Allosteric modulators and agonists of the cannabinoid receptor 1 (CB1) and uses thereof

Abstract

Provided herein are 3-amino-7 / 7-indole derivative compounds of general Formula (I): or a pharmaceutically acceptable salt, hydrate, or solvate thereof or pharmaceutical compositions that are allosteric modulators / allosteric agonists of the cannabinoid receptor 1 (CB1). Also provided is a method for treating a disorder associated with CB1 receptor activities.

Description

[0001] ALLOSTERIC MODULATORS AND AGONISTS OF THE CANNABINOID RECEPTOR 1 (CB1) AND USES THEREOF

[0002] Cross-Reference to Related Applications

[0003] This international patent application claims benefit of priority under 35 U.S.C. §119(e) of provisional application U.S. Serial No. 63 / 656,005, filed June 4, 2024, the entirety of which is hereby incorporated by reference.

[0004] Statement of Government License Rights

[0005] This invention was made with government support under Grant Numbers 1 R01 DA039942 and UG3NS128439 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] BACKGROUND OF THE INVENTION

[0007] Field of the invention

[0008] The present invention relates to the fields of chemical synthesis and medicine. More specifically, the present invention relates to the preparation of and therapeutic use of 3-amino- 7 / 7-indole derivatives of general Formula (I).

[0009] Description of the Related Art

[0010] CB1 is a member of the endocannabinoid system, which consists of at least two G- protein coupled receptors (GPCRs), CB1 and the cannabinoid type 2 receptor (CB2). Similar to A9-tetrahydrocannabinol (A9-THC), the main active ingredient of cannabis, a group of lipidderived molecules represented by A / -arachidonoyl ethanolamine and 2-arachidonoyl glycerol can function as endogenous agonists of the two cannabinoid receptors. There are several catabolic enzymes including fatty acid amide hydrolase and monoacylglycerol lipase that are responsible for degrading the endogenous cannabinoid ligands promptly so that the cannabinoid receptors will not be overly active under physiological conditions (1-3). The CB1 receptor has been linked to an array of disease states including chemotherapy-induced nausea, waste syndromes associated with cancer and AIDS, obesity, neurodegenerative disorders, pain and substance abuse disorders (2,4). Traditionally, drug discovery efforts that have focused on the CB1 have been concentrated on the ligands targeting the CB1 orthosteric sites where the endogenous cannabinoids bind. However, ligands targeting the orthosteric sites of CB1 have been found to have either psychotropic side effects from CB1 agonists (5) and / or psychiatric side effects from globally active CB1 antagonists / inverse agonists (6). Several cannabinoid-based drugs have been proved by FDA and European Medicines Agency for clinical application (e.g., Marinol; Nabilone, and Sativex) to manage chemotherapy-induced nausea; to control pain; to treat spasticity in patients with multiple sclerosis; and to improve appetite for patients with HIV / AIDS or cancer.

[0011] Traditionally, drug discovery efforts that have focused on CB1 have been concentrated on the ligands targeting CB1 orthosteric sites where the endogenous cannabinoids bind. However, ligands targeting the orthosteric sites of CB1 have been found to have either psychotropic side effects from CB1 agonists (5) and / or psychiatric side effects from globally active CB1 antagonists / inverse agonists (6) These untoward side effects hampered drug discovery efforts aimed at regulation of CB1 for therapeutic gain. The unmet need for therapeutic intervention of CB1 functions promoted the development of neutral antagonists of the CB1 (7,8), peripherally acting CB1 ligands (9) and other CB1 ligands that exhibit novel mechanisms of action such as the allosteric modulation of CB1. Historically, drug discovery programs aimed at regulation of GPCR functions have been dominated by the identification of ligands to compete with endogenous ligands at the orthosteric sites. Recently, there have been tremendous advances in the discovery of ligands that can regulate GPCR functions by binding to receptor sites topographically distinct from orthosteric sites. Such ligands are defined as allosteric modulators. Allosteric ligands of GPCRs can induce and stabilize unique conformations of GPCRs and therefore provide fundamentally different receptors, which are capable of delivering novel pharmacological effects. During the last 20 years, several structurally distinct molecules have been identified as allosteric modulators of CB1. These compounds include the small molecules 5-chloro-3-ethyl-A / -(4-(piperidin-1-yl)phenethyl)-1 / 7- indole-2-carboxamide (10, Org27569) (12), 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin- 2-yl)phenyl)urea (PSNCBAM-1 ) (13), 3-(4-chlorophenyl)-5-(8-methyl-3-p-tolyl-8- azabicyclo[3.2.1]octan-2-yl)-isoxazole (RTI-371 ) (14), 6-methyl-3-(2-nitro-1-(thiophen-2- yl)ethyl)-2-phenyl-1 H-indole (ZCZ011 ) (15), cannabidiol, and fenofibrate; and the endogenous molecules (5S,6R,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-9,11 ,13-trienoic acid (lipoxin A4) (16), pregnenolone (17), and pepcan-12 (18).

[0012] While CB1 orthosteric agonists and antagonists have traditionally been pursued to target the cannabinoid receptors, they were found with untoward side effects unacceptable for chronic applications in clinical settings. Generally, allosteric modulators provide several mechanism-based advantages to overcome the on- and off-target side effects and increase drug safety and specificity. First, they offer the potential for better receptor subtype selectivity because of the greater structural variance in allosteric sites over the orthosteric sites, which generally are highly conserved. Second, allosteric modulators without intrinsic activity have the ability to selectively exert biological responses only in tissues where the endogenous ligands are present and function. Third, once the allosteric sites are completely occupied, it produces a saturation of effect, and consequently limits the effect of the allosteric modulator on the response induced by the orthosteric ligand. This “ceiling” action can prevent overdosing of a drug. More importantly, allosteric modulators allow for the fine- tuning of receptor pharmacology through ligand-dependent and biased signaling. This may facilitate signal transductions towards the pathways that are more therapeutically relevant while sparing those involved in the untoward effects. The discovery of CB1 allosteric modulators has enhanced the approaches by which the functions of CB1 can be manipulated for potential therapeutic benefits with the aim of improving the pharmacology and drug safety over typical orthosteric CB1 ligands.

[0013] Thus, there is a lack of cannabinoid receptor 1 (CB1 ) allosteric modulators that lack the known side effects. Particularly, the prior art is deficient in 3-amino-7 / 7-indole derivatives as therapeutics. The present invention fulfills this long-standing need and desire in the art.

[0014] SUMMARY OF THE INVENTION

[0015] CB1 positive allosteric modulators may be advantageous, as safer alternatives to CB1 agonists, in all of the disorders that activation of the CB1 receptors leads to the relief of the symptoms or producing disease modifying effects. The disorders include but not limited to pain (acute and chronic neuropathic, inflammatory, chemotherapy-induced pain), neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s and Huntington’s diseases), neuronal injury (brain injury), chemotherapy-induced nausea and wasting syndromes, anxiety, neurological / mental diseases (e.g., post traumatic stress disorders, depression, schizophrenia and epilepsy), glaucoma and retinopathy, respiratory disorders, cardio- and cerebral-vascular diseases, asthma, migraine, cancer, insomnia, inflammation, liver disease, and osteoporosis. Furthermore, CB1 agonists have been shown to have additional therapeutic effects when in combination with other drugs for the treatment of a range of disorders. CB1 positive allosteric modulators may also be used as adjunctive therapy in other disorders.

[0016] Thus, this invention provides compounds of the Formula (I) in the form of a base or of an addition salt with an acid which is pharmaceutically acceptable, in the form of hydrates or of solvates, and also in the form of enantiomers, diastereoisomers and a mixture thereof. The disclosure also relates to processes for preparing these compounds, to pharmaceutical compositions containing a compound of general Formula (I), and to the therapeutic use of said compounds and compositions. Summary of the compounds of the invention:

[0017] The present invention provides compounds that are to 3-amino-1 / 7-indole derivatives, whose structures are represented by the Formula (I) in the form of a base or of an addition salt with an acid which is pharmaceutically acceptable, in the form of hydrates or of solvates, and also in the form of enantiomers, diastereoisomers and a mixture thereof.

[0018] Formula (I) wherein:

[0019] Xi, X2, X3 and X4 are independently a carbon atom (C), a methine group (CH) or a nitrogen (N) atom;

[0020] R1, R2, R3 and R4 are optionally and independently a hydrogen, a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), a cyano (CN), an alkoxyl, an alkyl, a substituent or absent;

[0021] R5is a hydrogen or a substituent;

[0022] Y1 is independently selected from (CH2)r, O, S, NH, a substituted amino group, a carbonyl, a sulfonyl, and a sulfinyl wherein the subscript r is 0, 1 , 2, 3, 4, or 5; subscript m is 0 or 1 ;

[0023] W1 is selected from an aryl, a heteroaryl, a cyclic ora heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituent(s) or a group selected from heterocyclic group or a heteroaryl group;

[0024] Y2 is independently (CH2)t, a carbonyl, a sulfonyl, or a sulfinyl wherein the subscript t is 0, 1 , 2, 3, 4 or 5; subscript n is 0 or 1 ;

[0025] W2 is an amino, an alkoxyl, or an alkyl, each of which is optionally and independently substituted with 1 to 4 substituents,

[0026] Y3 is a hydrogen, an aryl, a heteroaryl, a cyclic group, a heterocyclic group, or an amino group, each of which is optionally and independently substituted with 1 , 2, 3, or 4 of the substituents; Z is independently (CH2)w, O, S, an amino, a lower alkyl, a carbonyl, a sulfonyl, or a sulfinyl wherein the subscript w is 0, 1 , 2, 3, 4 or 5; subscript v is 0 or 1 ;

[0027] W3 is an aryl, a heteroaryl, a cyclic and a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituent(s); and

[0028] Y4 is hydrogen, (CH2)U, O, S, amino, carbonyl, sulfonyl, sulfinyl, or cyano (CN) wherein the subscript u is 0, 1 , 2, 3 or 4; subscript p is 0 or 1 ;

[0029] Y5is independently a hydrogen, an alkyl, a substituent or an aryl group a heterocyclic group, or a heteroaryl group, each of which is optionally and independently substituted with 1 , 2, 3, or 4 substituents; and subscript q is 0 or 1 .

[0030] The compounds of the present invention or pharmaceutical compositions thereof are useful in a method for treating a disorder associated with CB1 receptor activities via administration of a therapeutically effective amount thereof.

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIGS. 1A-1 B shows the structures of exemple compounds 1 to 48 that are derivatives of 3-amino-1 H-indole.

[0033] FIG. 2A shows general methods for synthesis of intermediates 2-phenyl-indole derivatives.

[0034] FIG. 2B shows general methods for synthesis of intermediates 3-amino-indole derivatives and some of the example compounds.

[0035] FIG. 2C shows general methods for synthesis of intermediates 3-amino-indole derivatives and some of the example compounds via reductive alkylation.

[0036] FIG. 2D shows general methods for synthesis of intermediates 3-phenyl-indole derivatives and some of the example compounds.

[0037] FIG. 2E shows general methods for synthesis of example compound 28.

[0038] FIG. 2F shows general methods for synthesis of example compound 34.

[0039] FIG. 2G shows general methods for synthesis of example compound 35.

[0040] FIG. 2H shows general methods for synthesis of example compound 39.

[0041] FIG. 2I shows general methods for synthesis of example compound 40.

[0042] FIG. 2J shows general methods for synthesis of example compounds 42 and 43.

[0043] FIG. 2K shows general methods for synthesis of example compound 44.

[0044] FIG. 2L shows general methods for synthesis of example compound 45. FIGS. 3A-3F show dose-response curves and ED5o values (mg / kg) of compounds 1 , 7, 1 , 16, 46, 47, and gabapentin in CCI-ION pain model.

[0045] DETAILED DESCRIPTION OF THE INVENTION

[0046] The present invention relates to 3-amino-indole derivatives, to the preparation thereof and to the therapeutic use thereof, wherein said compounds are of general Formula (I). These compounds selectively interact with the CB1 receptor and function as allosteric ligands of the CB1 receptor.

[0047] These compounds are useful in treating disorders associated with CB1 activities, including, but not limited to, pain (acute and chronic neuropathic, inflammatory, chemotherapeutics-induced pain), neurodegenerative diseases, neuronal injury, chemotherapy-induced nausea and wasting syndromes, anxiety, neurodegenerative disorders (e.g., Alzheimer’s disease and Parkinson’s disease), neurological diseases (e.g., depression, and schizophrenia), glaucoma and retinopathy, respiratory disorders, cardio- and cerebral-vascular diseases, asthma, migraine, cancer, insomnia, inflammation, liver disease, and osteoporosis.

[0048] Unless otherwise stated, the following terms used in the present invention have the meanings given below.

[0049] As used herein, the term “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and / or methods of the invention. It is contemplated that any method described herein can be implemented with respect to any other method described herein.

[0050] As used herein, the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.”

[0051] As used herein, “comprise” and its variations, such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated item, element or step or group of items, elements or steps but not the exclusion of any other item, element or step or group of items, elements or steps unless the context requires otherwise. Similarly, "another" or “other” may mean at least a second or more of the same or different claim element or components thereof.

[0052] As used herein, the terms "consist of" and "consisting of" are used in the exclusive, closed sense, meaning that additional elements may not be included. As used herein, the term “includes” or “including” refers to “including, but not limited to”. The terms “includes, “including” and “including, but not limited to” are used interchangeably.

[0053] As used herein, the term “subject” refers to any person who is treated with at least one of the compounds of Formula (I).

[0054] As used herein, the term “halogen” means a fluorine, a chlorine, a bromine or an iodine.

[0055] As used herein, the term “halo” means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.

[0056] As used herein, the term “alkyl group” means a saturated, linear or branched, aliphatic group. Examples of an alkyl group include the methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, 1 -methylethyl,

[0057] 1 -methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, 1 -methylbutyl, 2-methylbutyl, 3- methylbutyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3- dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 , 1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, 1 -ethylbutyl, 2- ethylbutyl, 1 -methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1 ,1- dimethylpentyl, 1 ,2-dimethylpentyl, 1 ,3-dimethylpentyl, 1 ,4-dimethylpentyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4- dimethylpentyl, 4,4-dimethylpentyl, 1 ,1 ,2-trimethylbutyl, 1 , 1 ,3-trimethylbutyl, 1 ,2,2- trimethylbutyl, 1 ,2,3-tri-methylbutyl, 1 ,3,3-trimethylbutyl, 2,2,3-trimethylbutyl, 2,3,3- trimethylbutyl, 1 ,1 ,2,2-tetramethylpropyl, 1 -ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-ethyl-1- methylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 2-ethyl-1 -methylbutyl, 2-ethyl-2- methylbutyl, 2-ethyl-3-methylbutyl, 1 -propylbutyl, 1 -(1 -methylethyl)butyl or 1-(1-methylethyl)-

[0058] 2-methylpropyl groups;

[0059] As used herein, the term “lower alkyl” means an alkyl group having 1 to 6 carbons linear or branched.

[0060] As used herein, the term “haloalkyl” means any alkyl radical having one or more of its hydrogen atoms replaced by a halogen atom or multiple (2-6) halogen atoms.

[0061] As used herein, the term “alkenyl group” means a mono- or polyunsaturated, linear or branched, aliphatic group comprising, for example, one or two ethylenic unsaturations.

[0062] As used herein, the term “alkynyl group” means a mono- or polyunsaturated, linear or branched, aliphatic group comprising, for example, one or two acetylenic unsaturations. As used herein, the term “cycloalkyl group” means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1 ]heptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl or adamantyl.

[0063] As used herein, the term “cycloalkenyl” means a closed ring structure of hydrocarbons, which have either one or two double bonds, but has no aromatic character. Representative examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1 ,3- cyclohexadienyl, 1 ,4-cyclohexadienyl and the like.

[0064] As used herein, the term “acyl” means a radical — C(O)R’, where R’ is a hydrogen, alkyl, trifluoromethyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl wherein alkyl, cycloalkyl, cycloalkyl-alkyl, and phenyl-alkyl are as defined herein. Representative examples include, but are not limited to formyl, acetyl, trifluoroacetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

[0065] As used herein, the term “alkoxyl” means a radical — OR where R is an alkyl or an alkyl substituted with 1 to 3 substituents as defined above. Representative examples include, but are not limited to trifluoromethoxy (CF3O), methoxy, ethoxy, propoxy, butoxy, t-butoxy and the like.

[0066] As used herein, the term “aryl” means a monovalent monocyclic or polycyclic aromatic hydrocarbon radical; it includes, but is not limited to, phenyl and naphthyl.

[0067] As used herein, the term “heteroaryl” means a monovalent monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms independently selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. More specifically the term heteroaryl includes, but is not limited to, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo[1 ,2-a]-pyridinyl, and imidazo[2,1-b]thiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,3,4-oxadiazolyl and 1 ,2,5-oxadiazolyl.

[0068] As used herein, the term “heterocyclic group” means a saturated or unsaturated nonaromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms independently selected from N, O, or S(O)e(where the subscript e is an integer selected from 0 to 2). More specifically the term heterocyclic ring includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, 2-oxo-piperidinyl, piperazinyl, N- methylpyrrolidin-3-yl, 3-pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1 -oxide, thiomorpholinyl-1 ,1 -dioxide, 4-(1 ,1-dioxo-tetrahydro-2H-thiopyranyl), pyrrolinyl, pyrrolidinyl, imidazolinyl, N-methanesulfonyl-piperidin-4-yl, azetidinyl, piperidinyl, piperazinyl, azepanyl, or diazepanyl.

[0069] As used herein, the term “substituted” means a hydrogen attaching to a carbon or a heteroatom including nitrogen and sulfur is replaced with a substituent.

[0070] As used herein, the term substituent means hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxyl, cycloalkyl, cyano (CN), hydroxyl (OH), acyl, haloalkyl, aryl, heteroaryl, heterocyclic group, C(halogen)3, -C(=O)CH3, -C(=0)NQIQ2, -C(=O)OQi, -C(=O)CF3, N3, NCS, CN, NO2, -S(=O)2NQIQ2, -S(=O)2NHQ2, -NQIS(=O)2Q2, -NQIC(=O)Q2, -S(=O)2QI or -S(=O)CF3, and -NQ1Q2, wherein each of Qi and Q2 is independently selected from H, substituted or unsubstituted alkyl, haloalkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, benzyl, aryl, heteroaryl, substituted aryl or substituted heteroaryl.

[0071] As used herein, the term “substituted aryl” means a hydrogen atom attaching to a carbon of the aryl is replaced with a substituent.

[0072] As used herein, the term “substituted heteroaryl” means a hydrogen attaching to a carbon or a nitrogen of the heteroaryl is replaced with a substituent.

[0073] As used herein, the term “sulfonyl” means -S(=O)2Q3, wherein Q3 is independently selected from alkyl, substituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, benzyl, aryl, heteroaryl, substituted aryl or substituted heteroaryl.

[0074] As used herein, the term “sulfinyl” means -S(=0)Q3, wherein Q3 is independently selected from alkyl, substituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, benzyl, aryl, heteroaryl, substituted aryl or substituted heteroaryl.

[0075] As used herein, the term “cyclic group” means at least some of its atoms are connected to form a ring structure containing single bonds or 1 to 3 carbon-carbon double bonds (C=C).

[0076] As used herein, the term “heterocyclic group” means a cyclic group that has its atoms of at least two different elements such as carbon (C), nitrogen (N), oxygen (O) or sulfur (S) as members of its ring(s) to from a ring structure containing single bonds or 1 to 2 double bond(s) in addition to the single bonds.

[0077] As used herein, the term “substituted cyclic group” means a hydrogen attaching to a carbon of the ring structure is replaced with a substituent.

[0078] As used herein, the term “substituted heterocyclic group” means a hydrogen attaching to a carbon or a nitrogen of the heterocyclic group is replaced with a substituent.

[0079] As used herein, the term “an amino” means a NH2, or a NQ1Q2 group, of which the Qi and Q2 each is independently selected from H, a substituted or unsubstituted alkyl, haloalkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, aryl, or heteroaryl.

[0080] As used herein, the term “amide” means a functional group consisting of a carbonyl group (C=O) that is linked to a nitrogen atom in the form of -NQI(C=0)Q2 or -(C=0)NQIQ2, of which the Qi and Q2 each is independently selected from H, a substituted or unsubstituted alkyl, haloalkyl, lower alkyl, cycloalkyl, arylalkyl, a heterocyclic group, an aryl, or a heteroaryl.

[0081] As used herein, the term “ester” means a functional group consisting of a carbonyl group (C=O) that is linked to an oxygen atom in the form of -O(C=O)Qi or -(C=O)OQi, of which the Qi is selected from a substituted or unsubstituted alkyl, haloalkyl, lower alkyl, cycloalkyl, arylalkyl, a heterocyclic group, an aryl, or a heteroaryl.

[0082] As used herein, the term “ether” means a functional group in which an oxygen atom is connected by single bound to two different or identical hydrocarbons and has the general formula R-O-R’, wherein the R and R’ are saturated or unsaturated hydrocarbons.

[0083] As used herein, the term “CB1 ” means the cannabinoid type 1 receptor.

[0084] As used herein, the term “CB2” means the cannabinoid type 2 receptor.

[0085] As used herein, the term “hydrate” means the crystalline of the invented compounds complexed with water molecules in the formula of (molecular formula of any of invented compound» H2O, in which is an integer selected from 1-8).

[0086] As used herein, the term “solvate” means that the crystalline of any of the invented compounds stoichiometrically or nonstoichiometrically form complex with the solvent including but not limited to methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, toluene, and ether employed in the recrystallization process of the invented compounds.

[0087] As used herein, the term “saturated” means that within the structure defined, there is no double or multiple bonds present.

[0088] As used herein, the term “unsaturated” means that within the structure defined, there is 1 to 4 double bond(s) or multiple bond(s) present.

[0089] As used herein, the term “addition salt” means those formed from reaction with acids selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (- L), malonic acid, mandelic acid (DL), methanesulfonic acid , naphthalene- 1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (- L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+ L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid.

[0090] As used herein, the term of “allosteric ligands” defines the compounds that bind to a receptor site topologically different from the receptor site where the endogenous ligands bind to and either to potentiate or inhibit activation of the given receptor.

[0091] As used herein, the term of “positive allosteric modulators” defines the allosteric ligands that can potentiate the binding affinity and / or the efficacy of an endogenous agonist of a given receptor.

[0092] As used herein, the term of “allosteric agonists” defines the compounds that can activate a given receptor by binding to a receptor site topologically different from the receptor site where the endogenous agonists bind to the given receptor.

[0093] Embodiments of the present invention

[0094] The compounds of this invention are allosteric ligands of the cannabinoid CB1 receptors. In one embodiment of the present invention, the compounds of this invention have the compositions of substituted-1 / 7-indol-3-amine derivatives having the general Formula (I):

[0095] Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

[0096] Xi, X2, X3 and X4 are independently a carbon atom, a methine group or a nitrogen atom;

[0097] R1, R2, R3 and R4 are optionally and independently a hydrogen, a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), a cyano (CN), an alkoxyl, an alkyl, a substituent or absent;

[0098] R5is a hydrogen or a substituent;

[0099] Y1 is independently selected from (CH2)r, O, S, NH, a substituted amino group, a carbonyl, a sulfonyl, and a sulfinyl wherein the subscript r is 0, 1 , 2, 3, 4, or 5; subscript m is 0 or 1 ; Wi is selected from an aryl, a heteroaryl, a cyclic ora heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituent(s) or a group selected from heterocyclic group or a heteroaryl group;

[0100] Y2 is independently (CH2)t, a carbonyl, a sulfonyl, or a sulfinyl wherein the subscript t is 0, 1 , 2, 3, 4 or 5; subscript n is 0 or 1 ;

[0101] W2 is an amino, an alkoxyl, or an alkyl, each of which is optionally and independently substituted with 1 to 4 substituents,

[0102] Y3 is a hydrogen, an aryl, a heteroaryl, a cyclic group, a heterocyclic group, or an amino group, each of which is optionally and independently substituted with 1 , 2, 3, or 4 of the substituents;

[0103] Z is independently (CH2)w, O, S, an amino, a lower alkyl, a carbonyl, a sulfonyl, or a sulfinyl wherein the subscript w is 0, 1 , 2, 3, 4 or 5; subscript v is 0 or 1 ;

[0104] W3 is an aryl, a heteroaryl, a cyclic and a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituent(s); and

[0105] Y4 is hydrogen, (CH2)U, O, S, amino, carbonyl, sulfonyl, sulfinyl, or cyano (CN) wherein the subscript u is 0, 1 , 2, 3 or 4; subscript p is 0 or 1 ;

[0106] Y5is independently a hydrogen, an alkyl, a substituent or an aryl group a heterocyclic group, or a heteroaryl group, each of which is optionally and independently substituted with 1 , 2, 3, or 4 substituents; and subscript q is 0 or 1 .

[0107] The compounds disclosed herein are clinically and commercially important compounds including, but not limited to the following embodiments.

[0108] In one embodiment, it is a compound of Formula (I) wherein the X2 is a carbon atom; the Xi, X3 and X4 are independently a carbon atom, a methine group or a nitrogen atom; the R2 is a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), or a cyano (CN), and the R1, R3 and R4 are optionally and independently a hydrogen, a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), a cyano (CN), an alkoxyl, an alkyl, or a substituent.

[0109] In another embodiment, it is a compound of Formula (I) wherein the subscript m is 0, and W1 is an aryl, hetero aryl, heterocyclic group, each of which is optionally and independently substituted with a heteroaryl, a heterocyclic group or 1 to 5 substituents.

[0110] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m, v and n are 0; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; and Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents.

[0111] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m, n and v are 0; the W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is a phenyl group, which is optionally and independently substituted with 1 to 5 substituents

[0112] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m and n are 0; the W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and Wsis a 2-pyridinyl group, which is optionally and independently substituted with 1 to 3 substituents.

[0113] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m, n and v are 0; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and the Ws is a pyrimidinyl group, which is optionally and independently substituted with 1 to 3 substituents.

[0114] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m, n and v are 0; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and Ws is a pyrazinyl group, which is optionally and independently substituted with 1 to 2 substituents.

[0115] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m, n and v are 0; and W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, and a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is a pyridazinyl group, which is optionally and independently substituted with 1 to 2 substituents.

[0116] In yet another embodiment, it is a compound of Formula (I) wherein the subscripts m and n are 0 and the subscript v is 1 ; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and Ws is an aryl and heteroaryl group, which is optionally and independently substituted with 1 to 2 substituents. Embodiments for utility and methods for using the derivatives of 3-amino-7 / 7-indole

[0117] In yet another embodiment, the present invention provides methods for using the compounds of Formula (I) as positive allosteric modulators and / or allosteric agonists of the cannabinoid CB1 receptor. Particularly provided is a method for treating a disorder associated with CB1 receptor activities, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound as described supra.

[0118] In aspects of this embodiment, the compounds of Formula (I) of the invention may be used for the treatment of disorders including, but not limited to, pathological pain conditions (acute and chronic neuropathic, inflammatory, chemotherapy-induced pain), neurodegenerative diseases, neuronal injury, chemotherapy-induced nausea and wasting syndromes, anxiety, neurological diseases (e.g. depression, schizophrenia and epilepsy), glaucoma and retinopathy, respiratory disorders, cardio- and cerebral-vascular diseases, asthma, migraine, cancer, insomnia, inflammation, liver disease, and osteoporosis.

[0119] For therapeutic applications, the compounds described in the Formula (I) can be formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier suitable for the desired method of administration. Pharmaceutically acceptable carriers are known in the art. The compounds described in Formula (I) can be administered systemically by oral, intravenous, subcutaneous, or topical administration. One of skill in the art is well-able to determine a therapeutic dose and dosing regimens depending on the subject and the disorder being treated.

[0120] The following examples are provided for the purpose of illustrating, not limiting the invention.

[0121] EXAMPLE 1

[0122] Assays

[0123] Assay of Inhibition of cAMP production

[0124] Positive allosteric modulation (PAM) of CB1 -mediated inhibition of forskolin-stimulated cyclic AMP accumulation response was measured using a DiscoverX HitHunter® cAMP Assay for Small Molecules (Eurofins DiscoverX, Fremont, CA). The technology of the HitHunter® cAMP Assay is based on enzyme fragment complementation (EFC) with - galactosidase activity as the final endpoint measurement and competition of endogenously generated cAMP for exogenously introduced cAMP containing an enzyme donor (cAMP-ED). Functional b-galactosidase activity is reconstituted by the complementation of an exogenously supplied enzyme acceptor and unbound cAMP-ED. The active enzyme converts a chemiluminescent substrate into a light signal that is proportional to the amount of endogenous cAMP generated in the cells. The human CBi receptor (hCBiR), stably transfected into CH0-K1 cells, were grown in DMEM / F12 supplemented with 10% FBS, 600 pg / mL G418, and 300 pg / mL hygromycin (Ross, 1999). hCBiR-CHO cells were seeded at a density of 40,000 cells / well in 96-well white plates and grown overnight at 37 °C, 5% CO2 in a humidified incubator. The following day, cell media was aspirated, and cells were serum-starved with cAMP assay buffer (HBSS containing 10 mM HEPES, 0.1 % BSA). After 60 min, this was replaced with 30 pL cAMP assay buffer containing 1 % DMSO, followed by immediate addition of 5 pL of a 9x concentration of allosteric (final concentrations of 3.3 x10'6or 10'6M for single concentration PAM measurements) and incubation for 30 min at 37°C, 5% CO2. For dose-response measurement of the PAM EC50, 5 pL of 9x concentrations of allosteric compounds (final concentrations of 10'10- 3.3x1 O'6M) were incubated for 30 min at 37°C, 5% CO2. Cells were subsequently treated with 5 pL 9x the EC20 concentration of CP55,940 (final concentration of 1 nM) and 5 pL 9x forskolin (final concentration of 10 pM) and incubated for 30 min at 37 °C, 5% CO2. Vehicle concentration was 1 % DMSO, 0.1 % BSA. Following CP55,940 agonist incubation, 15 I of cAMP antibody reagent and 60 I of working cAMP detection solution (containing 19 parts cAMP lysis buffer, 5 parts Substrate Reagent 1 , 1 part Substrate Reagent 2 and 25 parts of cAMP Solution D) were added to all wells. Assay plates were incubated in the dark for 1 hr at room temperature, followed by addition of 60 pL cAMP solution A to all wells and incubation for 3 hr at room temperature in the dark. Plates were read using a GloMax® Discover platereader (Promega, Madison, Wl). Results were calculated as the percent modulation as defined by the equation used for Gai-coupled receptors: %modulation = 100% x (1-(mean RLU of test sample - mean RLU of maximum CP55.940 control) / (mean RLU of EC20 CP55.940 control - mean RLU of maximum CP55.940 control). Percent modulation dose-response curves were analyzed by non-linear regression analysis of sigmoidal dose-response curves using GraphPad Prism 10.2.1 (GraphPad, San Diego, CA) or archived and analyzed using CCD Vault from Collaborative Drug Discovery (Burlingame, CA; www.collaborativedrug.com).

[0125] [35S1GTPyS binding assay

[0126] Membrane preparation: Cerebellum was dissected from male ICR mice and frozen at -80°C until use. On the day of assay, tissue was thawed, homogenized in membrane buffer (Tris-HCI, pH 7.4, 3 mM MgCh, 1 mM EGTA) and centrifuged at 40,000 x g for 10 min. The pellet was then homogenized in assay buffer (Tris-HCI, pH 7.4, 3 mM MgCh, 0.1 mM EGTA, 100 mM NaCI) and protein was determined using the Bradford method. Membranes were pretreated with adenosine deaminase for 15 min at 30°C prior to assay.

[0127] [35S]GTPgS binding assay: Membranes (6 pg protein) were incubated with 0.001-1 pM CP55.940 (orthosteric agonist), 0.01-10 pM allosteric ligands (ago-mode) or 2 nM CP55.940 ± 0.0003-10 pM allosteric ligands (PAM mode) in the presence of 30 pM GDP, and 0.1 nM [35S]GTPgS in assay buffer containing 1 % DMSO (v / v) and 0.1 % BSA (w / v) for 2 hr at 30°C in a 0.5 ml total volume. Basal binding was determined in the absence of agonist and nonspecific binding was measured using 20 pM unlabeled GTPgS. The assay was terminated by filtration through GF / B glass fiber filters, followed by 3 washes with ice-cold 50 mM Tris- HCI buffer. Bound radioactivity was determined by liquid scintillation spectrophotometry.

[0128] Data analysis: Specific binding was defined as total - non-specific [35S]GTPgS binding. Basal binding was defined as specific binding in the absence of ligand. Net-stimulation was defined as specific binding in the presence of ligand(s) - specific binding in the absence of ligand. % Maximum Net stimulation was defined as net-stimulation in the presence of ligand / net stimulation by 1 pM CP55.940 x 100% (ago-mode) or as (net-stimulation in the presence of allosteric ligand - net stimulation in the absence of allosteric ligand) / net stimulation by 1 pM CP55.940 x 100% (PAM-mode). % Maximum Net stimulation concentration-effect curves were fit by non-linear regression to 3-parameter logistic model (with the minimum constrained to 0) to obtain Emax and ECso values.

[0129] [3H1CP55,940 competition binding assays in mCB1-CHO cell membranes

[0130] Membrane preparation: Chinese hamster ovary (CHO) cells stably expressing the mouse CBi receptor were harvested and centrifuged at 500 x g for 10 min. The pellet was homogenized in membrane buffer (Tris-HCI, pH 7.4, 3 mM MgCh, 1 mM EGTA), centrifuged at 40,000 x g for 10 min and frozen in aliquots at -80°C until use. On the day of assay, membranes were thawed, homogenized in assay buffer (Tris-HCI, pH 7.4, 3 mM MgCh, 0.1 mM EGTA, 100 mM NaCI) and protein was determined using the Bradford method.

[0131] [3H]CP55,940 binding assay: Membranes (15-20 pg protein) were incubated with 0.5 nM [3H]CP55,940 and 0.0003-10 pM WIN55, 212-2 (orthosteric agonist) or 0.003-10 pM allosteric ligands in assay buffer containing 1 % DMSO (v / v) and 0.5% BSA (w / v) for 90 min at 30°C in a 0.5 ml total volume. Total and non-specific [3H]CP55,940 binding were determined in the absence of agonist of 5 pM unlabeled WIN55, 212-2. The assay was terminated by filtration through GF / B glass fiber filters that were presoaked in 50 mM Tris-HCI buffer with 0.5% BSA for 1 hr, followed by 3 washes with ice-cold 50 mM Tris-HCI buffer with 0.5% BSA. Bound radioactivity was determined by liquid scintillation spectrophotometry.

[0132] Data analysis: Specific binding was defined as total non-specific [3H]CP55,940 binding. % Bound was defined as specific at with each concentration of unlabeled ligand / specific binding in the absence of unlabeled ligand x 100%. IC50 and lmax values for ligands that inhibited [3H]CP55,940 binding were determined by non-linear regression to a 3- parameter logistic model with the top constrained to 100%. Ligands were considered to be inhibitory only when concentration-dependent inhibition of >20% of [3H]CP55,940 binding was obtained. For allosteric ligands that stimulated [3H]CP55,940 binding, Emax and EC50 values were obtained by non-linear regression to a 3-parameter logistic model with the bottom constrained to 100%.

[0133] EXAMPLE 2

[0134] Synthetic schema for the preparation of exemplary derivatives of 3-amino-1 / 7-indole

[0135] Following are general synthetic routes and procedures for preparing the compounds of the present invention. These are illustrative and are not meant to limit the possible techniques one skilled in the art any use to manufacture compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). In general, the compounds in this invention are prepared via indole derivatives as intermediates (IV, FIG. 3A) or commercially available aza-indole derivatives (V) such as 2- phenyl-1 / 7-pyrrolo[2,3-b]pyridine, 2-phenyl-1 / 7-pyrrolo[3,2-b]pyridine, 6-phenyl-7 / 7- pyrrolo[2,3-o(|pyrimidine, and 6-phenyl-5 / 7-pyrrolo[3,2-d]pyrimidine and their derivatives that can be prepared through prior methods (19). The chemical structures of the compounds are shown in FIGS. 1A-1 B and generally may be prepared using the methods illustrated in FIGS. 2A, 2B and 2C.

[0136] Example compound 1 : A / -ethyl-6-methyl-A / ,2-diphenyl-1 H-indol-3-amine. The example compound 1 was synthesized according to the methods illustrated in FIG. 2B from commercially available 6-methyl-2-phenyl-1 / 7-indole as a yellow solid, mp 130-132 °C.1H NMR (300 MHz, DMSO-d6): 5 11 .32 (s, 1 H), 7.74 (d, J = 7.8 Hz, 2H), 7.41-7.36 (m, 2H), 7.29- 7.25 (m, 1 H), 7.21 (s, 1 H), 7.09 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1 H), 6.77 (d, J = 7.8 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 3H), 3.61 (q, J = 6.9 Hz, 2H), 2.43 (s, 3H), 1 .05 (t, J = 6.9 Hz, 3H). ESI-MS m / z 327.1 (M+H)+.

[0137] Example compound 2: 6-Methyl-A / ,2-diphenyl-A / -(2,2,2-trifluoroethyl)-1 H-indol-3- amine. The example compound 2 was prepared through the methods described in FIG. 2C as a pale yellow solid, mp 168-170°C.1H NMR (300 MHz, DMSO-d6): 5 11 .42 (s, 1 H), 7.63 (d, J =7.8 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.5 Hz, 1 H), 7.24 (s, 1 H), 7.17 (t, J = 7.8 Hz, 2H), 7.05 (d, J = 7.8 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 6.79-6.73 (m, 3H), 4.36 (br s, 2H), 2.40 (s, 3H). ESI-MS m / z: 381.2 (M+H)+.

[0138] Example compound 3: A / -(2-Methoxyethyl)-6-methyl-A / ,2-diphenyl-1-((2-

[0139] (trimethylsilyl)ethoxy)methyl)-1 / 7-indol-3-amine. The example compound 3 was synthesized according to the methods illustrated in FIG. 2B from commercially available 6-methyl-2- phenyl-1 / 7-indole. The products is a yellow oil.1H NMR (300 MHz, DMSO-d6): 57.49 (s, 1 H), 7.41 (br s, 5H), 7.08 (t, J = 7.8 Hz, 2H), 7.02 (d, J = 7.8 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 6.65- 6.58 (m, 3H), 5.49 (s, 2H), 3.47 (t, J = 6.3 Hz, 2H), 3.29 (t, J = 7.8 Hz, 2H), 3.22 (t, J = 6.3 Hz, 2H), 3.01 (s, 3H), 2.44 (s, 3H), 0.69 (t, J = 7.8 Hz, 2H), -0.14 (s, 9H). ESI-MS m / z: 487.5 (M+H)+.

[0140] Example compound 4: A / -isobutyl-6-methyl-A / ,2-diphenyl-1 H-indol-3-amine. The example compound 4 was synthesized according to the methods illustrated in FIG. 2B from commercially available 6-methyl-2-phenyl-1 / 7-indole.1H NMR (500 MHz, DMSO) 6 11.31 (s, 1 H), 7.63 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1 H), 7.23 (s, 1 H), 7.12 (t, J = 8.0 Hz, 2H), 7.05 (d, J = 8.1 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.63 (m, 3H), 2.41 (s, 3H), 1.85 - 1 .73 (m, 1 H), 0.78 (d, J = 5.2 Hz, 6H).

[0141] Example compound 5: 2,2,2-Trifluoro-A / -(6-methyl-2-phenyl-1 / 7-indol-3-yl)-A / - phenylacetamide. Compound 5 was prepared through the methods described in FIG. 2C as a pale-yellow foam like solid, mp 80-82 °C.1H NMR (300 MHz, DMSO-d6): 5 11 .79 (s, 1 H), 7.72 (br s, 2H), 7.52 (t, J = 6.9 Hz, 2H), 7.45-7.29 (m, 6H), 7.24 (s, 2H), 6.93 (d, J = 8.1 Hz, 1 H),

[0142] 2.41 (s, 3H). ESI-MS m / z: 395.1 (M+H)+.

[0143] Example compound 6: A / -(6-Methyl-2-phenyl-1 / 7-indol-3-yl)-A / -phenyl propionamide. The example compound 6 was synthesized through the methods described in FIG. 2C as a white solid, mp 203-205 °C.1H NMR (300 MHz, DMSO-d6): 5 11.63 (s, 1 H), 7.74 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.37 (m, 1 H), 7.32-7.21 (m, 6H), 7.08 (t, J = 7.2 Hz, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 2.42 (s, 3H), 2.16 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H). ESI-MS m / z: 355.2 (M+H)+.

[0144] Example compound 7: 6-fluoro-A / -isobutyl-A / ,2-diphenyl-1 / 7-indol-3-amine. The example compound 7 was synthesized according to the methods illustrated in FIG. 2B from commercially available 6-fluroro-2-phenyl-1 / 7-indole.1H NMR (600 MHz, DMSO) 6 11.61 (s, 1 H), 7.62 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1 H), 7.18 (dd, J = 9.9, 2.3 Hz, 1 H), 7.16 - 7.10 (m, 3H), 6.87 - 6.81 (m, 1 H), 6.67 - 6.60 (m, 3H), 1.77 (hept, J = 6.7 Hz, 1 H), 0.77 (d, J = 6.7 Hz, 6H).

[0145] Example compound 8: 2-((6-fluoro-2-phenyl-1 H-indol-3-yl)(phenyl) amino) ethan-1-ol. Starting from commercially available 6-fluoro-2phenyl indole, the example compound 8 was synthesized according to the methods illustrated in FIG. 2D.1H NMR (500 MHz, DMSO) 6 11 .64 (s, 1 H), 7.71 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1 H), 7.18 (dd, J = 9.9, 2.3 Hz, 1 H), 7.15 - 7.08 (m, 3H), 6.83 (ddd, J = 9.9, 8.6, 2.4 Hz, 1 H), 6.69 - 6.59 (m, 3H), 4.62 (t, J = 5.5 Hz, 1 H), 3.59 (br s, 2H), 3.50 (s, 2H). Example compound 9: A / -isobutyl-A / ,2-diphenyl-6-(trifluoromethyl)-1 / 7-indol-3-amine. Starting from 2-phenyl-6-(trifluoromethyl)-1 / 7-indole that was prepared according to the method illustrated in FIG. 2A, the example compound 9 was synthesized according to the methods illustrated in FIG. 2B.1H NMR (500 MHz, DMSO) 6 12.01 (s, 1 H), 7.74 (s, 1 H), 7.67 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.40 - 7.34 (m, 2H), 7.28 (d, J = 8.1 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 2H), 6.70 - 6.61 (m, 3H), 1 .77 (hept, J = 6.7 Hz, 1 H), 0.77 (d, J = 6.7 Hz, 6H).

[0146] Example compound 10: 2-(3-Chlorophenyl)-7-fluoro-A / -isobutyl-A / -phenyl-1 / 7-indol-3- amine. Starting from 2-(3-chlorophenyl)-7-fluoro-1 / 7-indole that was prepared according to the methods illustrated in FIG. 2A, the example compound 10 was synthesized according to the methods illustrated in FIG. 2B as an off-white solid.1H NMR (500 MHz, DMSO-ofe) 11.94 (s, 1 H), 7.80 (dd, J = 1.9, 1.9 Hz, 1 H), 7.65-7.61 (m, 1 H), 7.44-7.40 (m, 1 H), 7.39-7.36 (m, 1 H), 7.17-7.10 (m, 2H), 7.03-6.93 (m, 3H), 6.67-6.63 (m, 3H), 3.43-3.31 (m, 2H), 1.75 (sept, J = 6.7 Hz, 1 H), 0.78 (d, J = 6.7 Hz, 6H) ppm;13C NMR (125 MHz, DMSO-d6) 5 149.3 (d, J = 243.8), 149.1 , 133.3, 132.6, 132.1 , 130.4, 129.2 (d, J = 5.0 Hz), 129.1 , 127.6, 126.3, 125.1 , 123.0 (d, J = 13.8 Hz), 128.9 (d, J = 3.8 Hz), 119.9 (d, J = 5.0 Hz), 116.8, 114.5 (d, J = 2.5 Hz), 112.6, 107.4 (d, J = 16.3 Hz), 59.7, 27.8, 20.4 ppm; ESI MS m / z 393 [M + H]+.

[0147] Example compound 11 : A / 1,A / 1-diethyl-A / 2-(6-fluoro-2-phenyl-1 H-indol-3-yl)-A / 2- phenylethane-1 ,2-diamine. Starting from 6-fluoro-2-phenyl-1 / 7-indole that was prepared according to the method illustrated in FIG. 2A, example compound 11 was synthesized according to the methods illustrated in FIG. 2B as an off-white solid.1H NMR (500 MHz, DMSO) 5 11 .67 (s, 1 H), 7.70 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1 H), 7.19 (dd, J = 10.1 , 2.1 Hz, 1 H), 7.17 - 7.08 (m, 3H), 6.87 - 6.80 (m, 1 H), 6.65 (m, 3H), 3.69 (s, 2H), 2.67 (s, 2H), 0.84 (s, 6H).

[0148] Example compound 12: (S)-6-fluoro-A / -(2-(2-methylmorpholino)ethyl)-A / ,2-diphenyl- 1 / 7-indol-3-amine. Starting from intermediate 6-fluoro-2-phenyl-1 / 7-indole that was prepared according to the method illustrated in FIG. 2A, example compound 12 was synthesized according to the methods illustrated in FIG. 2D.1H NMR (500 MHz, DMSO) 6 11.63 (s, 1 H), 7.72 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1 H), 7.18 (dd, J = 9.9, 2.3 Hz, 1 H), 7.15 - 7.08 (m, 3H), 6.86 - 6.79 (m, 1 H), 6.67 - 6.60 (m, 3H), 3.85 - 3.51 (m, 3H), 3.30 - 3.20 (m, 2H), 2.54 (s, 2H), 2.43 (t, J = 7.3 Hz, 2H), 1 .92 - 1 .81 (m, 1 H), 1 .61 - 1 .52 (m, 1 H), 0.92 (d, J = 6.3 Hz, 3H).

[0149] Example compound 13: A / -(3,5-dimethoxyphenyl)-A / -ethyl-6-methyl-2-phenyl-1 / 7- indol-3-amine. Starting from commercially available 6-methyl-2-phenyl-1 / 7-indole, the example compound 13 was synthesized according to the methods illustrated in FIG. 2B as an off-white solid.1H NMR (500 MHz, DMSO) 6 11 .36 (s, 1 H), 7.76 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1 H), 7.25 (s, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.83 (d, J = 7.9 Hz, 1 H), 5.90 (t, J = 2.1 Hz, 1 H), 5.80 (d, J = 2.1 Hz, 2H), 3.63 (s, 6H), 2.44 (s, 3H), 1 .06 (t, J = 7.1 Hz, 3H).

[0150] Example compound 14: 7-Chloro-A / -isobutyl-A / ,2-diphenyl-1 / 7-indol-3-amine. Starting from commercially available intermediate 7-chloro-2-phenyl-1 / 7-indole, the example compound 14 was synthesized according to the methods illustrated in FIG. 2B as a white solid.1H NMR (500 MHz, DMSO-d6) 5 11.56 (s, 1 H), 7.68-7.64 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.3 (m, 1 H), 7.22 (dd, J = 7.5, 0.8 Hz, 1 H), 7.16-7.11 (m, 3H), 7.01-6.97 (m, 1 H), 6.67- 6.63 (m, 3H), 3.31 (s, 2H, overlaps with water), 1.78-1.66 (m, 1 H), 0.73 (d, J = 6.6 Hz, 6H) ppm;13C NMR (125 MHz, DMSO-d6) 5 149.4, 134.4, 131.7, 130.6, 129.0, 128.4, 128.0, 127.5, 127.3, 121 .6, 120.3, 120.0, 117.0, 116.5, 116.4, 112.5, 59.5, 27.7, 20.3 ppm; ESI MS m / z 375 [M + H]+.

[0151] Example compound 15: 2-(3-chlorophenyl)-A / -(2-methoxypyrimidin-5-yl)-A / -propyl-1 / 7- indol-3-amine. Starting from commercially available intermediate 2-(3-chlorophenyl)-1 / 7- indole, example compound 15 was synthesized according to the methods illustrated in FIG. 2B.1H NMR (500 MHz, DMSO) 5 11 .73 (s, 1 H), 7.99 (s, 2H), 7.84 (s, 1 H), 7.73 (d, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.1 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1 H), 7.19 (dd, J = 12.2, 7.6 Hz, 2H), 7.00 (t, J = 6.9 Hz, 1 H), 3.80 (s, 3H), 3.55 (s, 2H), 1 .52 (q, J = 7.5 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H).

[0152] Example compound 16: 2-(3-Chlorophenyl)-A / -isobutyl-A / -phenyl-1 / 7-indol-3-amine. Starting from commercially available intermediate 2-(3-chlorophenyl)-1 / 7-indole, the example compound 16 was synthesized according to the methods illustrated in FIG. 2B as an off-white solid;1H NMR (500 MHz, DMSO-d6) 5 11 .59 (s, 1 H), 7.74 (dd, J = 1 .8, 1 .8 Hz, 1 H), 7.62-7.58 (m, 1 H), 7.47-7.40 (m, 2H), 7.36-7.33 (m, 1 H), 7.21-7.01 (m, 4H), 7.00-6.96 (m, 1 H), 6.67- 6.62 (m, 3H), 3.47-3.32 (m, 2H), 1 .78 (sept, J = 6.7 Hz, 1 H), 0.80 (d, J = 6.6 Hz, 6H) ppm;13C NMR (125 MHz, DMSO-d6) 5 149.2, 135.1 , 133.4, 133.2, 130.5, 130.3, 129.0, 127.0, 125.7, 125.2, 124.5, 122.5, 120.1 , 119.5, 118.3, 116.6, 112.5, 111.9, 59.7, 27.8, 20.5 ppm; ESI MS m / z 375 [M + H]+.

[0153] Example compound 17: 4,6-Difluoro-A / ,2-diphenyl-A / -propyl-1 / 7-indol-3-amine. Starting from commercially available 4,6-difluoro-2-phenyl-1 / 7-indole, the example compound 17 was synthesized according to the methods illustrated in FIG. 2B as an off-white solid.1H NMR (500 MHz, DMSO-d6) 11.90 (s, 1 H), 7.72 (d, J = 7.9 Hz, 2H), 7.42 (t, J = 8.4 Hz, 2H), 7.32 (t, J = 6.9 Hz, 1 H), 7.13 (t, J = 7.9 Hz, 2H), 7.05 (d, J = 8.9 Hz, 1 H), 6.73 (t, J = 8.9 Hz, 1 H), 6.76-6.58 (m, 3H), 3.55-3.28 (m, 2H), 1.50-1.41 (m, 2H), 0.74 (t, J = 7.8 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 5 158.5, (dd, J = 235.9, 11.8 Hz), 154.4 (dd, J = 247.0, 14.9 Hz), 149.1 , 136.7 (dd, J = 14.0, 14.0 Hz), 133.5 (d, J = 2.6 Hz), 130.6, 129.1 , 128.8, 128.0, 126.0, 116.6, 116.3, 112.4, 111.0 (d, J = 20.0 Hz), 95.1 (dd, J = 28.7, 23.8 Hz), 94.3 (dd, J = 25.5, 4.8 Hz), 53.8, 20.3, 111.2 ppm; ESI MS m / z 363 [M + H]+.

[0154] Example compound 18: A / -ethyl-6-methoxy-A / ,2-diphenyl-1 / 7-indol-3-amine. Starting from the intermediate 6-methoxy-2-phenyl-1H-indole that was prepared according to the methods illustrated in FIG. 2A, the example compound 18 was synthesized according to the methods illustrated in FIG. 2B.1H NMR (500 MHz, DMSO) 6 11 .33 (s, 1 H), 7.72 (dd, J = 8.4, 1 .2 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1 H), 7.10 (dd, J = 8.9, 7.2 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1 H), 6.92 (d, J = 2.1 Hz, 1 H), 6.66 - 6.57 (m, 4H), 3.79 (s, 3H), 3.61 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[0155] Example compound 19: A / -Ethyl-5-methoxy-A / ,2-diphenyl-1 / 7-indol-3-amine. Starting from commercially available intermediate 5-methoxy-2-phenyl-1 / 7-indole, the example compound 19 was synthesized according to the methods described in FIG. 2B as a light yellow solid.1H NMR (500 MHz, MeOD-d4) 5 7.70-7.66 (m, 2H), 7.34-7.29 (m, 3H), 7.25-7.21 (m, 1 H), 7.15-7.09 (m, 2H), 6.78 (dd, J = 8.6, 2.6 Hz, 1 H), 6.72-6.67 (m, 2H), 6.65-6.62 (m, 1 H), 6.61-6.59 (m, 1 H), 3.67 (s, 3H), 3.66-3.58 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, MeOD-d4) 6 155.5, 150.2, 134.9, 133.5, 132.1 , 130.1 , 129.7, 128.4, 128.4, 127.3, 119.9, 1174, 113.7, 113.6, 113.4, 101.1 , 56.1 , 47.0, 13.6 ppm; ESI MS m / z 341 [M - H]’.

[0156] Example compound 20: 3-(ethyl(phenyl)amino)-2-phenyl-1 / 7-indole-5-carbonitrile (PTDP-088, LD-4-149). Starting from the intermediate compound 2-phenyl-1 / 7-indole-5- carbonitrile that was prepared according to the methods illustrated in FIG. 2A, the example compound 20 was synthesized according to the methods described in FIG. 2B.1H NMR (500 MHz, DMSO) 6 12.18 (s, 1 H), 7.79 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 8.3 Hz, 1 H), 7.56 - 7.53 (m, 1 H), 7.50 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1 H), 7.15 (dd, J = 8.8, 7.2 Hz, 2H), 6.70 - 6.61 (m, 3H), 3.64 (s, 2H), 1 .05 (t, J = 7.1 Hz, 3H).

[0157] Example compound 21 : A / -Ethyl-5-fluoro-A / ,2-diphenyl-1 H-indol-3-amine. Starting from commercially available intermediate 5-fluoro-2-phenyl-1 / 7-indole, the example compound 21 was synthesized according to the methods described in FIG. 2B as a white solid;1H NMR (500 MHz, MeOD-d4) 5 7.72-7.68 (m, 2H), 7.39-7.32 (m, 3H), 7.29-7.24 (m, 1 H), 7.16-7.10 (m, 2H), 6.91-6.85 (m, 1 H), 6.74 (dd, J = 9.4, 2.5 Hz, 1 H), 6.71-6.63 (m, 3H), 3.61 (q, J = 6.3 Hz, 2H), 1 .08 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, MeOD-d4) 5 159.2 (d, J = 231 .0 Hz), 150.1 , 136.4, 133.3, 133.1 , 130.2, 129.8, 128.9, 128.4 (d, J = 8.8 Hz), 127.5, 120.1 (d, J = 3.8 Hz), 117.7, 113.7, 113.5 (d, J = 8.8 Hz), 111.4 (d, J = 27.5 Hz), 104.0 (d, J = 23.8 Hz), 47.0, 13.6; ESI MS m / z 329 [M - H]’.

[0158] Example compound 22: 7-fluoro-2-(3-fluorophenyl)-A / -isobutyl-A / -phenyl-1 H-indol-3- amine. Starting from the intermediate 7-fluoro-2-(3-fluorophenyl)-N-isobutyl-N-phenyl-1 H- indol-3-amine that was prepared according to the methods illustrated in FIG. 2A, the example compound 22 was synthesized according to the methods described in FIG. 2B.1H NMR (500 MHz, de-DMSO) (ppm) 5: 11.96 (s, 1 H), 7.59-7.53 (m, 2H), 7.48 (q, 1 H, J = 8.00 Hz), 7.22- 7.16 (m, 3H), 7.06-6.97 (m, 3H), 6.72-6.68 (m, 3H), 1.83-1.75 (m, 1 H), 0.81 (d, 6H, J = 6.32 Hz).13C NMR (125 MHz, de-DMSO) (ppm) 5: 149.75, 135.99, 134.16, 131.08, 129.67, 129.37, 128.95, 128.66, 127.03, 124.67, 122.92, 122.68, 119.80, 119.47, 117.18, 116.19, 113.00, 109.55, 60.12, 28.30, 20.95. ESI MS m / z 377 [M + H]’.

[0159] Example compound 23: A / -isobutyl-A / ,2-diphenyl-6-(trifluoromethoxy)-1 / 7-indol-3- amine. Starting from the intermediate 2-phenyl-6-(trifluoromethoxyl)-1 / 7-indole that was prepared according to the methods illustrated in FIG. 2A, the example compound 23 was synthesized according to the methods described in FIG. 2B.1H NMR (500 MHz, DMSO) 6 11 .78 (s, 1 H), 7.66 - 7.61 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.37 (s, 1 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.24 (d, J = 8.6 Hz, 1 H), 7.17 - 7.10 (m, 2H), 6.97 (d, J = 7.8 Hz, 1 H), 6.69 - 6.61 (m, 3H), 3.36 (s, 2H), 1.76 (hept, J = 6.7 Hz, 1 H), 0.77 (d, J = 6.6 Hz, 6H).

[0160] Example compound 24: A / 2-(7-fluoro-2-(3-fluorophenyl)-1 / 7-indol-3-yl)-A / 6,A / 6-dimethyl- A / 2-propylpyridine-2,6-diamine. Starting from the intermediate 7-fluoro-2-(3-fluorophenyl)-1 / 7- indole that was prepared according to the methods illustrated in FIG. 2A, the example compound 24 was synthesized according to the methods described in FIG. 2B.1H NMR (600 MHz, DMSO) 5 11 .94 (s, 1 H), 7.67 - 7.57 (m, 2H), 7.48 (m, 1 H), 7.17 (t, J = 8.3 Hz, 1 H), 7.09 (t, J = 7.9 Hz, 1 H), 7.03 - 6.91 (m, 3H), 5.87 (d, J = 8.4 Hz, 1 H), 5.37 (d, J = 7.9 Hz, 1 H), 4.01 (s, 1 H), 3.42 (s, 1 H), 3.03 (s, 6H), 1 .62 (s, 1 H), 1 .43 (s, 1 H), 0.77 (t, J = 7.2 Hz, 3H).

[0161] Example compound 25: Methyl 3-(Ethyl(phenyl)amino)-2-phenyl-1 H-indole-6- carboxylate. Starting from commercially available methyl 2-phenyl-1 / 7-indole-6-carboxylate, the example compound 25 was synthesized according to the methods described in FIG. 2B as a white solid.1H NMR (500 MHz, DMSO-d6) 6 11 .92 (s, 1 H), 8.09 (d, J = 0.9 Hz, 1 H), 7.80- 7.76 (m, 2H), 7.57 (dd, J = 8.4, 1.4 Hz, 1 H), 7.47-7.42 (m, 2H), 7.38-7.33 (m, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.14-7.09 (m, 2H), 6.65-6.61 (m, 3H), 3.86 (s, 3H), 3.68-3.54 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 6 148.1 , 136.3, 134.1 , 130.7, 129.6, 129.2, 128.9, 128.4, 126.2, 123.0, 120.1 , 118.4, 118.0, 116.5, 113.6, 112.3, 51.9, 45.5, 12.9 ppm; ESI MS m / z 371 [M + H]+.

[0162] Example compound 26: 6-Chloro-A / -isobutyl-A / ,2-diphenyl-1 / 7-indol-3-amine. Starting from commercially available 6-chloro-2-phenyl-1 / 7-indole, the example compound 26 was synthesized according to the methods described in FIG. 2B as a white solid.1H NMR (500 MHz, DMSO-ofe) 5 11.65 (s, 1 H), 7.64-7.60 (m, 2H), 7.45-7.38 (m, 3H), 7.34-7.29 (m, 1 H), 7.18-7.09 (m, 3H), 6.99 (dd, J = 8.4, 1 .9 Hz, 1 H), 6.67-6.61 (m, 3H), 3.41-3.26 (m, 2H, overlaps with water), 1.81 (sep, J = 6.7 Hz, 1 H), 0.77 (d, J = 6.6 Hz, 6H) ppm;13C NMR (125 MHz, DMSO-ofe) 6 148.7, 134.8, 132.5, 130.3, 128.5, 128.2, 127.4, 126.1 , 125.7, 123.8, 119.2, 119.0, 118.7, 116.0, 111.9, 110.8, 59.0, 27.2, 19.9 ppm; ESI MS m / z 375 [M + H]+.

[0163] Example compound 27: A / -(3-(benzyloxy)phenyl)-2-(3-chlorophenyl)-A / -isobutyl-1 / 7- indol-3-amine. Starting from commercially available 6-chloro-2-phenyl-1 H-indole, the example compound 27 was synthesized according to the methods described in FIG. 2B.1H NMR (600 MHz, DMSO) 6 11 .68 (s, 1 H), 7.71 (t, J = 1 .9 Hz, 1 H), 7.55 (dt, J = 7.8, 1 .3 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 7.45 - 7.41 (m, 3H), 7.40 - 7.34 (m, 3H), 7.34 - 7.27 (m, 2H), 7.23 - 7.17 (m, 2H), 7.05 - 6.99 (m, 1 H), 6.10 (d, J = 7.7 Hz, 1 H), 5.74 (d, J = 8.1 Hz, 1 H), 5.43 - 5.32 (m, 2H), 3.86 (dd, J = 13.5, 7.0 Hz, 1 H), 3.37 (dd, J = 13.4, 6.7 Hz, 1 H), 1.76 (hept, J = 6.6 Hz, 1 H), 0.81 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H).

[0164] Example compound 28: 1-(3-(Ethyl(phenyl)a.mino)-2-phenyl-1 / 7-indol-6-yl)ethan-1- one. The example compound 28 was prepared through the methods described in FIG. 2E, which include the following steps (1-4).

[0165] Step 1 . 1 -(2-Phenyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-indol-6-yl)ethan-1 -one (intermediate 28-2). A solution of lithium bis(trimethylsilyl)amide (1.6 mL, 1.6 mmol, 1.0 M in toluene) was added to a mixture of methyl 2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1 / 7- indole-6-carboxylate (intermediate 28-1 , 200 mg, 0.52 mmol, prepared from commercially available methyl 2-phenyl-1 / 7-indole-6-carboxylate as described in FIG. 3A) and sodium sulfinate (160 mg, 1 .6 mmol) in a resealable microwave vessel at ambient temperature under nitrogen, after which the vessel was sealed and heated at 80 °C for 3 h. The mixture was cooled to ambient temperature, diluted with saturated aqueous ammonium chloride solution (60 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 50:50) to provide 1-(2-phenyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1 / 7-indol-6-yl)ethan-1-one (intermediate 28-2) as a thick colorless oil (70 mg, 36%): ESI MS m / z 366 [M + H]+.

[0166] Step 2. 1 -(3-lodo-2-phenyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-indol-6-yl)ethan-1 - one (Intermediate 28-3). A / -lodosuccinimide (155 mg, 0.69 mmol) was added to a solution of 1 -(2-phenyl-1 -((2-(tri methy Isi ly I )ethoxy )methy I )- 1 H-indol-6-yl)ethan-1 -one (intermediate 28-2, 210 mg, 0.57 mmol) in anhydrous DMF (5.0 mL) at ambient temperature under nitrogen, after which the mixture was stirred at ambient temperature for 1 h. The reaction mixture was directly purified by reverse phase chromatography on C18 silica gel, eluting with 0.01 % TFA in acetonitrile / 0.1 % TFA in water (gradient from 20:80 to 0:100), to provide 1-(3-iodo-2-phenyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-indol-6-yl)ethan-1 -one (intermediate 28-3) as a colorless oil (270 mg, 96): ESI MS m / z 492 [M + H]+.

[0167] Step 3. 1-(3-(Ethyl(phenyl)amino)-2-phenyl-1-((2-(trimethylsilyl)ethoxy) methyl) -1 H- indol-6-yl)ethan-1-one (intermediate 28-4). A degassed (nitrogen-purged) solution of 1-(3- iodo-2-phenyl-1 -((2-(tri methy Isi ly I )ethoxy )methy I )- 1 H-indol-6-yl)ethan-1 -one (intermediate 28- 3, 270 mg, 0.55 mmol), aniline (76 mg, 0.82 mmol), BrettPhos-Pd-G1 (22 mg, 0.03 mmol), tert-BuBrettPhos (27 mg, 0.06 mmol) and sodium tert-butoxide (105 mg, 1.1 mmol) in anhydrous toluene (5 mL) in a resealable high-pressure vessel was sealed and the mixture was heated at 80 °C with vigorous stirring for 2 h. The resulting mixture was cooled to ambient temperature, toluene was removed by nitrogen gas flow and anhydrous DMF (5 mL) was added and the mixture was stirred under nitrogen at ambient temperature, lodoethane (170 mg, 1.1 mmol) was added followed by sodium tert-butoxide (105 mg, 1.1 mmol), after which the mixture was stirred at ambient temperature for 1 h. The mixture was diluted with saturated aqueous ammonium chloride solution (60 mL) and extracted with ethyl acetate (3 x 80 mL). The organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 50:50) to provide 1-(3-(ethyl(phenyl)amino)-2-phenyl- 1-((2-(trimethylsilyl)ethoxy)methyl)-1 / 7-indol-6-yl)ethan-1-one (intermediate 28-4) as a colorless oil (50 mg, 19%): ESI MS m / z 485 [M + H]+.

[0168] Step 4. 1-(3-(Ethyl(phenyl)amino)-2-phenyl-1 / 7-indol-6-yl)ethan-1-one (example compound 28). Tetra-A / -butylammonium fluoride solution (1.0 mL, 1.0 mmol, 1.0 M in THF) was added to a solution of 1-(3-(ethyl(phenyl)amino)-2-phenyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1 / 7-indol-6-yl)ethan-1-one (intermediate 28-4, 50 mg, 0.10 mmol) and ethylenediamine (31 mg, 0.51 mmol) in anhydrous THF (2.0 mL) in a resealable microwave vessel at ambient temperature under nitrogen, after which the vessel was sealed and heated at 90 °C for 1 h. The mixture was cooled to ambient temperature, diluted with saturated aqueous sodium chloride solution (60 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by reverse phase chromatography on C18 silica gel, eluting with 0.01 % TFA in acetonitrile / 0.1 % TFA in water (gradient from 20:80 to 0:100), to provide 1-(3-(Ethyl(phenyl)amino)-2-phenyl-1 / 7-indol-6- yl)ethan-1-one as a yellow solid (18 mg, 50%):1H NMR (500 MHz, DMSO-d6) 6 11 .94 (s, 1 H), 8.05 (d, J = 0.9 Hz, 1 H), 7.81-7.78 (m, 2H), 7.59 (dd, J = 8.4, 1.5 Hz, 1 H), 7.47-7.42 (m, 2H), 7.38-7.33 (m, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 7.14-7.08 (m, 2H), 6.65-6.61 (m, 3H), 3.72-3.51 (m, 2H), 2.61 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 5 197.3, 148.2, 136.5, 134.3, 131.2, 130.7, 129.6, 129.2, 128.9, 128.4, 126.2, 119.5, 118.4, 117.8,

[0169] 116.4, 112.7, 112.3, 45.4, 26.7, 12.8 ppm; ESI MS m / z 355 [M + H]+.

[0170] Example compound 29: A / -Ethyl-A / ,2-diphenyl-1 / 7-pyrrolo[2,3-b]pyridin-3-amine. Starting from commercially available 2-phenyl-1 / 7-pyrrolo[2,3-b]pyridine, the example compound 29 was synthesized according to the methods illustrated in FIG. 2B as a light brown solid.1H NMR (500 MHz, DMSO-d6) 5 12.12 (s, 1 H), 8.26 (dd, J = 4.7, 1.6 Hz, 1 H), 7.85-7.81 (m, 2H), 7.50 (dd, J = 7.8, 1.6 Hz, 1 H), 7.43-7.38 (m, 2H), 7.34-7.29 (m, 1 H), 7.15-7.09 (m, 2H), 7.02 (dd, J = 7.9, 4.7 Hz, 1 H), 6.66-6.61 (m, 3H), 3.70-3.55 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 5 148.1 , 147.3, 143.5, 133.3, 130.7, 129.2, 128.7, 128.1 , 126.3, 126.2, 118.3, 116.5, 116.5, 116.0, 112.4, 45.3, 12.8 ppm; ESI MS m / z 314 [M + H]+.

[0171] Example compound 30: A / -Ethyl-A / ,6-diphenyl-5 / 7-pyrrolo[3,2-o(|pyrimidin-7-amine. Starting from commercially available 6-phenyl-5 / 7-pyrrolo[3,2-o(|pyrimidine, the example compound 30 was synthesized according to the methods illustrated in FIG. 2B as a yellow solid.1H NMR (500 MHz, DMSO-d6) 5 12.30 (s, 1 H), 8.91 (s, 1 H), 8.74 (s, 1 H), 7.85 (d, J =

[0172] 7.4 Hz, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 8.4 Hz, 1 H), 7.10 (t, J = 7.8 Hz, 2H), 6.64- 6.60 (m, 3H), 3.66 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 6.5 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-ofe) 5 151.7, 150.2, 147.9, 147.2, 134.3, 129.9, 129.3, 128.9, 128.8, 126.7, 117.1 , 116.8, 115.9, 112.7, 45.3, 12.7 ppm; ESI MS m / z 314 [M + H]+.

[0173] Example compound 31: A / -Ethyl-A / ,6-diphenyl-7 / 7-pyrrolo[2,3-o(|pyrimidin-5-amine. Starting from commercially available 6-phenyl-7 / 7-pyrrolo[3,2-o(|pyrimidine, the example compound 31 was synthesized according to the methods illustrated in FIG. 2B as a yellow solid.1H NMR (500 MHz, DMSO-d6) 5 12.62 (s, 1 H), 8.80 (s, 1 H), 8.55 (s, 1 H), 7.84 (d, J =

[0174] 6.4 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.38 (t, J = 8.8 Hz, 1 H), 7.15 (t, J = 7.2 Hz, 2H), 6.70- 6.67 (m, 3H), 3.63 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 5.6 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-ofe) 5 150.4, 148.5, 146.8, 140.7, 139.8, 130.0, 129.4, 129.1 , 129.0 126.8, 126.4, 117.2,

[0175] 116.5, 112.5, 45.5, 13.0 ppm; ESI MS m / z 314 [M + H]+.

[0176] Example compound 32: A / -Ethyl-A / ,2-diphenyl-1 / 7-pyrrolo[3,2-b]pyridin-3-amine. Starting from commercially available 2-phenyl-1 / 7-pyrrolo[3,2-b]pyridine, the example compound 32 was synthesized according to the methods illustrated in FIG. 2B as an off-white solid.1H NMR (500 MHz, DMSO-d6) 6 11 .74 (s, 1 H), 8.24 (d, J = 4.6 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1 H), 7.43 (t, J = 6.6 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1 H), 7.15-7.12 (m, 1 H), 7.09-7.06 (m, 2H), 6.61-6.57 (m, 3H), 3.72-3.66 (m, 2H), 1.07 (t, J = 6.4 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 5 148.9, 143.2, 142.8, 136.2, 130.9, 129.9, 128.8, 128.3, 128.1 , 126.1 , 118.5, 117.9, 117.2, 116.1 , 112.4, 45.5, 13.1 ppm; ESI MS m / z 314 [M + H]+. Example compound 33: W-Ethyl-W-phenyl-2-(pyridin-3-yl)-1 H-indol-3-amine. Starting from commercially available 2-(3-pyridinyl)-1 H-indole, the example compound 33 was synthesized according to the methods illustrated in FIG. 2B as a light yellow solid;1H NMR (500 MHz, DMSO-de) 6 11 .68 (s, 1 H), 8.94-8.92 (m, 1 H), 8.47 (dd, J = 6.4, 1 .6 Hz, 1 H), 8.09- 8.06 (m, 1 H), 7.48-7.42 (m, 2H), 7.19-7.09 (m, 4H), 6.99-6.95 (m, 1 H), 6.66-6.61 (m, 3H), 3.71-3.59 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 6 148.3, 148.2, 146.9, 135.5, 132.8, 129.7, 129.2, 127.4, 125.6, 123.8, 122.6, 119.6, 119.2, 118.3, 116.5, 112.4, 112.0, 45.6, 13.0 ppm; ESI MS m / z 314 [M + H]+.

[0177] Example compound 34: 2-(3,6-Dihydro-2H-pyran-4-yl)-A / -isobutyl-N-phenyl-1 H-indol- 3-amine. The example compound 34 was prepared through the methods described in FIG. 3F, which include the following steps (1-3).

[0178] Step 1. tert-Butyl-2-(3,6-dihydro-2H-pyran-4-yl)-1 H-indole-1 -carboxylate (intermediate 34-2). A degassed (nitrogen purged) solution of commercially available (1 -(tert- butoxycarbonyl)-1 H-indol-2-yl)boronic acid ( 2.5 g, 9.4 mmol), 4-bromo-3,6-dihydro-2H-pyran (2.0 g, 12.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.94 mmol) in 2M sodium carbonate solution (14.4 mL) and 1 ,4-dioxane (32 mL) at ambient temperature under nitrogen was heated to 100 °C to stir for 3 h. The mixture was cooled to ambient temperature, diluted with saturated aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 20:80) to provide tert-butyl-2-(3,6-dihydro-2H-pyran-4-yl)-1 H-indole-1 -carboxylate (intermediate 34- 2) as a light green solid (2.45 g, 85%):1H NMR (300 MHz, CDCh) 6 8.08-8.02 (m, 1 H), 7.52- 7.47 (m, 1 H), 7.31-7.17 (m, 2H), 6.43 (s, 1 H), 5.90-5.86 (m, 1 H), 4.34-4.30 (m, 2H), 3.94 (t, J = 5.4 Hz, 2H), 2.44-2.34 (m, 2H), 1.65 (s, 9H) ppm.

[0179] Step 2. tert-Butyl-2-(3,6-dihydro-2H-pyran-4-yl)-3-iodo-1 H-indole-1 -carboxylate (intermediate 34-3). W-lodosuccinimide (376 mg, 1.7 mmol) was added to a solution of tert- butyl-2-(3,6-dihydro-2H-pyran-4-yl)-1 H-indole-1 -carboxylate (intermediate 34-2, 500 mg, 1.7 mmol) in anhydrous DMF (5.0 mL) at ambient temperature under nitrogen, after which the mixture was stirred at ambient temperature for 3 h. The reaction was diluted with water (80 mL) and extracted with ethyl acetate (120 mL). The organic extract was washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 15:85) to provide tert-butyl-2-(3,6-dihydro-2H-pyran-4-yl)-3-iodo-1 H-indole-1 -carboxylate (intermediate 34-3) as an off-white solid (263 mg, 37%):1H NMR (300 MHz, CDCh, mixture of rotamers) 6 8.10-8.02 (m, 1 H), 7.52-7.16 (m, 5H), 5.90-5.83 (m, 1 H), 4.39-4.28 (m, 2H), 4.01-3.90 (m, 2H), 2.43-2.32 (m, 2H), 1.65 (s, 9H) ppm.

[0180] Step 3. A degassed (nitrogen-purged) solution of tert-butyl-2-(3,6-dihydro-2 / 7-pyran-4- yl)-3-iodo-1 / - / -indole-1 -carboxylate (3, 100 mg, 0.24 mmol), aniline (33 mg, 0.35 mmol), BrettPhos-Pd-G1 (19 mg, 0.03 mmol), tert-BuBrettPhos (23 mg, 0.05 mmol) and sodium tert- butoxide (45 mg, 0.47 mmol) in anhydrous toluene (2 mL) in a resealable high-pressure vessel was sealed and the mixture was heated at 90 °C with vigorous stirring for 4 h. The resulting mixture was cooled to ambient temperature, toluene was removed by nitrogen gas flow and anhydrous DMF (2 mL) was added, and the mixture was stirred under nitrogen at ambient temperature. / so-Butyl iodide (0.47 mmol) was added followed by sodium tert-butoxide (45 mg, 0.47 mmol), after which the mixture was stirred at ambient temperature for 16 h. The mixture was diluted with saturated aqueous ammonium chloride solution (60 mL) and extracted with ethyl acetate (3 x 80 mL). The organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 50:50) to provide semipurified product. A second purification was carried out using reverse phase chromatography on C18 silica gel, eluting with 0.01 % TFA in acetonitrile / 0.1 % TFA in water (gradient from 20:80 to 0:100), to provide 2-(3,6-dihydro-2 / 7-pyran-4-yl)-A / -ethyl-A / -phenyl-1 / 7-indol-3-amine (example compound 34) as an off-white solid (20 mg, 27%)1H NMR (500 MHz, DMSO-ofe) 5

[0181] I I .02 (s, 1 H), 7.37-7.34 (m, 1 H), 7.13-7.03 (m, 4H), 6.94-6.90 (m, 1 H), 6.59-6.52 (m, 3H), 6.11-6.08 (m, 1 H), 4.17-4.14 (m, 2H), 3.74 (t, J = 5.4 Hz, 2H), 3.48-3.30 (m, 2H), 2.72-2.09 (m, 2H), 1.91-1.80 (m, 1 H), 0.9 (d, J = 6.2 Hz, 6H) ppm;13C NMR (125 MHz, DMSO-d6) 5 149.6, 134.4, 132.6, 128.9, 125.9, 125.5, 124.7, 121.7, 119.1 , 118.6, 117.8, 116.0, 112.3,

[0182] I I I .6, 64.9, 63.4, 59.8, 27.9, 25.9, 20.7 ppm; ESI MS m / z 347 [M + H]+.

[0183] Example compound 35: A / -Ethyl-A / -phenyl-2-(pyrimidin-2-yl)-1 / 7-indol-3-amine. The example compound 35 was prepared through the methods described in FIG. 3G, which include the following steps (1-3).

[0184] Step 1. tert-Butyl3-(ethyl(phenyl)amino)-1 / 7-indole-1 -carboxylate (intermediate 35-2). A degassed (nitrogen-purged) solution of commercially available tert-butyl-3-iodo-1 / 7-indole- 1 -carboxylate (2.50 g, 7.3 mmol), aniline (1 .02 g, 10.9 mmol), BrettPhos-Pd-G1 (290 mg, 0.36 mmol), tert-BuBrettPhos (353 mg, 0.73 mmol) and sodium tert-butoxide (1.40 g, 14.6 mmol) in anhydrous toluene (40 mL) in a resealable high-pressure vessel was sealed and the mixture was heated at 65 °C with vigorous stirring for 20 min. The resulting mixture was cooled to ambient temperature, toluene (~20 mL) was removed by nitrogen gas flow and anhydrous DMF (20 mL) was added and the mixture was stirred under nitrogen at ambient temperature. lodoethane (1.7 g, 10.9 mmol) was added followed by sodium tert-butoxide (700 mg, 7.3 mmol), after which the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with saturated aqueous ammonium chloride solution (60 mL) and extracted with ethyl acetate (3 x 80 mL). The organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 50:50) to provide semi-purified product. A second purification was carried out using reverse phase chromatography on C18 silica gel, eluting with 0.01 % TFA in acetonitrile / 0.1 % TFA in water (gradient from 20:80 to 0:100), to provide tert-butyl-3-(ethyl(phenyl)amino)-1 H-indole-1 -carboxylate (intermediate 35- 2) as a pink oil (630 mg, 26%):1H NMR (500 MHz, CDCh) 6 8.16 (s, 1 H), 7.48 (s, 1 H), 7.32- 7.27 (m, 1 H), 7.19-7.08 (m, 4H), 6.81-6.75 (m, 3H), 3.77 (q, J = 7.1 Hz, 2H), 1.68 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H) ppm.

[0185] Step 2. tert-Butyl-3-(ethyl(phenyl)amino)-2-(pyrimidin-2-yl)-1 H-indole-1 -carboxylate (intermediate 35-4). A tert-butyllithium solution (3.1 mL, 5.4 mmol, 1.7 M in pentane) was added over 60 min to a solution of tert-butyl-3-(ethyl(phenyl)amino)-1 H-indole-1 -carboxylate (intermediate 35-2, 300 mg, 0.89 mmol) and triisopropyl borate (839 mg, 4.5 mmol) in anhydrous THF (8.0 mL) at -78 °C under nitrogen. The mixture was warmed to -20 °C, diluted with saturated aqueous ammonium chloride solution (1 mL) and warmed to ambient temperature. The mixture was extracted with THF (2 x 30 mL) and the solvents were partially removed under reduced pressure to a volume of ~8 mL to provide a solution of (1-(tert- butoxycarbonyl)-3-(ethyl(phenyl)amino)-1 H-indol-2-yl)boronic acid (intermediate 35-3, estimated at full conversion). This mixture was treated with 2-iodopyrimidine (367 mg, 1.78 mmol), tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.089 mmol), potassium carbonate 246 mg, 1 .8 mmol) and water (1 mL), after which the mixture was heated to 70 °C to stir for 16 h. The mixture was cooled to ambient temperature, diluted with saturated aqueous sodium chloride solution (70 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / dichloromethane (gradient from 0:100 to 50:50) to provide semi-purified product. A second purification was carried out using reverse phase chromatography on C18 silica gel, eluting with 0.01 % TFA in acetonitrile / 0.1 % TFA in water (gradient from 20:80 to 0:100), to provide tert-butyl-3-(ethyl(phenyl)amino)-2-(pyrimidin-2-yl)-1 H-indole-1 -carboxylate (4) as an off-white solid (110 mg, 20%): ESI MS m / z 415 [M + H]+.

[0186] Step 3. W-Ethyl-W-phenyl-2-(pyrimidin-2-yl)-1 H-indol-3-amine (example compound 35). Trifluoroacetic acid (1 .0 mL) was added to a solution of tert-butyl-3-(ethyl(phenyl)amino)- 2-(pyrimidin-2-yl)-1 H-indole-1 -carboxylate (intermediate 35-4, 110 mg, 0.265 mmol) in anhydrous dichloromethane (5 mL) at ambient temperature under nitrogen, after which the mixture was stirred for 16 h. The mixture was diluted with acetonitrile (50 mL) and the solvents were removed under reduced pressure. The residue was diluted with ethyl acetate (60 mL) washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 50:50) to provide W-ethyl-W-phenyl-2-(pyrimidin-2-yl)-1 H-indol-3-amine (example compound 35) as a yellow solid (32 mg, 38%):1H NMR (500 MHz, DMSO-d6) 6 11 .74 (s, 1 H),

[0187] 8.81 (d, J = 4.8 Hz, 2H), 7.54-7.51 (m, 1 H), 7.30 (dd, J = 4.8, 4.8 Hz, 1 H), 7.21-7.16 (m, 2H), 7.04-6.93 (m, 3H), 6.55-6.49 (m, 3H), 3.81 (q, J = 6.7 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 6 158.5, 157.3, 148.5, 135.2, 129.6, 128.5, 126.3, 123.6, 123.3, 119.5, 116.2, 118.7, 115.3, 112.6, 112.2, 45.7, 12.9 ppm; ESI MS m / z 315 [M + H]+.

[0188] Example compound 36: W-Ethyl-W-phenyl-2-(thiophen-2-yl)-1 H-indol-3-amine. Starting from commercially available 2-(2-thienyl)-1 H-indole, the example compound 36 was prepared according to the methods illustrated in FIG. 2B as a tan solid;1H NMR (500 MHz, DMSO-ofe) 11 .60 (s, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7.15-7.06 (m, 5H), 6.94 (t, J = 7.9 Hz, 1 H), 6.62-6.58 (m, 3H), 3.89-3.52 (br s, 2H), 1.15 (t, J = 6.9 Hz, 3H) ppm; ESI MS m / z 319 [M + H]+.

[0189] Example compound 37: N-Ethyl-2-(oxazol-2-yl)-W-phenyl-1 H-indol-3-amine. Starting from commercially available 2-(2-oxazolyl)-1 H-indole, the example compound 37 was synthesized according to the methods illustrated in FIG. 2B as a white solid;1H NMR (500 MHz, DMSO-ofe) 6 11 .92 (s, 1 H), 8.17 (d, J = 0.7 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.39 (d, J = 0.7 Hz, 1 H), 7.24-7.17 (m, 2H), 7.07-7.02 (m, 2H), 7.01-6.97 (m, 1 H), 6.59-6.53 (m, 3H), 3.78 (q, J = 7.1 Hz, 2H), 1 .13 (t, J = 7.1 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 6 155.6,

[0190] 148.8, 140.2, 136.1 , 129.3, 128.7, 125.7, 124.3, 122.4, 121.7, 120.4, 119.5, 116.6, 113.0,

[0191] 112.9, 46.2, 13.4 ppm; ESI MS m / z 302 [M - H]’.

[0192] Example compound 38: W-Ethyl-2-(naphthalen-2-yl)-W-phenyl-1 H-indol-3-amine. Starting from commercially available 2-(2-naphthylenyl)-1 H-indole, the example compound 38 was synthesized according to the methods illustrated in FIG. 2B as an orange-brown solid.1H NMR (500 MHz, DMSO-d6) 11 .67 (s, 1 H), 8.28 (s, 1 H), 7.91 (S, 2H), 7.88 (d, J = 8.6 Hz, 1 H),

[0193] 7.81 (d, J = 8.5 Hz, 1 H), 7.54-7.47 (m, 3H), 7.17-7.12 (m, 4H), 6.96 (t, J = 6.9 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 2H), 6.63 (t, J = 7.2 Hz, 1 H), 3.76-3.60 (br s, 2H), 1 .08 (t, J = 6.9 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 6 148.4, 133.0, 132.2, 129.1 , 128.9, 128.2, 127.9, 127.5, 126.6, 126.2, 126.0, 124.5, 124.0, 122.3, 119.4, 118.8, 118.2, 116.3, 112.4, 111.8, 45.6, 12.9 ppm; ESI MS m / z 363 [M + H]+.

[0194] Example compound 39: A / -Ethyl-A / -phenyl-2-(2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine. The example compound 39 was synthesized according to the methods illustrated in FIG. 2H and include the following steps (1-6).

[0195] Step 1. 2-(2 / 7-Tetrazol-5-yl)-1 / 7-indole (intermediate 39-2). A mixture of commercially available 1 H-indole-2-carbonitrile (intermediate 39-1 , 1 .0 g, 7.0 mmol), sodium azide (914 mg, 1.1 mmol) and ammonium chloride (376 mg, 7.0 mmol) in anhydrous DMF (35 mL) at ambient temperature under nitrogen was heated at 120 °C for 19 h. The mixture was cooled to ambient temperature, diluted with water (80 mL) and the pH was adjusted to 1 with 2N HCL The mixture was extracted with ethyl acetate (2 x 100 mL) and the combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol / dichloromethane (gradient from 0:100 to 5:96), to provide 2-(2 / 7-tetrazol-5-yl)-1 / 7-indole (2) as a yellow solid (1.30 g, 99%): ESI MS m / z 184 [M - H]’. The1H NMR (300 MHz, DMSO-d6) spectrum matched the data reported in the literature: (a) Zeidan, N.; Bognar, S.; Lee, S.; Lautens, M. Org. Lett. 2017, 19, 5058-5061. (b) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z Chem. Eur. J. 2013, 19, 16880-16886.

[0196] Step 2. 3-lodo-2-(2 / 7-tetrazol-5-yl)-1 / 7-indole (intermediate 39-3). A / -lodo succinimide (729 mg, 3.2 mmol) was added to a solution of 2-(2 / 7-tetrazol-5-yl)-1 / 7-indole (intermediate 39-2, 600 mg, 3.2 mmol) in anhydrous DMF (6.0 mL) at ambient temperature under nitrogen, after which the mixture was stirred at ambient temperature for 2 h. The reaction was diluted with ethyl acetate (100 mL), washed with water (60 mL) and saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure to provide crude 3-iodo-2-(2 / 7-tetrazol-5-yl)-1 / 7-indole (intermediate 39-3) as a red oil that was used in the next step without further purification (1 .0 g crude): ESI MS m / z 310 [M - H]’.

[0197] Step 3. 3-lodo-1 -((2-(tri methy Isi ly I )eth oxy )methy I )-2-(2-((2-(tri methy Isi ly I ) ethoxy)methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indole (intermediate 39-4, RJH-AV-171-1 ). Sodium hydride (389 mg, 9.7 mmol, 60% suspension in mineral oil) was added portion-wise to a solution of crude 3-iodo-2-(2 / 7-tetrazol-5-yl)-1 / 7-indole from the previous step (intermediate 39-3, 1.0 g, 3.2 mmol) in anhydrous DMF (10.0 mL) at 0 °C under nitrogen, after which the mixture was stirred at 0 °C for 15 min. 2-(Trimethylsilyl)ethoxylmethyl chloride (1.4 mL, 7.5 mmol) was added drop-wise, after which the mixture was warmed to ambient temperature, stirring for a total of 4 h. The reaction was slowly treated with water (1 mL), diluted with ethyl acetate (120 mL) and the solution was washed with water (100 mL) and saturated aqueous sodium chloride solution (70 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 10:90), to provide a compound that was tentatively assigned as 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-2-(2- ((2-(trimethylsilyl)ethoxy)methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indole (intermediate 39-4) as a colorless oil (655 mg, 35% over two steps):1H NMR (300 MHz, CDCh) 6 7.46-7.35 (m 2H), 7.27-7.18 (m, 1 H), 7.17-7.07 (m, 1 H), 5.86 (s, 2H), 5.76 (s, 2H), 3.75-3.64 (m, 2H), 3.29-3.17 (m, 2H), 0.90-0.80 (m, 2H), 0.65-0.57 (m, 2H), -0.12 (s, 9H), -0.29 (s, 9H) ppm. A later eluting fraction was also isolated and tentatively assigned as A / -phenyl-1-((2- (trimethylsilyl)ethoxy)methyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 / 7-tetrazol-5-yl)-1 / 7- indol-3-amine as a colorless oil (495 mg, 27% over two steps):1H NMR (300 MHz, CDCI3) 6 7.63-7.54 (m, 2H), 7.51-7.43 (m, 1 H), 7.39-7.33 (m, 1 H), 5.77 (s, 2H), 5.44 (s, 2H), 3.73-3.61 (m, 2H), 3.51-3.42 (m, 2H), 0.95-0.76 (m, 4H), 0.00 (s, 9H), -0.03 (s, 9H) ppm.

[0198] Step 4. A / -Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-2-(2-((2-(trimethylsilyl) ethoxy)- methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine (intermediate 39-5). A degassed (nitrogen- purged) solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-2-(2-((2- (trimethylsilyl)ethoxy)methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indole (intermediate 39-4, 650 mg, 1.1 mmol), aniline (0.080 mL, 1.3 mmol), tert-BuBrettPhos-Pd-G3 (97 mg, 0.11 mmol), tert- BuBrettPhos (110 mg, 0.22 mmol) and sodium tert-butoxide (219 mg, 2.3 mmol) in anhydrous dioxane (3.5 mL) in a resealable microwave vessel was sealed and the mixture was heated at 90 °C with vigorous stirring for 16 h. The resulting mixture was cooled to ambient temperature, diluted with ethyl acetate (40 mL), treated with Celite and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with (20:80 ethyl acetate / heptane) / heptane (gradient from 0:100 to 50:50), to provide A / -phenyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-2-(2-((2-

[0199] (trimethylsilyl)ethoxy)methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine (intermediate 39-5) as an off-white solid (430 mg, 71 %):1H NMR (300 MHz, CDCh) 6 7.60-7.55 (m, 1 H), 7.48-7.42 (m, 2H), 7.40-7.30 (m, 1 H), 7.23-7.15 (m, 2H), 7.12-7.06 (m, 1 H), 6.97-6.91 (m, 2H), 6.88-6.80 (m, 1 H), 6.07 (s, 2H), 5.94 (s, 2H), 3.79-3.72 (m, 2H), 3.52-3.45 (m, 2H), 1.00-0.98 (m, 2H), 0.84-0.78 (m, 2H), -0.02 (s, 9H), -0.15 (s, 9H) ppm; ESI MS m / z 538 [M + H]+.

[0200] Step 5. A / -Ethyl-A / -phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-2-(2-((2-(trimethyl silyl)- ethoxy)methyl) -2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine (intermediate 39-6). Sodium tert-butoxide (154 mg, 1.6 mmol) was added portion-wise to a solution of A / -phenyl-1-((2- (trimethylsilyl)ethoxy)methyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2 / 7-tetrazol-5-yl)-1 / 7- indol-3-amine (intermediate 39-5, 430 mg, 0.80 mmol) and iodoethane (0.38 mL, 4.8 mmol) in anhydrous DMF (4.5 mL) at ambient temperature under nitrogen, after which the mixture was stirred at ambient temperature for 1 .5 h. The mixture was diluted with saturated aqueous ammonium chloride solution (60 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 50:50) to provide A / -ethyl-A / -phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 2-(2-((2-(trimethylsilyl)-ethoxy)methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine (intermediate 39-6) as a colorless waxy solid (324 mg, 72%):1H NMR (300 MHz, CDCh) 6 7.66-7.60 (m, 1 H), 7.44-7.31 (m, 2H), 7.16-7.01 (m, 3H), 6.64-6.57 (m, 3H), 6.04 (s, 2H), 5.85 (s, 2H), 3.85 (q, J = 7.1 Hz, 2H), 3.69-3.60 (m, 2H), 3.50-3.40 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 0.95-0.86 (m, 2H), 0.83-0.73 (m, 2H), -0.03 (s, 9H), -0.15 (s, 9H) ppm; ESI MS m / z 466 [M + H]+.

[0201] Step 6. A / -Ethyl-A / -phenyl-2-(2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine (example compound 39). Tetra-A / -butylammonium fluoride solution (4.6 mL, 4.6 mmol, 1 .0 M in THF) was added to a solution of A / -ethyl-A / -phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-2-(2-((2- (trimethylsilyl)ethoxy)-methyl)-2 / 7-tetrazol-5-yl)-1 / 7-indol-3-amine (intermediate 39-6, 324 mg, 0.57 mmol) and ethylene diamine (0.15 mL, 2.3 mmol) in anhydrous THF (3.2 mL) in a resealable microwave vessel at ambient temperature under nitrogen, after which the vessel was sealed and heated at 90 °C for 5 h. The mixture was cooled to ambient temperature and treated with additional tetra-A / -butylammonium fluoride solution (2.6 mL, 1.1 mmol, 1.0 M in THF) after which the vessel was re-sealed and the mixture was heated at 90 °C for an additional 19 h. The mixture was cooled to ambient temperature, diluted with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol / dichloromethane (gradient from 0:100 to 10:90) to provide A / -ethyl-A / -phenyl-2-(2 / 7- tetrazol-5-yl)-1 / 7-indol-3-amine (example compound 39) as an off-white solid (17 mg, 21 %):1H NMR (500 MHz, DMSO-d6) 6 12.03 (s, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.22 (t, J = 7.1 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1 H), 7.09 (t, J = 8.3 Hz, 2H), 6.98 (t, J = 8.3 Hz, 1 H), 6.70-6.58 (m, 3H), 3.74 (q, J = 6.7 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-d6) 6 170.3, 148.4, 136.2, 128.7, 124.6, 123.9, 122.6, 119.9, 119.6, 119.3, 116.9, 113.4, 112.8, 45.4, 12.5 ppm; ESI MS m / z 305 [M + H]+.

[0202] Example compound 40: A / -benzyl-A / -ethyl-6-methyl-2-phenyl-1 / 7-indol-3-amine. The example compound 40 was prepared through the methods illustrated in FIG. 2I, which included the following steps (1-4). Step 1. 6-Methyl-3-nitroso-2-phenyl-1 / 7-indole (intermediate 40-2). A solution of sodium nitrite (313 mg, 4.5 mmol) in water (1 mL) was added drop-wise to a solution of commercially available 6-methyl-2-phenyl-1 / 7-indole (1.05 g, 5.1 mmol) in acetic acid (20 mL) at ambient temperature under nitrogen at a rate which kept the internal reaction temperature at ambient temperature, after which the mixture was stirred at ambient temperature for 4 h. The crude product was collected by vacuum filtration and then triturated with methanol (150 mL) and collected by vacuum filtration to produce 6-methyl-3-nitroso-2-phenyl-1 / 7-indole (intermediate 40-2) as a bright yellow solid (824 mg, 69%):1H NMR (300 MHz, DMSO-ofe) 5 13.69 (s, 1 H), 8.24 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 7.4 Hz, 1 H), 7.56-7.50 (m, 3H), 7.39 (s, 1 H), 7.14 (d, J = 7.5 Hz, 1 H), 2.41 (s, 3H) ppm.

[0203] Step 2. 6-Methyl-2-phenyl-1 / 7-indol-3-amine (intermediate 40-3). Iron powder (400 mg, 7.3 mmol) was added to a mixture of 6-methyl-3-nitroso-2-phenyl-1 / 7-indole (intermediate 40- 2, 200 mg, 0.85 mmol) and ammonium chloride (100 mg, 1.9 mmol) in ethanol (17 mL) and water (4.2 mL) at ambient temperature under nitrogen, after which the mixture was heated to reflux to stir for 6 h. The mixture was cooled to ambient temperature, the solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with methanol / dichloromethane (gradient from 0:100 to 10:90), to provide 6- methyl-2-phenyl-1 / 7-indol-3-amine (intermediate 40-3) as a purple solid (131 mg, 72%):1H NMR (300 MHz, DMSO-d6) 5 10.30 (s, 1 H), 7.75 (d, J = 6.8 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 6.8 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1 H), 7.01 (s, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 4.44 (br s, 2H), 2.37 (s, 3H) ppm.

[0204] Step 3. N-Benzyl-6-methyl-2-phenyl-1 / 7-indol-3-amine (intermediate 40-4). Sodium triacetoxyborohydride (1.5 g, 7.0 mmol) was added portion-wise to a solution of 6-methyl-2- phenyl-1 / 7-indol-3-amine (intermediate 40-3, 518 mg, 2.3 mmol) and benzaldehyde (235 mg, 2.2 mmol) in acetic acid (0.3 mL) and anhydrous dichloroethane (30 mL) at ambient temperature under nitrogen, after which the mixture was stirred at ambient temperature for 2 h. Additional sodium triacetoxyborohydride (1.5 g, 7.0 mmol) was added, after which the mixture was stirred at ambient temperature for an additional 17 h. The mixture was poured into water (90 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 30:70), to provide N-benzyl-6-methyl-2-phenyl-1 / 7- indol-3-amine (intermediate 50-4) as a colorless oil (246 mg, 28%).1H NMR (500 MHz, DMSO-ofe) 5 10.63 (s, 1 H), 7.89 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.2 Hz, 1 H), 7.44 (t, J = 7.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.25 (t, J = 7.6 Hz, 3H), 7.18 (t, J = 7.6 Hz, 1 H), 7.06 (s, 1 H), 6.74 (d, J = 8.2 Hz, 1 H), 4.15 (d, J = 7.1 Hz, 2H), 2.52 (s, 3H) ppm.

[0205] Step 4. A / -Benzyl-A / -ethyl-6-methyl-2-phenyl-1 / 7-indol-3-amine (example compound 40). Sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added portion-wise to a solution of N-benzyl-6-methyl-2-phenyl-1 / 7-indol-3-amine (intermediate 40-4, 63 mg, 0.20 mmol) and acetaldehyde (0.011 mL, 0.20 mmol) in acetic acid (0.03 mL) and anhydrous dichloroethane (3 mL) at ambient temperature under nitrogen, after which the mixture was stirred at ambient temperature for 16 h. Additional acetaldehyde (0.011 mL, 0.20 mmol) and sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added, after which the mixture was stirred at ambient temperature for an additional 1 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / heptane (gradient from 0:100 to 20:80), to provide A / -benzyl-A / -ethyl-6-methyl-2- phenyl-1 / 7-indol-3-amine (example compound 40) as an off-white solid (16 mg, 23%):1H NMR (500 MHz, CD3OD) 6 7.96 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 8.9 Hz, 1 H), 7.34 (t, J = 8.2 Hz, 2H), 7.24-7.20 (m, 3H), 7.15-7.10 (m, 4H), 6.80 (d, J = 8.2 Hz, 1 H), 3.32 ((s, 2H), 3.21 (q, J = 8.9 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-rt6) 6 140.1 , 135.9,

[0206] 133.1 , 131.0, 130.9, 129.0, 128.6, 128.4, 127.9, 127.6, 127.1 , 127.1 , 124.2, 120.7, 120.1 , 112.0, 59.8, 48.4, 21.9, 13.8 ppm; ESI MS m / z 341 [M + H]+.

[0207] Example compound 41 : A / -(6-Fluoro-2-phenyl-1 / 7-indol-3-yl)-A / -propylthiazol-2-amine. Starting from commercially available 6-fluoro-2-phenyl-1 / 7-indole, the example compound 41 was synthesized according to the methods illustrated in FIG. 2B.1H NMR (500 MHz, DMSO- d6) 5 11 .84 (s, 1 H), 7.70 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 8.2 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1 H), 7.31-7.24 (m, 1 H), 7.21 (d, J = 9.8 Hz, 1 H), 7.18 (d, J = 3.7 Hz, 1 H), 6.92 (t, J = 9.8 Hz, 1 H), 6.63 (d, J = 3.7 Hz, 1 H), 3.97 (br s, 1 H), 3.51 (br s, 1 H), 1 .61 (br s, 1 H), 1 .49 (br s, 1 H), 0.78 (t, J = 7.4 Hz, 3H) ppm;13C NMR (125 MHz, DMSO-rt6) 6 148.1 , 136.3, 134.1 , 130.7, 129.6,

[0208] 129.2, 128.9, 128.4, 126.2, 123.0, 120.1 , 118.4, 118.0, 116.5, 113.6, 112.3, 51.9, 45.5, 12.9 ppm; ESI MS m / z 352 [M + H]+.

[0209] Example compound 42: A / -benzyl-A / -ethyl-6-methyl-2-phenyl-1 / 7-indol-3-amine. The example compound 42 was prepared through the methods illustrated in FIG. 2J, which included the following steps (1-4).

[0210] Step 1 : tert-butyl-3-((2-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 / 7-indol- 3-yl)amino)benzoate (intermediate 42-2). To solution of 2-(3-chlorophenyl)-3-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1 / - / -indole (744.0 mg, 1.5 mmol) in dry toluene (4.0 mL) was added tert-butyl 4-aminobenzoate (445.7 mg, 2.3 mmol), BrettPhos-Pd-G1 (123.0 mg, 0.15 mol),fBuBrettPhos (149.3 mg, 0.31 mmol) and NaOfBu (296.0 mg, 3.1 mmol). The resulting mixture was degassed and backfilled with argon. This procedure was repeated 3 times. The resulting mixture was stirred at 50°C for 1 h and cooled down to room temperature. The reaction mixture was filtered through a short pad of Celite and the inorganic cake was washed with EtOAc. The filtrate was concentrated to dryness. The residue was purified by column eluting with EtOAc in hexane (0-8%) to give the desired product (200.0 mg, 23.6% yield) as a pale-yellow foam.1H NMR (500 MHz, DMSO) 6 8.17 (s, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.64 - 7.57 (m, 3H), 7.52 - 7.45 (m, 3H), 7.28 (t, J = 7.9 Hz, 1 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.10 (t, J = 7.6 Hz, 1 H), 6.53 (d, J = 8.7 Hz, 2H), 5.52 (s, 2H), 3.39 (t, J = 8.1 Hz, 2H), 1 .48 (s, 9H), 0.75 (t, J = 8.4 Hz, 2H), -0.12 (s, 9H).

[0211] Step 2: tert-butyl-3-((2-(3-chlorophenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-indol- 3-yl)(propyl)amino)benzoate (intermediate 42-3). To a solution of tert-butyl-3-((2-(3- chlorophenyl)-1 -((2-(tri methy Isi ly I )eth oxy )methy I )- 1 / 7-indol-3-yl)amino) benzoate

[0212] (intermediate 42-2, 200.0 mg, 0.36 mmol) in dry DMF (2.5 mL) was added NaOfBu (140.3 mg, 1 .46 mmol) and 1 -iodopropane (247.6 mg, 1 .46 mmol). The resulting mixture was stirred under an argon atmosphere at 50°C for 3 h and cooled down to room temperature. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column eluting with EtOAc in hexane (0-10%) to give the desired product (203.0 mg, 94.4% yield) as a yellow oil.1H NMR (500 MHz, DMSO) 6 7.75 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 9.2 Hz, 2H), 7.52 - 7.45 (m, 3H), 7.39 - 7.34 (m, 1 H), 7.32 - 7.26 (m, 1 H), 7.17 - 7.06 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.54 (s, 2H), 3.37 (s, 2H), 1 .49 (s, 9H), 1 .41 (s, 2H), 0.76 - 0.66 (m, 5H), -0.13 (s, 9H).

[0213] Step 3: tert-butyl-3-((2-(3-chlorophenyl)-1 / 7-indol-3-yl)(propyl)amino)benzoate (intermediate 42-4). To a solution of tert-butyl-3-((2-(3-chlorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 / 7-indol-3-yl)(propyl)amino)benzoate (203.0 mg, 0.34 mmol) in dry THF (1.0 mL) was added TBAF (1.0 M THF solution, 3.0 mL) and ethylenediamine (50 pL). The resulting solution was stirred under an argon atmosphere overnight at 70°C and cooled down to room temperature. The reaction mixture was concentrated to dryness. The residue was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column eluting with EtOAc in hexane (0-10%) to give the desired product (150 mg, 95.0% yield) as a white foam.1H NMR (500 MHz, DMSO) 5 11 .75 (s, 1 H), 7.75 (t, J = 1 .9 Hz, 1 H), 7.68 (d, J = 9.3 Hz, 2H), 7.64 - 7.60 (m, 1 H), 7.50 - 7.41 (m, 2H), 7.40 - 7.35 (m, 1 H), 7.23 - 7.16 (m, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 7.03 - 6.97 (m, 1 H), 6.67 (d, J = 8.6 Hz, 2H), 3.77 (s, 1 H), 1.62 (s, 1 H), 1.49 (s, 10H), 0.80 (t, J = 7.4 Hz, 3H). Step 4: 3-((2-(3-chlorophenyl)-1 / 7-indol-3-yl)(propyl)amino)benzoic acid (Intermediate 42-5). To a solution of tert-butyl-3-((2-(3-chlorophenyl)-1 / 7-indol-3-yl)(propyl)amino)benzoate (intermediate 42-4,150 mg, 0.33 mmol) in dry DCM (2.0 mL) was added TFA (0.5 mL). The resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated to dryness. The residue was purified by column eluting with EtOAc in hexane (0-50%) to give the desired product (122 mg, 93.15 yield) as a brown-colored foam.1H NMR (500 MHz, DMSO) 5 11 .75 (s, 1 H), 7.76 (t, J = 1 .9 Hz, 1 H), 7.73 (d, J = 9.3 Hz, 2H), 7.63 (dt, J = 7.9, 1.4 Hz, 1 H), 7.50 - 7.43 (m, 2H), 7.40 - 7.35 (m, 1 H), 7.22 - 7.17 (m, 1 H), 7.15 (d, J = 7.9 Hz, 1 H), 7.03 - 6.97 (m, 1 H), 6.67 (d, J = 8.5 Hz, 2H), 3.77 (s, 1 H), 1 .63 (s, 1 H), 1 .49 (s, 1 H), 0.80 (t, J = 7.4 Hz, 3H).

[0214] Step 5. 3-((2-(3-chlorophenyl)-1 / 7-indol-3-yl)(propyl)amino)-A / -(6-methylpyrazin -2- yl)benzamide (example compound 42). To a solution of 3-((2-(3-chlorophenyl)-1 H-indol-3- yl)(propyl)amino)benzoic acid (30.0 mg, 0.074 mmol) in dry DMF (0.8 mL) was added 6- methylpyrazin-2-amine (9.7 mg, 0.088 mmol), HATU (41.8 mg, 0.11 mmol) and DIPEA (28.6 mg, 0.22 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column eluting with EtOAc in hexane (0-25%) to give the desired product (30 mg, 81.7% yield) as a yellow foam.1H NMR (500 MHz, DMSO) 5 11 .76 (s, 1 H), 8.81 (dd, J = 4.6, 1 .4 Hz, 1 H), 8.73 (dd, J = 8.4, 1 .5 Hz, 1 H), 7.81 (dt, J = 4.4, 2.0 Hz, 1 H), 7.68 (d, J = 7.6 Hz, 2H), 7.65 (dd, J = 8.4, 4.4 Hz, 1 H), 7.62 (d, J = 7.6 Hz, 1 H), 7.51 - 7.45 (m, 4H), 7.41 - 7.37 (m, 2H), 7.25 (d, J = 7.7 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 3H), 7.02 (t, J = 7.5 Hz, 1 H), 3.79 (s, 1 H), 3.45 (s, 1 H), 1.63 (s, 1 H), 1.51 (s, 1 H), 0.81 (s, 3H); ESI MS m / z 496 [M + H]+.

[0215] Example compound 43: 3-((2-(3-chlorophenyl)-1 / 7-indol-3-yl)(propyl)amino)-A / -(2- morpholinoethyl)benzamide. The example compound 43 was synthesized though the methods described for the synthesis of example compound 42 by coupling the intermediate 42-5 with 2-morpholinoethan-1 -amine. The product was obtained as a yellow gum-like compound.1H NMR (500 MHz, DMSO) 6 11 .68 (s, 1 H), 8.23 (t, J = 5.7 Hz, 1 H), 7.81 (t, J = 1 .9 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.49 - 7.41 (m, 2H), 7.36 (dd, J = 8.0, 1 .1 Hz, 1 H), 7.21 - 7.14 (m, 2H), 7.13 - 7.07 (m, 3H), 6.96 (t, J = 7.4 Hz, 1 H), 6.72 (d, J = 7.5 Hz, 1 H), 3.69 (s, 1 H), 3.53 (t, J = 4.7 Hz, 4H), 3.42 (s, 1 H), 3.32 - 3.27 (m, 2H), 2.44 - 2.33 (m, 6H), 1 .55 (s, 2H), 0.80 (t, J = 7.4 Hz, 3H). ESI MS m / z 517 [M + H]+.

[0216] Example compound 44: A / -(3-(1 / 7-tetrazol-5-yl)phenyl)-7-fluoro-2-(3-fluorophenyl)- / V- propyl-1 / 7-indol-3-amine. The example compound 44 was synthesized through the methods illustrated in FIG. 2K, which included the following steps (1-4). Steps 1-3 were carried out through similar procedures described in the synthesis of example compound 43.

[0217] Step 4. To a solution of NaNs (9.7 mg, 0.1 mmol) in dry DMF (0.5 mL) was added AgNO3 (3.4 mg, 0.02 mmol). After the mixture was stirred at room temperature for 5 minutes, 3-((7-fluoro-2-(3-fluorophenyl)-1 / 7-indol-3-yl)(propyl)amino)benzonitrile (38.7 mg, 0.1 mmol) was added. The resulting mixture was stirred under an argon atmosphere at 120°C for 15 hours and cooled down to room temperature. Water (1 mL) was added before the reaction mixture was acidified to pH 2 with aqueous 1 N HCI solution. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by column eluting with MeOH in DCM (0-10%) to give the desired product (9.0 mg, 21 % yield) as a yellow foam.1H NMR (500 MHz, DMSO) 6 12.05 (s, 1 H), 7.68 - 7.60 (m, 2H), 7.51 - 7.44 (m, 1 H), 7.39 - 7.32 (m, 3H), 7.18 (td, J = 8.7, 2.6 Hz, 1 H), 7.06 - 6.92 (m, 3H), 6.85 - 6.78 (m, 1 H), 3.72 (s, 1 H), 1 .59 (s, 2H), 0.81 (t, J = 7.4 Hz, 3H).

[0218] Example compound 45: A / -Ethyl-A / -(6-methyl-2-phenyl-1 / 7-indol-3-yl) benzamide. The example compound 45 was prepared through the methods illustrated in FIG. 2L, which included the following steps (1-5).

[0219] Step 1. 2-((Cyano(phenyl)methyl)amino)-4-methylbenzonitrile (intermediate 45-2). To a solution of 2-amino-4-methylbenzonitrile (2.8 g, 21 mmol) in EtOH (30 mL) was added mandelonitrile (3.3 g, 25 mmol). The reaction was stirred at reflux under argon atmosphere for 15 hours. The reaction mixture was cooled down to rt and concentrated to dryness. The residue was purified by Combi-Flash (0 - 30% EtOAc in hexane) to give a crude product. Trituration with hexane / EtOAc (3:1 , 20 mL) gave the desired product (1 .3 g, 25.8% yield) as a white solid, mp 157-159 °C.1H NMR (300 MHz, DMSO- 6): 6 7.59 (d, J = 7.5 Hz, 2H), 7.51- 7.42 (m, 4H), 7.18 (d, J = 9.0 Hz, 1 H), 6.83 (br s, 1 H), 6.72 (d, J = 7.8 Hz, 1 H), 6.16 (d, J = 9.0 Hz, 1 H), 2.28 (s, 3H). ESI-MS m / z: 248.1 (M+H)+.

[0220] Step 2. (E)-N-(1-Benzoyl-2-cyano-6-methyl-2-phenylindolin-3-ylidene)benz amide (intermediate 45-3). To a solution of 2-((cyano(phenyl)methyl)amino)-4-methylbenzonitrile (intermediate 45-2, 696 mg, 2.8 mmol) in toluene (5 mL) was added benzoyl chloride (1.6 g, 11.2 mmol) and DIPEA (1.5 g, 11.2 mmol). The reaction was stirred at 70 °C under argon atmosphere for 3 hours. The reaction mixture was cooled down to rt, partitioned with EtOAc (20 mL) and water (5 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (0 - 40% EtOAc in hexane) to give a crude product. Trituration with ether (2 mL) gave the desired product (555 mg, 43.7% yield) as a white solid, mp 159-161 °C.1H NMR (300 MHz, DMSO- dG): 67.72-7.42 (m, 15 H), 7.23 (d, J = 8.1 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 6.20 (s, 1 H), 2.21 (s, 3H). ESI-MS m / z: 456.3 (M+H)+.

[0221] Step 3. N-(1-Benzoyl-6-methyl-2-phenyl-1 H-indol-3-yl)benzamide (intermediate 45-4). To a solution of (E)-A / -(1-benzoyl-2-cyano-6-methyl-2-phenylindolin-3-ylidene)benzamide (intermediate 45-3, 455 mg, 1 mmol) in dry THF (3 mL) was added allyl bromide (363 mg, 3 mmol) and indium powder (172 mg, 1.5 mmol). The reaction was stirred at reflux for 1 hour under argon atmosphere. The reaction mixture was cooled down to rt, partitioned with EtOAc (20 mL) and water (10 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by Combi-Flash (0 - 40% EtOAc in hexane) to give a crude product. Trituration with acetone (1 mL) gave the desired product (100 mg, 23.2% yield) as a yellow solid, mp 218-220 °C.1H NMR (300 MHz, DMSO-56): <5 10.03 (br s, 1 H), 7.96 (d, J = 7.5 Hz, 2H), 7.58-7.42 (m, 6H), 7.41-7.32 (m, 6H), 7.21-7.09 (m, 4H), 2.39 (s, 3H). ESI-MS m / z: 431.2 (M+H)+.

[0222] Step 4. N-(1-Benzoyl-6-methyl-2-phenyl-1 H-indol-3-yl)-N-ethylbenzamide (intermediate 45-5). To a solution of A / -(1-benzoyl-6-methyl-2-phenyl-1 H-indol-3- yl)benzamide (intermediate 45-4, 43 mg, 0.1 mmol) and Etl (30 mg, 0.2 mmol) in DMF (0.2 mL) was added NaH (8 mg, 60% dispersion in mineral oil, 0.2 mmol) in one portion at 0°C under argon atmosphere protection. The resulting mixture was warmed to rt and stirred for 1 hour. The reaction mixture was poured into ice-water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (0 - 30% EtOAc in hexane) to give the desired product (40 mg, 87.3% yield) as a yellow solid, mp 110-112 °C.1H NMR (300 MHz, DMSO-56): 6 7.69 (d, J = 7.8 Hz, 2H), 7.52-7.40 (m, 3H), 7.26-7.18 (m, 6H), 7.15-7.09 (m, 4H), 7.00 (d, J = 7.5 Hz, 2H), 6.86 (m, 2H), 3.89 (q, J = 6.6 Hz, 1 H), 3.76 (q, J = 6.6 Hz, 1 H), 2.40 (s, 3H), 1 .12 (t, J = 6.9 Hz, 3H). ESI-MS m / z 459.2 (M+H)+.

[0223] Step 5. A / -Ethyl-A / -(6-methyl-2-phenyl-1 / 7-indol-3-yl)benzamide (example compound 45). To a solution of A / -(1-benzoyl-6-methyl-2-phenyl-1 / 7-indol-3-yl)-A / -ethylbenzamide (40 mg, 87 pmol) in MeOH I THF I H2O (0.2 mL I 0.2 mL I 0.1 mL) was added LiOH (21 mg, 870 pmol). The resulting mixture was stirred at rt for 30 min. The reaction mixture was concentrated and the residue was partitioned between EtOAc (10 mL) and H2O (5 mL). The aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (0 - 30% EtOAc in hexane) to give the desired product (13 mg, 42.2% yield) as a white solid, mp 195-197 °C.1H NMR (300 MHz, DMSO-56): 6 11 .26 (s, 1 H), 7.64 (d, J = 8.1 Hz, 2H), 7.49 (t, J =8.1 Hz, 2H), 7.08-7.03 (m, 4H), 6.97-6.92 (m, 2H), 6.86 (d, J = 8.4 Hz, 1 H), 4.20 (q, J = 6.6 Hz, 1 H), 3.47 (q, J = 6.6 Hz, 1 H), 2.36 (s, 3H), 1 .16 (t, J = 6.9 Hz, 3H). ESI-MS m / z: 355.3 (M+H)+.

[0224] Example compound 46: A / -isobutyl-A / -(6-methoxypyridin-2-yl)-2-phenyl-6- (trifluoromethyl)-l H-indol-3-amine. Starting from the intermediate 2-phenyl-6-(trifluoromethyl)- 1 / - / -indole that was prepared according to the methods illustrated in FIG. 2A, the example compound 46 was synthesized according to the methods illustrated in FIG. 3B.1H NMR (500 MHz, DMSO) 6 12.07 (s, 1 H), 7.74 (s, 1 H), 7.67 - 7.62 (m, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.39 (dd, J = 7.9, 4.4 Hz, 2H), 7.30 (dd, J = 8.4, 1 .7 Hz, 1 H), 7.27 (t, J = 7.9 Hz, 1 H), 6.04 (d, J = 7.6 Hz, 1 H), 5.72 (d, J = 7.9 Hz, 1 H), 3.95 (dd, J = 13.4, 7.0 Hz, 1 H), 3.86 (s, 3H), 3.30 (m, 1 H), 1 .78 (hept, J = 6.6 Hz, 1 H), 0.85 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H).

[0225] Example compound 47: 2-(3-fluorophenyl)-A / -isobutyl-A / -(6-methoxypyridin-2-yl)-6- (trifluoromethyl)-1 / 7-indol-3-amine. Starting from 2-(3-fluorophenyl)-6-(trifluoromethyl)-1 / 7- indole that was prepared according to the methods illustrated in FIG. 2A, the example compound 47 was synthesized according to the methods illustrated in FIG. 3B.1H NMR (500 MHz, DMSO) 6 12.18 (s, 1 H), 7.76 (s, 1 H), 7.57 - 7.48 (m, 2H), 7.47 - 7.40 (m, 2H), 7.35 - 7.21 (m, 3H), 6.06 (d, J = 7.6 Hz, 1 H), 5.71 (d, J = 7.9 Hz, 1 H), 3.96 - 3.89 (m, 1 H), 3.86 (s, 3H), 3.41 (m, 1 H), 1.78 (hept, J = 6.6 Hz, 1 H), 0.85 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.7 Hz, 3H).

[0226] Example compound 48: A / -isobutyl-A / -(6-methoxypyridin-2-yl)-2-phenyl-1 / 7-pyrrolo [2,3-b]pyridin-3-amine. Starting from commercially available 2-phenyl-1 / 7-pyrrolo[2,3- b]pyridine, the example compound 48 was synthesized according to the methods illustrated in FIG. 2B as a pale-yellow foam-like solid.1H NMR (500 MHz, DMSO) 6 12.22 (s, 1 H), 8.32 (dd, J = 4.7, 1 .6 Hz, 1 H), 7.75 - 7.69 (m, 2H), 7.65 (dd, J = 7.9, 1 .6 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1 H), 7.32 (t, J = 7.9 Hz, 1 H), 7.11 (dd, J = 7.9, 4.7 Hz, 1 H), 6.08 (d, J = 7.6 Hz, 1 H), 5.78 (d, J = 7.9 Hz, 1 H), 4.04 - 3.96 (m, 1 H), 3.89 (s, 3H), 3.35 - 3.27 (m, 1 H), 1 .83 (hept, J = 6.7 Hz, 1 H), 0.89 (d, J = 6.7 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H).

[0227] EXAMPLE 3

[0228] Results

[0229] Allosteric modulation of the CB1 cannabinoid receptor

[0230] Table 1 Allosteric modulation properties from example compounds of this invention

[0231] Table 1 notes: aAllosteric modulation (M%). Percentage of the response of the compound tested at 1.0 pM in the presence of the CB1 orthosteric agonist (CP55.940 at EC20 concentration 1.0 nM) to the response (i.e., inhibition of cAMP production) evoked by a maximally effective concentration of orthosteric agonist CP55.940 (CP55,940Max: 166 nM). bThe EC50 value represents the compound’s concentration at which 50% of the maximal achievable effect is observed. The effect is positive modulation of the inhibition of cAMP production induced by CB1 agonist CP55.940. cThe Emax percentage represents the response of the test compound to a percentage of the response evoked by a maximally effective concentration of orthosteric agonist CP55940 (CP55940Max). dThe EC50 value represents the compound’s concentration at which 50% of the maximal achievable effect is observed, and the effect is the potentiation of the CB1 agonist CP55.940 (EC2o)-induced [35S]GTPyS binding to mouse CB1 receptor using mouse cerebellum. eThe EC50 value represents the compound’s concentration at which 50% of the maximal achievable effect is observed, and the effect is assessed in the absence of CB1 agonist CP55.940.

[0232] Pain suppression via compounds of Formula (I)

[0233] Pain suppressing effects of some invented compounds, were assessed using chronic constriction injury (CCI) of infraorbital nerves (ION) induced neuropathic pain in mice (FIGS. 3A-3F). The ED50 was measured at 6 hrs post drug administration with doses of compounds 1 , 7, 16, 46, 47, and gabapentin. The respective ED50 were 17.17 mg / kg, 6.45 mg / kg, 6.65 mg / kg, 7.4 mg / kg, 7.0 mg / Kg, and 38.66 mg / kg. The following references are cited herein:

[0234] 1. Howlett, et al. Neuropharmacology 2004, 47:345-358.

[0235] 2. Pacher, et al. Pharmacol. Rev. 2006, 58(3):389-462.

[0236] 3. Howlett, A., Cannabinoid receptor signaling. In Cannabinoids, Pertwee, R., Ed. Springer: Berlin Heidelberg, 2005; pp. 53-79.

[0237] 4. Mackie, K., Annu. Rev. Pharmacol. Toxicol. 2006, 46, 101-122.

[0238] 5. Grotenhermen, et al. Dtsch. Arztebl. Int. 2012, 109(29-30):495-501 .

[0239] 6. Cridge, B. J. and Rosengren, R. J., Cancer Manag. Res. 2013, 5:301-313.

[0240] 7. Janero, D. R. and Makriyannis, A., Expert opinion on emerging drugs 2009, 14(1 ):43-65.

[0241] 8. Pertwee, et al. Life Sci. 2005, 76(12):1307-1324.

[0242] 9. Kunos, et al. Pharmacol. Sci. 2009, 30(1 ):1-7.

[0243] 10. Christopoulos, A., Nat. Rev. Drug Discov. 2002, 1 (3): 198-210.

[0244] 11. Ross, R., Br. J. Pharmacol. 2007, 152(5):565-566.

[0245] 12. Price, et al., Mol. Pharmacol. 2005, 68(5): 1484-1495.

[0246] 13. Horswill, et al., Br. J. Pharmacol. 2007, 152(5):805-814.

[0247] 14. Navarro, et al., Br. J. Pharmacol. 2009, 156(7): 1178-1184.

[0248] 15. Ignatowska-Jankowska, et al., Neuropsychopharmacology 2015, 40(13):2948- 2959.

[0249] 16. Pamplona, et al., Proc. Natl. Acad. Sci. U S A. 2012, 109(51 ):21134-21139.

[0250] 17. Vallee, et al., Science 2014, 343(6166):94-98.

[0251] 18. Bauer, et al., Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors.

[0252] 19. Garai et al., J. Med. Chem. 2020, 63:542-568.

Claims

WHAT IS CLAIMED IS:1 . A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:Xi, X2, X3 and X4 are independently a carbon atom, a methine group or a nitrogen atom;R1, R2, R3 and R4 is optionally and independently a hydrogen, a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), a cyano (CN), an alkoxyl, an alkyl, a substituent or absent;R5is a hydrogen or a substituent;Y1 is independently selected from (CH2)r, O, S, NH, a substituted amino group, a carbonyl, a sulfonyl, and a sulfinyl wherein the subscript r is 0, 1 , 2, 3, 4, or 5; subscript m is 0 or 1 ;W1 is selected from an aryl, a heteroaryl, a cyclic ora heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituent(s) or a group selected from heterocyclic group or a heteroaryl group;Y2 is independently (CH2)t, a carbonyl, a sulfonyl, or a sulfinyl wherein the subscript t is 0, 1 , 2, 3, 4 or 5; subscript n is 0 or 1 ;W2 is an amino, an alkoxyl, or an alkyl, each of which is optionally and independently substituted with 1 to 4 substituents,Y3 is a hydrogen, an aryl, a heteroaryl, a cyclic group, a heterocyclic group, or an amino group, each of which is optionally and independently substituted with 1 , 2, 3, or 4 of the substituents;Z is independently (CH2)w, O, S, an amino, a lower alkyl, a carbonyl, a sulfonyl, or a sulfinyl wherein the subscript w is 0, 1 , 2, 3, 4 or 5; subscript v is 0 or 1 ;\N is an aryl, a heteroaryl, a cyclic and a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituent(s); andY4 is hydrogen, (CH2)U, O, S, amino, carbonyl, sulfonyl, sulfinyl, or cyano (CN) wherein the subscript u is 0, 1 , 2, 3 or 4; subscript p is 0 or 1 ;Y5is independently a hydrogen, an alkyl, a substituent or an aryl group a heterocyclic group, or a heteroaryl group, each of which is optionally and independently substituted with 1 , 2, 3, or 4 substituents; and subscript q is 0 or 1 .

2. The compound of claim 1 , wherein the X2 is a carbon atom; the Xi, X3 and X4 are independently a carbon atom, a methine group or a nitrogen atom; the R2 is a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), or a cyano (CN), and the R1, R3 and R4 are optionally and independently a hydrogen, a halogen, a CF3, a CF3O, a methanesulfonyl (CH3S(=O)2), a cyano (CN), an alkoxyl, an alkyl, or a substituent.

3. The compound of claim 1 , wherein the subscript m is 0, and W1 is an aryl, hetero aryl, or a heterocyclic group, each of which is optionally and independently substituted with a heteroaryl, a heterocyclic group or 1 to 5 substituents.

4. The compound of claim 1 , wherein the subscripts m, v and n are 0; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; and Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents.

5. The compound of claim 1 , wherein the subscripts m, n and v are 0; the W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is a phenyl group, which is optionally and independently substituted with 1 to 5 substituents.

6. The compound of claim 1 , wherein the subscripts m and n are 0; the W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is a 2-pyridinyl group, which is optionally and independently substituted with 1 to 3 substituents.

7. The compound of claim 1 , wherein the subscripts m, n and v are 0; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and the Wa is a pyrimidinyl group, which is optionally and independently substituted with 1 to 3 substituents.

8. The compound of claim 1 , wherein the subscripts m, n and v are 0; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is a pyrazinyl group, which is optionally and independently substituted with 1 to 2 substituents.

9. The compound of claim 1 , wherein the subscripts m, n and v are 0; and W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, and a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is a pyridazinyl group, which is optionally and independently substituted with 1 to 2 substituents.

10. The compound of claim 1 , wherein the subscripts m and n are 0 and the subscript v is 1 ; W2 is an alkyl which is optionally and independently substituted with 1 to 4 substituents; Y3 is a hydrogen, an amino group, or a heterocyclic group, each of which is optionally and independently substituted with 1 to 5 substituents; and W3 is an aryl and heteroaryl group, which is optionally and independently substituted with 1 to 2 substituents.

11. A pharmaceutical composition comprising at least one of the compounds of claim 1 and a pharmaceutically acceptable carrier.

12. A method for treating a disorder associated with CB1 receptor activities, comprising: administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1 .

13. The method of claim 12, wherein the disorders associated with CB1 consist of pathological pain conditions.

14. The method of claim 13, wherein the pathological pain conditions are acute and chronic neuropathic, inflammatory and chemotherapy-induced pain15. The method of claim 12, wherein the disorders associated with CB1 consist of neurodegenerative diseases, neuronal injury, chemotherapy-induced nausea and wasting syndromes, anxiety, neurological diseases, glaucoma and retinopathy, respiratory disorders, cardio- and cerebral-vascular diseases, asthma, migraine, cancer, insomnia, inflammation, liver disease, and osteoporosis.

16. The method of claim 15, wherein the neurological diseases are depression and schizophrenia.

17. The method of claim 12, wherein the compound is given by oral, parenteral, intravenous, transdermal, inhalation, intracerebral, or topical administration in pharmaceutical formulation form.

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