35 μl/well assay buffer (5 mM KCl, 0.1 mM CaCl2, ₅ mM glucose, 10 mM HEPES buffer containing 125 mM NaCl, pH 7.4). The compound was serially diluted using a Bravo liquid handling instrument and added to the cell assay well plate using the Bravo, starting at a concentration of 2.5 uM and three dilutions for 10 points. The positive control inhibitor compound was added to row 23. The well plate was slowly shaken on a plate shaker for 10 seconds. The cells were incubated with the compound at room temperature for 20 minutes. After the incubation period, YO PRO dye (1 uM) was added to the cells together with BzATP (10 uM) at 10 ul/well. The well plate was centrifuged at 1000 rpm for 5 seconds and incubated at room temperature for 30 minutes. The YO PRO dye uptake into the cells was measured using an Envision fluorescence plate reader (Perkin Elmer).

Understand the data using the following definitions:

Example 218: Pharmaceutical Formulation

(A) Injection vial: A solution of 100 g of the compound of the present invention as the active ingredient and 5 g of sodium dihydrogen phosphate in 3 L of redistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, transferred to an injection vial, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each injection vial contains 5 mg of the active ingredient.

(B) Suppositories: 20 g of the compound of the present invention as the active ingredient is mixed with 100 g of soybean lecithin and 1400 g of cocoa butter, poured into a mold, and cooled. Each suppository contains 20 mg of the active ingredient.

(C) Solution Formulation: Prepare a solution consisting of 1 g of the active ingredient compound of the present invention, 9.38 g _{of NaH₂PO₄} · _2H₂O , 28.48 g _{of Na₂HPO₄} · _12H₂O , and 0.1 g of benzalkonium chloride in 940 mL of redistilled water. Adjust the pH of the solution to 6.8, make up to 1 L, and sterilize by radiation. Use the solution as eye drops.

(D) Ointment: 500 mg of the compound of the present invention as an active ingredient is mixed with 99.5 g of vaseline under sterile conditions.

(E) Tablets: 1 kg of the compound of the present invention as an active ingredient, 4 kg of lactose, 1.2 kg of potato flour, 0.2 kg of talc and 0.1 kg of magnesium stearate are compressed into tablets according to a conventional method so that each tablet contains 10 mg of the active ingredient.

(F) Coated tablets: Tablets are compressed similarly to Example E and then coated with sucrose, potato flour, talc, tragacanth and dye according to conventional methods.

(G) Capsules: 2 kg of the compound of the present invention as an active ingredient is introduced into hard capsules according to a conventional method so that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of the compound of the present invention as the active ingredient in 60 L of redistilled water is sterile filtered, transferred into ampoules, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each ampoule contains 10 mg of the active ingredient.

(I) Inhalation spray: Dissolve 14 g of the active ingredient of the compound of the present invention in 10 L of isotonic sodium chloride solution. Transfer the solution to a commercially available spray container with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) is equivalent to a dose of approximately 0.14 mg.

Although many embodiments of the present invention are described herein, it is apparent that the basic embodiments can be modified using the compounds and methods of the present invention to provide other embodiments. It should be understood, therefore, that the scope of the invention is to be limited by the appended claims rather than by the specific embodiments provided by way of example.

Claims (6)

1. Compounds selected from the following group or their pharmaceutically acceptable salts: 2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable adjuvant, carrier, or mediator. 3. Use of the compound of claim 1 or a physiologically acceptable salt thereof in the preparation of a medicament for modulating P2X7 activity in a subject or biological sample. 4. Use of the compound of claim 1 or a physiologically acceptable salt thereof in the preparation of a medicament for treating a P2X7-mediated disease or condition in patients in need. 5. Use of the compound of claim 1 or a physiologically acceptable salt thereof in the preparation of a medicament for treating the following diseases or conditions: Parkinson's disease, multiple sclerosis (MS); Alzheimer's disease, traumatic brain injury, encephalitis; depression, bipolar disorder, anxiety, schizophrenia, eating disorder, sleep disorder, cognitive impairment; epilepsy, seizure disorder; urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hyperplasia, inflammatory bowel disease; allergic rhinitis, asthma, reactive airway disease, chronic obstructive pulmonary disease; rheumatoid arthritis, osteoarthritis, myocardial infarction, uveitis, atherosclerosis; or psoriasis. 6. Use of the compound of claim 1 or a physiologically acceptable salt thereof in the preparation of a medicament for treating multiple sclerosis in patients.