Pyrrolopyrimidineamines as complement inhibitors

Abstract

To provide an inhibitor of complement system.SOLUTION: Compounds of Formula (I), and pharmaceutically acceptable salts thereof, are disclosed. Also provided are pharmaceutical compositions comprising such compounds, and methods of using the compounds and compositions in the treatment or prevention of diseases or conditions characterized by aberrant complement system activity.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 004,799, filed April 3, 2020. [Background technology]

[0002] The complement system is part of the body's immune system, enhancing the ability of antibodies and phagocytes to destroy and eliminate foreign substances (e.g., pathogens) within the body. The complement system comprises a group of plasma proteins that interact to attack the extracellular structures of pathogens and induce a series of inflammatory responses that help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to a specific pathogen or by antibody binding to the pathogen. Activation of complement proteins triggers a cascade, with one complement protein in turn inducing the activation of the next. The activation of a few complement proteins at the beginning of the pathway is greatly amplified by each successive enzymatic reaction, rapidly generating a disproportionately large complement response (Non-Patent Document 1). Healthy organisms have regulatory mechanisms to prevent unregulated complement activation.

[0003] Once activated, complement proteins can bind to pathogens, opsonizing them for uptake by phagocytes bearing complement receptors. Small fragments of some complement proteins then act as chemoattractants, recruiting more phagocytes to the site of complement activation and further activating these phagocytes. Complement proteins then form holes or pores in the invading organism, leading to its destruction. Complement plays an important role in defending the body against foreign substances but can also destroy healthy cells and tissues. Inappropriate activation of complement is implicated in a long list of pathologies affecting the immune, renal, cardiovascular, and nervous systems (Non-Patent Document 2). Therefore, there is a need for the development of additional complement inhibitors that are therapeutically effective in treating numerous disorders. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Marrides, S.Pharmacological Reviews1998,Vol.50,pages 59-88 [Non-patent document 2] Morgan,B.Eur J Clin Invest1994,Vol.24,pages 219-228 Summary of the Invention [Means for solving the problem]

[0005] In certain embodiments, the present invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts thereof: [ka] wherein, independently for each occurrence: X is a bond or C(R X )2, Y is a bond, C(R Y )2, or -N(R b )- and G is S or C(R 3 )2, R a and R b are each independently H or (C1-C6) alkyl; R 1 represents an optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl; R 2 represents an optionally substituted bicyclic or tricyclic heteroaryl; R 3 is independently at each occurrence H, halogen, —CN, —NH, —CHNH, (C-C)alkoxy, or (C-C)alkyl, or R 3two vicinal occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted fused (C-C)cycloalkyl or (C)aryl, or R 3 two geminal occurrences of, taken together with the carbon atoms to which they are attached, form an optionally substituted spiro(C-C)cycloalkyl, or R 3 two homonymous occurrences of together with the carbon atoms to which they are attached form an optionally substituted bridged (C-C)cycloalkyl; R X is independently at each occurrence H, (C-C) alkyl, or (C-C) cycloalkyl; R Y is independently at each occurrence H, (C1-C6) alkyl, or (C3-C7) cycloalkyl; Or, R Y The existence of R 2 and the above substituents together with the intervening atoms form a ring, R 1 or R 2 The optional substituents above are each independently selected from halogen, -CN, -NO2, -OR 13 , -NR 13 R 14 , -C(O)R 13 , -C(O)OR 13 , -C(O)NR 13 R 14 , -OC(O)R 13 , -NR 13 C(O)R 14 , -OC(O)NR 13 R 14 , -OC(O)OR 13 , -NR 13 C(O)OR 14 , -NR 13 C(O)NR 13 R 14 , -OS(O) p (R 13 ), -SR 13 , -NR 13 S(O) p (R 14), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; Or, R 1 The above two substituents or R 2 two substituents form a ring together with the intervening atoms, R 13 and R 14 represents independently at each occurrence H or an optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; p is 0, 1, or 2].

[0006] In certain aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] In certain aspects, the present invention provides methods of treating a disease or condition characterized by abnormal complement system activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immunological disorder. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiometabolic disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposition disease, cold agglutinin disease, and fulminant antiphospholipid syndrome. In other specific aspects, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of adult respiratory distress syndrome, myocardial infarction, pulmonary inflammation, sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ failure, Guillain-Barré syndrome, hemorrhagic shock, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, multiple sclerosis, platelet storage, and hemodialysis. In other specific embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis. In further embodiments, the disease or condition characterized by abnormal complement system activity is a hematological disorder. In further embodiments, the disease or condition characterized by abnormal complement system activity is an ocular disorder or eye disorder.In yet another aspect, the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye, Fuchs' endothelial dystrophy, retinal vein occlusion, or post-surgical inflammation. In certain other aspects, the disease or condition characterized by abnormal complement system activity is obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, neuropathy, angioedema, e.g., hereditary angioedema or acquired angioedema, thrombotic microangiopathy, Parkinson's disease, schizophrenia, periodontitis, Crohn's disease, C3 nephropathy, membranous nephropathy, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, ischemia / reperfusion injury, acute kidney injury, and organ transplantation, e.g., For example, the disease is selected from the group consisting of kidney transplantation, systemic inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, Buerger's disease, delayed onset of allograft function, granulomatosis with polyangiitis, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangiitis, pyoderma gangrenosum, and Stargardt's disease. DETAILED DESCRIPTION OF THE INVENTION

[0008] Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in treating disorders of the immune, renal, cardiovascular, and nervous systems. Provided herein are compounds of formula (I) and pharmaceutically acceptable salts thereof that are useful for treating or preventing diseases or conditions characterized by abnormal activity of the complement system.

[0009] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0010] The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or are oxygen, nitrogen, or sulfur.

[0011] As used herein, the term "alkyl" is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C5 for straight chain). 30 , for branched chains, C3-C 30 ), or about 20 or less, or 10 or less. In certain embodiments, the term "alkyl" refers to C1-C 10 In certain embodiments, the term "alkyl" refers to a C1-C6 alkyl group, e.g., a C1-C6 straight chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3-C6 alkyl group. 12 It refers to a branched alkyl group. In certain embodiments, the term "alkyl" refers to a C3-C8 branched alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0012] The term "cycloalkyl" refers to monocyclic, bicyclic, or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Some cycloalkyls have from 5 to 12 carbon atoms in their ring structure, and some have 6 to 10 carbons in the ring structure. Preferably, a cycloalkyl is a (C3-C7)cycloalkyl, which refers to a monocyclic saturated carbocyclic ring having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings are rings in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form -(CH2) w - (where w is 1, 2, or 3) bridging group). Representative examples of bicyclic systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. Bridged or fused bicyclic cycloalkyls are attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group is optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0013] The term "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a cycloalkylalkyl group is a cyclohexylmethyl group.

[0014] The term "heterocycloalkyl," as used herein, refers to radicals of non-aromatic ring systems, including but not limited to monocyclic, bicyclic, and tricyclic rings, which may be fully saturated or which may contain one or more units of unsaturation, where, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, having from 3 to 12 atoms including at least one heteroatom, e.g., nitrogen, oxygen, or sulfur. For illustrative purposes, and not to be construed as limiting the scope of the invention, examples of heterocycles are listed below: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl , isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, trithianyl, and 2-azobicyclo[3.1.0]hexane. Heterocycloalkyl groups are optionally substituted with one or more substituents, as described below.

[0015] As used herein, the term "(heterocycloalkyl)alkyl" refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0016] The term "alkenyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) in an alkenyl group can be located at any position in the moiety and can have either the (Z) or (E) configuration around the double bond(s).

[0017] The term "alkynyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0018] The term "alkylene" is art-recognized and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from an alkyl group, as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at both positions with a substituent such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, or the like. That is, in one embodiment, a "substituted alkyl" is an "alkylene."

[0019] The term "amino" is a term of art and as used herein refers to both unsubstituted and substituted amines, for example, those of the general formula: [ka] (In the formula, R a , R b , and R c each independently represents hydrogen, alkyl, or alkenyl, and -(CH2) x -R d or R taken together with the N atom to which it is attached a and R b completes a heterocycle with 4 to 8 atoms in the ring structure, and R d represents aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl, and x is zero or an integer ranging from 1 to 8. In certain embodiments, R a or R b where only one of the groups is a carbonyl, e.g., R a , R b In other embodiments, R a and R b (and optionally, R c) are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d In certain embodiments, R a and R b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which can be further substituted (e.g., with halogen, alkyl, alkoxy, hydroxy, etc.). In certain embodiments, the term "amino" refers to -NH.

[0020] In certain embodiments, the term "alkylamino" refers to -NH(alkyl).

[0021] In certain embodiments, the term "dialkylamino" refers to -N(alkyl)2.

[0022] The term "amide," as used herein, means -NHC(=O)-, where the amide group is attached to the parent molecular moiety through a nitrogen. Examples of amides include alkylamides such as CHC(=O)N(H)- and CHCHC(=O)N(H)-.

[0023] The term "acyl" is a term of art and, as used herein, refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0024] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group, i.e., -CHNH.

[0025] The term "aminoacyl" is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

[0026] The term "aminothionyl" as used herein refers to the analog of aminoacyl in which the O of RC(O)-- is replaced by sulfur, thus the form RC(S)--.

[0027] The term "phosphoryl" is a term of art and as used herein generally refers to a group having the formula: [ka] where Q50 represents S or O, and R59 represents hydrogen, lower alkyl, or aryl, such as -P(O)(OMe)- or -P(O)(OH). For example, when used to substitute an alkyl, the phosphoryl group of the phosphorylalkyl has the general formula: [ka] wherein Q50 and R59 are each independently defined above, and Q51 represents O, S, or N, for example, -OP(O)(OH)OMe or -NH-P(O)(OH). When Q50 is S, the phosphoryl moiety is a "phosphorothioate."

[0028] The term "aminophosphoryl," as used herein, refers to a phosphoryl group substituted with at least one amino group, as defined herein, for example, -P(O)(OH)NMe2.

[0029] The terms "azide" or "azido" as used herein refer to an -N3 group.

[0030] The term "carbonyl" as used herein refers to -C(=O)-.

[0031] The term "thiocarbonyl" as used herein refers to -C(=S)-.

[0032] The term "alkylphosphoryl," as used herein, refers to a phosphoryl group substituted with at least one alkyl group, as defined herein, e.g., -P(O)(OH)Me.

[0033] The term "alkylthio" as used herein refers to alkyl-S-. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0034] The term "carboxy" as used herein means a -CO2H group.

[0035] The term "aryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, including, for example, benzene, naphthalene, anthracene, and pyrene. Typically, aryl groups contain 6 to 10 carbon ring atoms (i.e., (C-C 10) aryl). Aromatic rings can be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings (the rings are "fused rings"), at least one of the rings is aromatic hydrocarbon, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group.

[0036] The term "heteroaryl" is a term of art and as used herein refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms and including one or more heteroatoms, such as nitrogen, oxygen, or sulfur, in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. "Heteroaryl" refers to a group that can be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjacent rings (the rings are "fused rings"), and at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Such heteroaryl groups may be connected to the remainder of the molecule via either an aromatic group or other cyclic group having one or more heteroatoms in the ring structure.For example, heteroaryl includes indole, which comprises a benzene ring and a pyrrole ring fused together. The indole substituent may be attached to the parent structure through either the benzene ring or through the pyrrole ring of the indole.

[0037] The term "aralkyl" or "arylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with an aryl group, where the moiety is attached to the parent molecule through the alkyl group.

[0038] The term "heteroaralkyl" or "heteroarylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through an alkyl group.

[0039] The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0040] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0041] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein, represented by -C(=O)-. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0042] The term "alkylcarbonyl," as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0043] The term "arylcarbonyl," as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0044] The terms "alkylcarbonyloxy" and "arylcarbonyloxy" as used herein mean an alkylcarbonyl group or an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to, phenylcarbonyloxy.

[0045] The terms "alkenoxy" or "alkenoxyl" mean an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propene-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-).

[0046] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0047] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0048] The term "carbocyclyl," as used herein, means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms and being fully saturated or having one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0049] The term "cyano" is a term of art and as used herein refers to --CN.

[0050] The term "halo" is a term of art and as used herein refers to -F, -Cl, -Br, or -I.

[0051] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with halogen atoms.

[0052] The term "hydroxy" is a term of art and as used herein refers to --OH.

[0053] The term "hydroxyalkyl," as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0054] The term "silyl," as used herein, includes hydrocarbyl derivatives of the silyl (HSi-) group (i.e., (hydrocarbyl)Si-), where the hydrocarbyl group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl group may be a combination of different groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM), and can be varied to provide multiple silyl groups.

[0055] The term "silyloxy" as used herein means a silyl group, as defined herein, appended to the parent molecule through an oxygen atom.

[0056] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis and trans isomers, (R) and (S) enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0057] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0058] It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the valences allowed for the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0059] The term "substituted" is also contemplated to include all permissible substituents of organic compounds. Broadly speaking, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for suitable organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0060] In certain embodiments, optional substituents contemplated by the present invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl, sulfonamide, ketone (e.g., -CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano.

[0061] As used herein, the terms "optionally substituted" or "substituted or unsubstituted," when preceding a list of chemical moieties, mean that the following list of chemical moieties is substituted or unsubstituted, respectively. For example, "substituted or unsubstituted aryl, heteroaryl, and cycloalkyl" or "optionally substituted aryl, heteroaryl, and cycloalkyl" means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0062] The term "vicinal" refers to the positional relationship between two substituents, moieties, or functional groups, each of which is bonded to one of two adjacent carbon atoms that are bonded to each other (i.e., the two substituents, moieties, or functional groups are in a 1,2-relationship). The methyl groups in 3,4-dimethylheptane are vicinal.

[0063] The term "geminal" describes the positional relationship between two substituents, moieties, or functional groups that are attached to the same carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,1-relationship). The methyl groups in 3,3-dimethylheptane are geminal.

[0064] The term "hominal" describes the positional relationship between two substituents, moieties, or functional groups, each of which is bonded to one of two carbon atoms that are themselves each bonded to a single carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,3-relationship). The methyl group in 3,5-dimethylheptane is hominal.

[0065] As used herein, the phrase "protecting group" refers to temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals of aldehydes and ketals of ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGMP Protective Groups in Organic Synthesis, 2004). nd ed.; Wiley: New York, 1991) Protected forms of the compounds of the invention are included within the scope of the invention.

[0066] For purposes of this invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover).

[0067] Other chemical terms herein are used in accordance with conventional usage in the art as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0068] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of salt-containing molecules is not 1:1. For example, a salt may contain multiple inorganic or organic acid molecules per molecule of base, such as two hydrochloric acid molecules per molecule of the compound of Formula I. As another example, a salt may contain less than one inorganic or organic acid molecule per molecule of base, e.g., two molecules of the compound of Formula I per molecule of tartaric acid.

[0069] The term "prodrug," as used herein, refers to a compound that can be metabolized in vivo to provide a compound of Formula I. Thus, prodrugs include compounds that can be prepared by modifying one or more functional groups in a compound of Formula I to obtain a corresponding compound that can be metabolized in vivo to provide a compound of Formula I. Such modifications are known in the art. For example, one or more hydroxyl or amine groups in a compound of Formula I can be acylated with an alkyl-C(=O)- group or the residue of an amino acid to obtain a prodrug.

[0070] Prodrug forms of compounds with various nitrogen-containing functional groups (amino, hydroxyamino, amide, etc.) may include the following types of derivatives, where each R p The groups may individually be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, arylalkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl. (a)-NHC(O)R p Carboxamide represented by (b)-NHC(O)OR p Carbamates represented by (c)NHC(O)OROC(O)R p (Acyloxy) alkyl carbamates represented by the formula: (d)-NHCR(=CHCO2R p ) or -NHCR(=CHCONR p R p ) enamine (e)-N=CR p R p A Schiff base represented by (f)RCONHCH2NR p R p Mannich bases (derived from carboximide compounds) represented by

[0071] The preparation of such prodrug derivatives is discussed in various publications (eg Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO0041531, p. 30).

[0072] Prodrug forms of carboxyl-containing compounds are esters (-COR m ), where R m The group corresponds to any alcohol, and the alcohol released into the body via an enzymatic or hydrolytic process is at a pharmaceutically acceptable level. Another prodrug derived from the carboxylic acid form of the present disclosure can be a quaternary salt type structure as described by Bodor et al., J. Med. Chem. 1980, 23, 469.

[0073] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle that is administered with or formulated for administration with a compound. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oil, and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, and urea. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may also be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin (incorporated herein in its entirety by reference).

[0074] As used herein, the term "treating" means preventing, halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" means halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" means reducing at least one objective manifestation of a disease or condition in a subject.

[0075] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0076] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired therapeutic effect.

[0077] As used herein, the term "inhibit" refers to a reduction in an objectively measurable amount or extent. In various embodiments, "inhibit" refers to a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, "inhibit" refers to a 100 percent reduction, i.e., cessation or elimination.

[0078] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0079] compound The present invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts thereof: [ka] wherein, independently for each occurrence: X is a bond or C(R X )2, Y is a bond, C(R Y )2, or -N(R b )- and G is S or C(R 3 )2, R a and R b are each independently H or (C1-C6) alkyl; R 1 represents an optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl; R 2 represents an optionally substituted bicyclic or tricyclic heteroaryl; R 3 is independently at each occurrence H, halogen, —CN, —NH, —CHNH, (C-C)alkoxy, or (C-C)alkyl, or R 3 two vicinal occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted fused (C-C)cycloalkyl or (C)aryl, or R 3 two geminal occurrences of, taken together with the carbon atoms to which they are attached, form an optionally substituted spiro(C-C)cycloalkyl, or R 3two homonymous occurrences of together with the carbon atoms to which they are attached form an optionally substituted bridged (C-C)cycloalkyl; R X is independently at each occurrence H, (C-C) alkyl, or (C-C) cycloalkyl; R Y is independently at each occurrence H, (C1-C6) alkyl, or (C3-C7) cycloalkyl; Or, R Y The existence of R 2 and the above substituents together with the intervening atoms form a ring, R 1 or R 2 The optional substituents above are each independently selected from halogen, -CN, -NO2, -OR 13 , -NR 13 R 14 , -C(O)R 13 , -C(O)OR 13 , -C(O)NR 13 R 14 , -OC(O)R 13 , -NR 13 C(O)R 14 , -OC(O)NR 13 R 14 , -OC(O)OR 13 , -NR 13 C(O)OR 14 , -NR 13 C(O)NR 13 R 14 , -OS(O) p (R 13 ), -SR 13 , -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; Or, R 1The above two substituents or R 2 two substituents form a ring together with the intervening atoms, R 13 and R 14 represents independently at each occurrence H or an optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; p is 0, 1, or 2].

[0080] In certain embodiments, Y is C(R Y )2, preferably CH2.

[0081] In certain embodiments, X represents a bond. Alternatively, X may represent CH.

[0082] In certain embodiments, R 1 represents an optionally substituted aryl or heteroaryl. In some embodiments, R 1 is an optionally substituted heteroaryl. 1 Exemplary embodiments of include optionally substituted phenyl (e.g., 3-halophenyl, or 2,3-dihalophenyl), (C3-C6)cycloalkyl, alkenyl, pyridinyl (e.g., 6-halopyridin-2-yl), or pyrazinyl (e.g., 6-halopyrazin-2-yl).

[0083] In certain embodiments, R 1 is mono-, di-, or tri-substituted.

[0084] In certain embodiments, R 1 represents optionally substituted pyridinyl, preferably optionally substituted 2-pyridinyl. For example, R 1 teeth, [ka] can be represented as:

[0085] In other embodiments, R 1 represents an optionally substituted phenyl. For example, R 1 teeth, [ka] can be represented as:

[0086] In certain embodiments, R 2 teeth, [ka] represents Z 1 But N or CR 1Z represents Z 2 But N or CR 2Z represents Z 3 represents N or C, Z 4 But N or CR 4Z represents Z 5 But N or CR 5Z represents Z 6 But N or CR 6Z represents Z 7 But N or CR 7Z represents Z 8 represents C, Z 9 represents N or C, k is an integer from 1 to 4, m is an integer from 1 to 3, R 1Z , R 2Z , R 4Z , R 5Z , R 6Z , R 7Z , R 2A Each occurrence of is independently H, halogen, -CN, -NO2, -OR 13 , -NR 13 R 14 , -C(O)R 13 , -C(O)OR 13 , -C(O)NR13 R 14 , -OC(O)R 13 , -NR 13 C(O)R 14 , -OC(O)NR 13 R 14 , -OC(O)OR 13 , -NR 13 C(O)OR 14 , -NR 13 C(O)NR 13 R 14 , -OS(O) p (R 13 ), -SR 13 , -NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; R 6Z The existence of R 7Z The presence of forms a ring together with the intervening atoms, or R Y The existence of R 2Z The presence of forms a ring together with the intervening atoms.

[0087] In certain embodiments, Z 2 , Z 3 , Z 4 , and Z 6 represents N.

[0088] In certain embodiments, Z 3 , Z 4 , and Z 6 represents N.

[0089] In certain embodiments, Z 9 , Z 4 , and Z 6 represents N.

[0090] In certain embodiments, Z 3 and Z 4 represents N.

[0091] In certain embodiments, Z 1 , Z 3 , Z 4 , and Z 6 represents N.

[0092] In certain embodiments, R 2 teeth, [ka] For example, R 2 teeth, [ka] In some embodiments, k is 2.

[0093] In certain embodiments, R 2 teeth, [ka] Represents.

[0094] In certain embodiments, R 2 teeth, [ka] Represents.

[0095] In certain embodiments, R 2 teeth, [ka] for example, [ka] Represents.

[0096] In certain embodiments, R 2 teeth, [ka] Represents.

[0097] In certain embodiments, R 2 teeth, [ka] for example, [ka] Represents.

[0098] In certain embodiments, R 7Z is -NR 13 R 14 , for example, -NH2.

[0099] In certain embodiments, R 6Z is -C(O)R 13 , -C(O)OR 13 , -C(O)NR 13 R 14 , or hydroxyalkyl.

[0100] In certain embodiments, R 5Z is alkyl, halo, or -NR 13 R 14 Represents.

[0101] In certain embodiments, R 1Z is —CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, —C(O)R 13 , -SR 13 , -NR 13 R 14 , -OR 13 , -C(O)OR 13 , -C(O)NR 13 R 14 , or -NR 13 C(O)R 14 Represents.

[0102] In certain embodiments, R 2A each occurrence is independently selected from -CN, -NO, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, -C(O)R 13 , -C(O)OR 13 , -NR 13 C(O)OR 14 , -SR 13 , -NR 13 R 14 , -OR 13 , -C(O)NR 13 R 14 , or -NR 13 C(O)R 14 Represents.

[0103] In certain embodiments, G is C(R 3 )2.

[0104] In certain embodiments, compounds of the invention have the structure of Formula (Ia): [ka]

[0105] In certain embodiments, R 3 two vicinal occurrences of together with the carbon atoms to which they are attached form an optionally substituted fused C3-cycloalkyl.

[0106] In certain embodiments, R 3 At least one occurrence of is halo, preferably fluoro.

[0107] In certain embodiments, R 3 At least one occurrence of is methyl.

[0108] In certain embodiments, R 3two vicinal occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted fused C3-cycloalkyl, and R 3 Another occurrence of is methyl.

[0109] In certain embodiments, the compound of formula (I) is selected from the following table of compounds and pharmaceutically acceptable salts thereof: JPEG2026009184000019.jpg180164JPEG2026009184000020.jpg176164JPEG2026009184000021.jpg182164JPEG2026009184000022.jpg181164JPEG2026009184000023.jpg183164JPEG2026009184000024.jpg174164JPEG2026009184000025.jpg180164JPEG2026009184000026.jpg194164JPEG2026009184000027.jpg190164JPEG2026009184000028.jpg191164JPEG2026009184000029.jpg190164JPEG2026009184000030.jpg190164JPEG2026009184000031.jpg183164JPEG2026009184000032.jpg190164JPEG2026009184000033.jpg184164JPEG2026009184000034.jpg143164JPEG2026009184000035.jpg161164JPEG2026009184000036.jpg159164JPEG2026009184000037.jpg148164JPEG2026009184000038.jpg204164JPEG2026009184000039.jpg180164JPEG2026009184000040.jpg148164JPEG2026009184000041.jpg194164JPEG2026009184000042.jpg191164JPEG2026009184000043.jpg195164JPEG2026009184000044.jpg189164JPEG2026009184000045.jpg195164JPEG2026009184000046.jpg192164JPEG2026009184000047.jpg183164JPEG2026009184000048.jpg192164JPEG2026009184000049.jpg159164JPEG2026009184000050.jpg167164JPEG2026009184000051.jpg196164JPEG2026009184000052.jpg168164JPEG2026009184000053.jpg193164JPEG2026009184 000054.jpg198164JPEG2026009184000055.jpg191164JPEG2026009184000056.jpg203164JPEG2026 009184000057.jpg155164JPEG2026009184000058.jpg163164JPEG2026009184000059.jpg159164J PEG2026009184000060.jpg169164JPEG2026009184000061.jpg157164JPEG2026009184000062.jpg1 61164JPEG2026009184000063.jpg150164JPEG2026009184000064.jpg158164JPEG20260091840000 65.jpg192164JPEG2026009184000066.jpg150164JPEG2026009184000067.jpg166164JPEG20260091 84000068.jpg175164JPEG2026009184000069.jpg195164JPEG2026009184000070.jpg151164JPEG20 26009184000071.jpg194164JPEG2026009184000072.jpg195164JPEG2026009184000073.jpg58164.

[0110] Pharmaceutical Composition The present invention provides pharmaceutical compositions, each comprising one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises multiple compounds of the present invention, which may include a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0111] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compound of the present invention, which may be an agent useful in the treatment of a disease or condition characterized by abnormal complement system activity.

[0112] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0113] How to use The present invention provides compounds and pharmaceutically acceptable salts thereof that are useful for treating or preventing diseases or conditions characterized by abnormal complement system activity.

[0114] In certain aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0115] In certain aspects, the present invention provides a method for treating or preventing a disease or condition characterized by abnormal complement system activity. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the disease or condition characterized by abnormal complement system activity. By reducing the subject's complement system activity, the disease or condition characterized by abnormal complement system activity is treated.

[0116] Alternatively, in certain aspects, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition characterized by abnormal complement system activity.

[0117] Alternatively, in certain aspects, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of a disease or condition characterized by abnormal complement system activity.

[0118] As used herein, a "disease or condition characterized by abnormal complement system activity" refers to any disease or condition in which it is desirable to reduce complement system activity. For example, it may be desirable to reduce complement system activity in situations of inappropriate or excessive activation of the complement system.

[0119] In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immunological disorder.

[0120] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

[0121] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

[0122] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a kidney disease.

[0123] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

[0124] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiometabolic disease.

[0125] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposition disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

[0126] In certain embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

[0127] In certain embodiments, the disease or condition is atypical hemolytic uremic syndrome.

[0128] In certain embodiments, the disease or condition is organ transplant rejection.

[0129] In certain embodiments, the disease or condition is myasthenia gravis.

[0130] In certain embodiments, the disease or condition is neuromyelitis optica.

[0131] In certain embodiments, the disease or condition is membranoproliferative glomerulonephritis.

[0132] In certain embodiments, the disease or condition is densitosis.

[0133] In certain embodiments, the disease or condition is cold agglutinin disease.

[0134] In certain embodiments, the disease or condition is fulminant antiphospholipid syndrome.

[0135] In other embodiments, the disease or condition characterized by abnormal complement system activity is adult respiratory distress syndrome, myocardial infarction, pneumonia, hyperacute rejection (transplant rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barré syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, organ rejection (transplant), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis.

[0136] In other embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

[0137] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a hematological disorder.

[0138] In another embodiment, the disease or condition characterized by abnormal complement system activity is an ocular disorder or eye disorder.

[0139] In certain embodiments, the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye, Fuchs' endothelial dystrophy, retinal vein occlusion, or post-surgical inflammation.

[0140] In certain embodiments, the disease or condition characterized by abnormal complement system activity is angioedema, eg, hereditary angioedema or acquired angioedema.

[0141] In certain embodiments, the disease or condition characterized by abnormal complement system activity is obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, or neuropathy.

[0142] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy.

[0143] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of Alzheimer's disease, multiple sclerosis, neuromyelitis optica, generalized myasthenia gravis, Guillain-Barré syndrome, Parkinson's disease, and schizophrenia.

[0144] In certain embodiments, the disease or condition characterized by abnormal complement system activity is periodontitis.

[0145] In certain embodiments, the disease or condition characterized by abnormal complement system activity is Crohn's disease.

[0146] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.

[0147] In certain embodiments, the disease or condition characterized by abnormal complement system activity is atherosclerosis.

[0148] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of age-related macular degeneration (AMD), uveitis, glaucoma, and wet AMD.

[0149] In certain embodiments, the disease or condition characterized by abnormal complement system activity is myocardial infarction.

[0150] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of atypical hemolytic uremic syndrome, C3 nephropathy, lupus nephritis, IgA nephropathy, and membranous nephropathy.

[0151] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of rheumatoid arthritis, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, and burns.

[0152] In certain embodiments, the disease or condition characterized by abnormal complement system activity is hemodialysis.

[0153] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of ischemia / reperfusion injury, acute kidney injury, and organ transplantation, eg, kidney transplantation.

[0154] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of systemic inflammatory response syndrome, sepsis, septic shock, trauma, systemic lupus erythematosus, hereditary angioedema, and cancer.

[0155] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antibody-mediated rejection, antiphospholipid anti-inflammatory syndrome, Buerger's disease, C3 glomerulonephritis, cold agglutinin disease, cardiopulmonary bypass, dense deposition disease, delayed onset of allograft function, geographic atrophy, granulomatosis with polyangiitis, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangiitis, pyoderma gangrenosum, Stargardt's disease 1, and warm autoimmune hemolytic anemia.

[0156] Formulation, Route of Administration, and Administration The compounds of the present invention, and pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms compatible with the chosen route of administration, for example, orally or parenterally, by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the present invention.

[0157] Thus, the compounds may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentage of the compositions and preparations may vary and may conveniently be about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0158] Tablets, troches, pills, capsules, etc. may also contain the following diluents and carriers: binders, such as tragacanth gum, acacia, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as peppermint, wintergreen oil, and cherry flavoring. When the unit dosage form is a capsule, in addition to the above-mentioned materials, it may contain liquid carriers such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or otherwise be present to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, etc. Syrup or elixir may contain active compound, sucrose or fructose as sweetener, methyl and propylparaben as preservative, dye, and flavoring agent, for example, cherry or orange flavor.Of course, any material used to prepare any unit dosage form must be pharmaceutically acceptable and substantially non-toxic in the amount used.In addition, active compound can be incorporated into sustained-release preparations and devices.

[0159] Active compound can also be administered intravenously or intraperitoneally by infusion or injection.The solution of active compound or its salt can be prepared in water or physiologically acceptable aqueous solution, and optionally can be mixed with non-toxic surfactant.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, triacetin and its mixture, and oil.These preparations contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0160] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally containing the active ingredient encapsulated in liposomes. In all cases, the final dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage. Liquid carriers or vehicles can be solvents or liquid dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by the formation of liposomes, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0161] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients as listed above, as needed, and then filtering and sterilizing. In the case of sterile powders for preparing sterile injectable solutions, the preparation method can include vacuum drying and freeze-drying techniques, which yields a powder of the active ingredient and any additional desired ingredients that are present in a previously sterile-filtered solution.

[0162] For topical administration, the compounds can be applied in pure form (i.e., when they are liquids), however, it is generally desirable to administer the compounds to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which can be solid or liquid.

[0163] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol, or glycol, or water-alcohol / glycol blends, in which the compound can be dissolved or dispersed at effective concentrations, optionally with the use of nontoxic surfactants. Adjuvants such as fragrances and additional antibacterial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-action or aerosol sprayers.

[0164] Thickening agents such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified cellulose or modified inorganic materials may also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps and the like for direct application to the user's skin.

[0165] Examples of useful dermatological compositions that can be used to deliver the compounds of the present invention to the skin are known in the art; see, e.g., Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; ​​incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

[0166] The useful dosage of the compound of the present invention can be determined at least initially by comparing in vitro activity and in vivo activity in animal model.The method for extrapolating the effective dosage of mice and other animals to humans is known in the art.See, for example, U.S. Patent No. 4,938,949 (incorporated herein by reference).

[0167] The amount of the compound or pharmaceutically acceptable salt thereof required for therapeutic use will vary not only with the particular compound or salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.

[0168] In general, however, suitable dosages will be in the range of about 0.5 to about 100 mg / kg body weight of the recipient per day, e.g., about 3 to about 90 mg / kg body weight per day, about 6 to about 75 mg per kilogram of body weight per day, about 10 to about 60 mg / kg body weight per day, or about 15 to about 50 mg / kg body weight per day.

[0169] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be conveniently formulated in unit dosage form, for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated in such unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses to be administered at appropriate intervals, e.g., two, three, four, or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of individual loosely spaced administrations.

[0170] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can also be administered in combination with other therapeutic agents, such as other agents useful for treating or preventing ischemia, blood loss, or reperfusion injury. In certain embodiments, the compounds of the present invention, and pharmaceutically acceptable salts thereof, can also be administered in combination with one or more other therapeutic agents useful for treating or preventing ocular disorders or ocular disorders.

[0171] Other delivery systems may include sustained-release, delayed-release, or sustained-release delivery systems, as are well known in the art. Such systems may avoid repeated administration of active compounds, which increases the convenience of patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. The use of long-term sustained-release implants may be desirable. Long-term release, as used herein, means that the delivery system or implant is constructed and arranged to deliver therapeutic concentrations of the active ingredient for at least 30 days, preferably 60 days.

[0172] In certain embodiments, the compounds of the present invention are formulated for intraocular administration, for example, by direct injection or insertion into or in connection with a medical device in the eye. In certain embodiments, the compounds of the present invention are formulated as eye drops. In certain embodiments, the compounds of the present invention can be administered via ocular delivery, for example, by local administration to the eye, including topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, suprachoroidal, or subtenon administration. The compounds of the present invention can be administered via ocular delivery, either alone or in combination with one or more additional therapeutic agents.

[0173] The compounds of the present invention can be formulated for attachment within a medical device, which can include a variety of conventional grafts, stents, including stent-grafts, catheters, balloons, baskets, or any other device that can be placed or permanently implanted within a body lumen. In certain instances, it is desirable to have devices and methods that can deliver the compounds of the present invention to a body region being treated by an interventional technique.

[0174] In an exemplary embodiment, the compounds of the invention can be deposited within a medical device, such as a stent, and delivered to a treatment site for treatment of a body part.

[0175] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral arteries. Stent designs include those in U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor). Such designs include both metallic and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver drugs to sites of contact with the vascular system, as disclosed, for example, in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and International Patent Applications WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center).

[0176] The term "deposited" means that the compound is coated, adsorbed, positioned, or otherwise incorporated into the device by methods known in the art. For example, the compound may be embedded and released from within a polymeric material ("matrix-type"), or may be surrounded and released from a polymeric material ("reservoir-type") that coats or contains the medical device. In the latter example, the compound may be entrapped within the polymeric material or bound to the polymeric material using one or more techniques for producing such materials known in the art. In other formulations, the compound may be bound to the surface of the medical device without the need for a coating, e.g., by a detachable bond, and released over time, or may be removed by aggressive mechanical or chemical processes. In other formulations, the compound may be in a permanently immobilized form, providing the compound at the implantation site.

[0177] In certain embodiments, the compounds may also be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices such as stents. The coatings produced from these components are typically homogeneous and useful for coating many devices designed for implantation.

[0178] The polymer can be either a biostable polymer or a bioabsorbable polymer, depending on the desired release rate or the degree of polymer stability desired, although bioabsorbable polymers are often preferred for this embodiment because, unlike biostable polymers, they do not persist long after implantation and do not cause any adverse chronic local reactions. Bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoesters, polyphosphoric acid, and polyisopropyl esters. Examples of suitable bioabsorbable polymers include, but are not limited to, ester urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), copoly(ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art.Biostable polymers with relatively low chronic tissue response, such as polyurethanes, silicones, and polyesters, can also be used, as can other polymers such as polyolefins, polyisobutylene, and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers, and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers. olefin copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymers; polyhydroxypropyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose can also be used if they can be dissolved and cured or polymerized on the medical device.

[0179] The polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubing, prostheses, and the like.

[0180] In certain embodiments of the present invention, the compounds of the present invention are bound to a polymer or semipermeable polymer matrix formed into a stent or stent-graft device.

[0181] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be used for this purpose. Spraying methods include conventional methods as well as microdeposition techniques using inkjet-type dispensers. Additionally, the polymer can be deposited onto the implantable device using photopatterning, which places the polymer only on specific portions of the device. This coating of the device provides a uniform layer around the device, allowing for improved diffusion of various analytes through the device coating.

[0182] In certain embodiments of the present invention, the compound is formulated to be released from the polymer coating into the environment in which the medical device is placed. Preferably, the compound is released in a controlled manner over an extended time frame (e.g., several months) using at least one of several well-known techniques for polymeric carriers or layers that control elution. Some of these techniques are described in U.S. Patent Application No. 2004 / 0243225A1, the entire disclosure of which is incorporated herein by reference in its entirety.

[0183] Additionally, the reagents and reaction conditions of the polymer composition can be manipulated to thereby control the release of a compound from the polymer coating, as described, for example, in U.S. Pat. No. 6,770,729 (incorporated herein in its entirety). For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of a compound from the polymer coating. In a variation on this theme, the diffusion coefficient of one or more polymer coatings can be controlled to adjust the ability of an analyte present in the environment in which the medical device is placed (e.g., an analyte that promotes the breakdown or hydrolysis of a portion of the polymer) to access one or more components within the polymer composition (and thereby, for example, adjust the release of a compound from the polymer coating). Yet another embodiment of the present invention includes a device having multiple polymer coatings, each with multiple diffusion coefficients. In such an embodiment of the present invention, the release of a compound from the polymer coating can be adjusted by the multiple polymer coatings.

[0184] In yet another embodiment of the present invention, the release of the compound from the polymer coating is controlled by the presence of one or more endogenous or exogenous compounds, or alternatively by adjusting one or more properties of the polymer composition, such as the pH of the polymer composition. For example, certain polymer compositions can be designed to release the compound in response to a decrease in the pH of the polymer composition.

[0185] kit The present invention also provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent(s) to a mammal to treat or prevent a disease or condition characterized by abnormal complement activity. In one embodiment, the mammal is a human.

[0186] It will be appreciated by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and can be made without departing from the scope of the invention or any embodiment thereof. [Example]

[0187] Having now described the invention in detail, the same will be more clearly understood by reference to the following examples, which are included herein for purposes of illustration only and are not intended to limit the invention.

[0188] Scheme 1 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (1e) Step 1: Preparation of tert-butyl 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (1b) A mixture of 9H-pyrimido[4,5-b]indol-4-amine (1a) (0.50 g, 2.71 mmol; CAS#400754-64-5), tert-butyl 2-bromoacetate (0.582 g, 2.99 mmol), and CsCO (1.061 g, 3.26 mmol) in DMF (20 mL) was stirred at room temperature for 3 h, diluted with HO (30 mL), and extracted with EtOAc (30 mL × 3). The combined organics were washed with HO (30 mL × 4), brine (30 mL), dried, filtered, concentrated in vacuo, and purified by flash column chromatography [silica gel (24 g), eluted with MeOH (0–3%) in DCM] to give tert-butyl 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (1b) (0.64 g, 79% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J = 7.8 Hz, 1H), 8.29 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.3, 7.1 Hz, 1H), 7.35 - 7.18 (m, 3H), 5.12 (s, 2H), 1.41 (s, 9H).

[0189] Step 2: Preparation of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) tert-Butyl 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate 1b (0.63 g, 2.112 mmol) and 2,2,2-trifluoroacetic acid (12.12 mL, 31.7 mmol) in DCM (20 mL) were stirred at room temperature for 16 h and concentrated to dryness in vacuo to give 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid 1c (0.74 g, 99%) TFA salt as an orange slide. 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.43 - 8.20 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 5.26 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -74.71.

[0190] Step 3: Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (1e) To a solution of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (50.7 mg, 0.142 mmol) TFA salt, (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (1d) HCl salt [(43 mg, 0.129 mmol); prepared according to the procedure reported in Wiles, Jason A. et al., PCT International Application (2017), WO2017035353A1 20170302 (incorporated by reference)], and HATU (59.0 mg, 0.155 mmol) in DMF (5 mL), DIPEA (84 mg, 0.646 mmol) was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (20 mL x 2). The combined organics were washed with 0.5 M NaOH (25 mL), HO (25 mL x 3), brine (25 mL), dried, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] to give the product as a pale oil, which was dissolved in MeOH (5 mL) and purified by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (containing 0.1% HCl) in water (0-60%)] to give (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido)[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (1e) (48 mg, 71% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H, D2O exchangeable), 8.83 - 8.59 (m, 3H, 2H D2O exchangeable), 8.54 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (m, 2H), 5.75 (d, J = 17.5 Hz, 1H), 5.47 (d, J = 17.3 Hz, 1H), 4.39 (dd, J = 9.1, 5.1 Hz, 1H), 3.93 - 3.86 (m, 1H), 2.41 (m, 1H), 2.27 (m, 1H), 1.99 (s, 4H), 1.11 (m, 1H), 0.82 (m, 1H);MS (ES+): 520.0 (M+1);(ES-): 518.0 (M-1);C 24 H 22 Analysis calculated for BrNO.sub.2.1.1HCl.sub.2.5H.sub.2O: C, 47.60; H, 4.68; Cl, ​​6.44; N, 16.19; Found: C, 47.57; H, 4.60; Cl, ​​6.33; N, 16.19.

[0191] Scheme 2 [ka] Preparation of (1R,3S,5R)-2-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (2d) Step 1: Preparation of tert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetate (2b) To a suspension of zinc (1.842 g, 28.2 mmol) (Note: zinc dust was activated using 0.1 M aqueous HCl, washed thoroughly with HO, EtOH, and EtO, and dried under vacuum at 100 °C prior to use) and TMSCl (0.179 mL, 1.408 mmol) in THF (5 mL) at 50 °C under an argon atmosphere was added tert-butyl 2-bromoacetate (2.75 g, 14.08 mmol) in THF (5 mL) dropwise. The mixture was heated at 50 °C for 30 min, cooled to room temperature, and added via syringe to a suspension of 7-bromopyrrolo[1,2-f][1,2,4]triazin-4-amine (2a) (1.00 g, 4.69 mmol; CAS#937046-98-5), Pd(dba) (0.215 g, 0.235 mmol), and XPhos (0.224 g, 0.469 mmol) in THF (10 mL) at room temperature under an argon atmosphere and heated at 60 °C for 16 h under argon. The reaction mixture was cooled to room temperature with EtOAc (30 mL), solid NHCl (2 g) was added, stirred at room temperature for 15 min, and filtered to remove insoluble solids. The insoluble residue was washed with EtOAc (20 mL), and the filtrate was washed with saturated NH4Cl (30 mL), HO (30 mL), brine (30 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [SiO2 gel (24 g), eluted with 0–50% EtOAc in hexanes] to afford tert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetate (2b) (0.65 g, 56% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.66 (s, 2H), 6.83 (d, J = 4.3 Hz, 1H), 6.52 (d, J = 4.3 Hz, 1H), 3.84 (s, 2H), 1.40 (s, 9H);MS (ES+): 249 (M+1), (ES-): 247 (M-1).

[0192] Step 2: Preparation of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetic acid (2c) Compound 2c was prepared from tert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetate 2b (0.65 g, 2.62 mmol) using TFA (4.01 mL, 52 mmol) in DCM (20 mL) and stirring at room temperature for 16 hours according to the procedure reported in Step 4 of Scheme 1. The reaction mixture was concentrated in vacuo to give 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetic acid 2c (1.05 g) TFA salt as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (dd, J = 5.7, 2.9 Hz, 1H), 9.11 (s, 1H), 8.18 (s, 1H), 7.37 (d, J = 4.6 Hz, 1H), 6.80 (d, J = 4.5 Hz, 1H), 3.96 (s, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -74.71; MS (ES+): 193 (M+1), (ES-): 191 (M-1).

[0193] Step 3: Preparation of (1R,3S,5R)-2-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (2d) Compound 2d was prepared from the TFA salt of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetic acid (2c) (54.7 mg, 0.179 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (1d) (54 mg, 0.162 mmol), HATU (74.1 mg, 0.195 mmol), DIPEA (105 mg, 0.812 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (1R,3S,5R)-2-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (2d) (20 mg, 26% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (containing 0.1% HCl) in water (0-60%)]. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H, D2O exchangeable), 10.01 (s, 1H, D2O exchangeable), 9.21 (s, 1H, D2O exchangeable), 8.20 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 4.38 (dd, J = 9.1, 5.2 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 17.0 Hz, 1H), 3.68 - 3.66 (m, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.07 (s, 3H), 1.92 - 1.77 (m, 1H), 0.96 (m, 1H), 0.62 (m, 1H);MS (ES+): 470.0 (M+1), (ES-): 468.0 (M-1).

[0194] Scheme 3 [ka] Preparation of (2S,4R)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (3b) Following the procedure reported in Step 3 of Scheme 1, the HCl salt of (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (3a) [(143 mg, 0.421 mmol); Wiles, Jason A. et al., PCT International Application (2017), WO2017035355A1 Compound 3b was prepared from the TFA salt of (2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (150 mg, 0.421 mmol) in DMF (5 mL) using HATU (192 mg, 0.505 mmol), DIPEA (272 mg, 2.105 mmol), and stirring at room temperature for 16 h. This allowed for easy workup and After purification by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (containing 0.1% HCl) in water (0–60%)], (2S,4R)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (3b) (123 mg, 56% yield) HCl salt was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ (two rotor mix) 10.92 (s) and 10.48 (s) (2s, 1H, DO interchangeable), 8.73 (s, 3H, DO interchangeable), 8.62 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 - 7.49 (m, 2H), 7.43 (t, J = 7.9 Hz, 2H), 5.67 (d, J = 4.0 Hz, 1H), 5.63 - 5.45 (m, 1H), 5.37 (d, J = 17.3 Hz, 1H), 4.57 (t, J = 9.4, 7.6 Hz, 1H), 4.48 - 4.23 (m, 1H), 4.20 - 3.95 (m, 1H), 2.79 - 2.49 (m, 4H), 2.32 - 2.05 (m, 1H); 19F NMR (282 MHz, DMSO-d6) δ -176.05, -176.37;MS (ES+): 526.0 (M+1), 524.0 (M-1);C 23 H 21 Analysis calculated for BrFN7O2.HCl 2.75H2O: C, 45.11; H, 4.53; Cl, ​​5.79; N, 16.01; Found: C, 45.12; H, 4.29; Cl, ​​5.71; N, 15.84.

[0195] Scheme 4 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4b) Following the procedure reported in Step 3 of Scheme 1, the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) [(134 mg, 0.421 mmol); Altmann, Eva et al., PCT International Application (2012), WO2012093101A1] was prepared. Compound 4b was prepared from the TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (150 mg, 0.421 mmol) in DMF (5 mL) using HATU (192 mg, 0.505 mmol), DIPEA (272 mg, 2.105 mmol), and stirring at room temperature for 16 h. This gave (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4b) (110 mg, 52% yield) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.63 (m, 3H, 2H D2O exchangeable), 8.53 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 17.3 Hz, 1H), 4.43 (dd, J = 9.0, 5.5 Hz, 1H), 3.93 (m, 1H), 2.44 - 2.16 (m, 2H), 2.01 - 1.86 (m, 1H), 1.08 (m, 1H), 0.78 (m, 1H);MS (ES+) 506.0 (M+1);(ES-): 504.0 (M-1);C 23 H 20 Analysis calculated for BrNO.HCl.2.25H.sub.2O: C, 47.36; H, 4.41; Cl, ​​6.08; N, 16.81; Found: C, 47.25; H, 4.18; Cl, ​​6.02; N, 16.70.

[0196] Scheme 5 [ka] Preparation of (2S,4R)-1-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5e) Step 3: Preparation of tert-butyl 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (5b) Compound 5b was prepared from 7H-pyrrolo[2,3-d]pyrimidin-4-amine (5a) (1.0 g, 7.45 mmol; CAS#1500-85-2) in DMF (20 mL) using tert-butyl 2-bromoacetate (1.600 g, 8.20 mmol), CsCO (2.91 g, 8.95 mmol), and stirring at room temperature for 3 h, according to the procedure reported in Scheme 1, Step 1. After workup and purification by flash column chromatography [silica (24 g), eluting with MeOH (0–3%) in DCM], tert-butyl 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (5b) (0.62 g, 34% yield) was obtained as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.12 (d, J = 3.5 Hz, 1H), 6.99 (s, 2H), 6.54 (d, J = 3.5 Hz, 1H), 4.86 (s, 2H), 1.41 (s, 9H);MS (ES+): 249 (M+1).

[0197] Step 4: Preparation of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) Compound 5c was prepared from tert-butyl 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate 5b (0.62 g, 2.497 mmol) using TFA (19.11 mL, 49.9 mmol) in DCM (20 mL) and stirring at room temperature for 16 hours according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid 5c (1.42 g) TFA salt as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 2H), 8.39 (s, 1H), 7.50 (d, J = 3.5 Hz, 1H), 6.93 (d, J = 3.5 Hz, 1H), 5.05 (s, 2H);MS (ES+): 193 (M+1);(ES-): 191 (M-1).

[0198] Step 5: Preparation of (2S,4R)-1-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5e) Compound 5e was prepared from the TFA salt of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (137 mg, 0.448 mmol) in DMF (5 mL) using the procedure reported in Scheme 1, Step 3: (2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5d) TFA salt [(150 mg, 0.373 mmol); prepared according to the procedure reported in Wiles, Jason A. et al., PCT International Application (2017), WO2017035348A1 20170302 (incorporated by reference)], HATU (170 mg, 0.448 mmol), DIPEA (241 mg, 1.865 mmol), and stirring at room temperature for 16 hours. This gave (2S,4R)-1-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5e) (84 mg, 49% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ (two rotor mixture) 11.36 (s) and 11.03 (s) (2s, 1H, DO interchangeable), 9.22 (s, 2H, DO interchangeable), 8.36 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 3.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 3.5 Hz, 1H), 5.66 - 5.39 (m, 1H), 5.33 (d, J = 17.1 Hz, 1H), 5.18 (d, J = 17.1 Hz, 1H), 4.65 (t, J = 8.5 Hz, 1H), 4.26 - 4.06 (m, 1H), 3.89 (ddd, J = 38.2, 12.2, 3.0 Hz, 1H), 2.63 - 2.43 (m, 1H), 2.25 - 1.95 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -175.70, -175.96;MS (ES+): 462.0 (M+1), 460.0 (M-1);C 18 H 17 Analysis calculated for BrFN7O2.HCl.2H2O: C, 40.43; H, 4.15; Cl, ​​6.63; N, 18.33; Found: C, 40.19; H, 3.86; Cl, ​​6.98; N, 17.96.

[0199] Scheme 6 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (6e) Step 1: Preparation of 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b) To a solution of triethyl orthoformate (47.7 mL, 450 mmol), AcOH (6.43 mL, 112 mmol), 2-amino-5-methyl-1H-indole-3-carbonitrile (6a) (3.85 g, 22.49 mmol) and NHOAc (8.67 g, 112 mmol) was added in a 350 mL pressure vessel and heated at 100 °C under pressure for 16 h. The reaction mixture was diluted with HO (20 mL) and stirred for 15 min. The mixture was then filtered, and the solid was washed with HO and air-dried to give 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b) (3.60 g, 81%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.3, 1.5 Hz, 1H), 7.07 (s, 2H), 2.45 (s, 3H); MS (ES+): 1.99 (M+1), (ES-): 197 (M-1).

[0200] Step 2: Preparation of tert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (6c) Compound 6c was prepared from 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b) (2.00 g, 10.09 mmol; CAS# 1242140-67-5) in DMF (20 mL) using tert-butyl 2-bromoacetate (2.362 g, 12.11 mmol), CsCO (6.57 g, 20.18 mmol), and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (6c) (2.57 g, 82% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (20 g), eluting with MeOH (0–3%) in DCM]. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.18 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.29 - 7.15 (m, 3H), 5.08 (s, 2H), 2.47 (s, 3H), 1.40 (s, 9H);MS (ES+): 313 (M+1), (ES-): 311 (M-1).

[0201] Step 3: Preparation of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) Compound 6d was prepared from tert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate 6c (0.220 g, 0.704 mmol) using TFA (8.03 mg, 7.04) in DCM (10 mL) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid 6d (300 mg) TFA salt as a purple solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J = 1.1 Hz, 1H), 8.48 - 8.26 (m, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 5.24 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -74.24; MS (ES+): 257 (M+1), (ES-): 255 (M-1).

[0202] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (6e) Compound 6e was prepared from the TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (43 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM], followed by purification using reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (6e) (48 mg, 68% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.88 (s, 2H, D2O exchangeable), 8.68 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.3, 1.6 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.76 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 17.1 Hz, 1H), 4.42 (dd, J = MS (ES+): 520.0 (M+1);(ES-): 518.0 (M-1);C24 H 22 Analysis calculated for BrNO.1.25HCl.2.75H.sub.2O: C, 46.83; H, 4.71; Cl, ​​7.20; N, 15.93; Found: C, 46.68; H, 4.62; Cl, ​​7.26; N, 15.75.

[0203] Scheme 7 [ka] Preparation of (2S,4R)-1-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7b) Compound 7b was prepared from the TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using the TFA salt of (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) [(52.5 mg, 0.135 mmol); prepared according to the procedure reported in Scheme 1, Step 3, Wiles, Jason A. et al., PCT International Application (2017), WO2017035349A1 20170302 (incorporated by reference)], HATU (61.6 mg, 0.162 mmol), DIPEA (0.118 mL, 0.675 mmol), and stirring at room temperature for 16 hours. This gave (2S,4R)-1-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7b) (30 mg, 43% yield) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ (two rotor mixture) 9.12 (s) and 8.73 - 8.47 (m) (s and m, 4H, 2H interchangeable), 8.37 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.35 - 7.25 (m, 1H), 7.14 (td, J = 8.8, 8.4, 3.0 Hz, 1H), 6.86 (t, J = 7.9 Hz, 1H), 5.65 - 5.49 (m, 1H), 5.46 - 5.37 (m, 1H), 5.32 (d, J = 17.3 Hz, 1H), 4.51 - 4.13 (m, 4H), 4.00 (ddd, J = 37.1, 12.7, 3.1 Hz, 1H), 2.45 (s, 4H), 2.25 - 1.90 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.26, -121.77, -176.26, -176.48;MS (ES+): 513.0 (M+1), 511.0 (M-1);C 25 H 23 Analysis calculated for ClF2N6O2.HCl.2H2O: C, 51.29; H, 4.82; Cl, ​​12.11; N, 14.36; Found: C, 51.22; H, 4.90; Cl, ​​12.01; N, 14.43.

[0204] Scheme 8 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8b) Following the procedure reported in Step 3 of Scheme 1, the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) [(44.9 mg, 0.135 mmol); Wiles, Jason A. et al., PCT International Application (2017), WO2017035353A1 Compound 8b was prepared from the TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol), and stirring at room temperature for 16 h. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8b) (40 mg, 55% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.57 (s, 1H), 8.47 (s, 2H, D2O exchangeable), 8.33 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.68 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 17.2 Hz, 1H), 4.36 (dd, J = 9.0, 5.9 Hz, 1H), 3.71 - 3.66 (m, 1H), 2.59 - 2.39 (m, 4H), 1.97 (dd, J = 13.2, 5.8 Hz, 1H), 1.30 (s, 3H), 1.05 - 0.96 (m, 1H), 0.96 - 0.88 (m, 1H); MS (ES+) 534.0 (M+1), 532.0 (M-1).

[0205] Scheme 9 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (9a) Compound 9a was prepared from the TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (50 mg, 0.14 mmol) in DMF (1.5 mL) using the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (46.7 mg, 0.14 mmol), HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (9a) (49 mg, 67% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H, D2O exchangeable), 8.77 (s, 2H, D2O exchangeable), 8.66 (s, 1H), 8.54 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.61 - 7.55 (m, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.75 (d, J = 17.4 Hz, 1H), 5.39 (d, J = 17.3 Hz, 1H), 4.38 (dd, J = 9.1, 5.9 Hz, 1H), 3.71 (dd, J = 5.5, 2.4 Hz, 1H), 2.49 - 2.41 (m, 1H), 1.99 (dd, J = 13.3, 5.9 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J = 5.4 Hz, 1H), 0.94 (dd, J = 5.4, 2.4 Hz, 1H);MS (ES+): 520.0 (M+1), 542.0 (M+Na);(ES-): 518.0 (M-1);C 24 H 22 Analysis calculated for BrNO.1.75(H.sub.2O).1.25(HCl): C, 48.25; H, 4.51; Cl, ​​7.42; N, 16.41; Found: C, 48.06; H, 4.27; Cl, ​​7.28; N, 16.27.

[0206] Scheme 10 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10b) Following the procedure reported in Step 3 of Scheme 1, the HCl salt of (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10a) [(46.7 mg, 0.14 mmol); Wiles, Jason A. et al., PCT International Application (2018), WO2018160889A1] was prepared. Compound 10b was prepared from the TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (2 mL) using HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol), and stirring at room temperature for 16 h. This gave (1R,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10b) (49 mg yield, 67%) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H, D2O exchangeable), 8.72 - 8.51 (m, 3H, 2H D2O exchangeable), 8.37 (s, 1H), 7.71 - 7.53 (m, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 5.67 (d, J = 17.4 Hz, 1H), 5.38 (d, J = 17.3 Hz, 1H), 4.36 (dd, J = 9.2, 5.2 Hz, 1H), 3.66 (dd, J = 5.6, 2.4Hz, 1H), 2.61 - 2.52 (m, 4H), 2.05 (d, J = 5.4 Hz, 1H), 2.01 (s, 3H), 1.33 (s, 3H), 1.14 - 0.91 (m, 2H);MS (ES+): 548.0 (M+1), 569.9 (M+Na);(ES-): 546.0 (M-1);C 26 H 26 Analysis calculated for BrNO.3H.sub.2O.1.15HCl: C, 48.46; H, 5.19; Cl, ​​6.33; N, 15.21; Found: C, 48.64; H, 5.03; Cl, ​​6.07; N, 15.02.

[0207] Scheme 11 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (11f) Step 1: Preparation of 2-amino-5-(trifluoromethyl)-1H-indole-3-carbonitrile (11b) A mixture of 2,2,2-trifluoro-N-(2-iodo-4-(trifluoromethyl)phenyl)acetamide (11a) (4.00 g, 10.44 mmol), malononitrile (0.828 g, 12.53 mmol), L-proline (0.240 g, 2.089 mmol), CuI (0.199 g, 1.044 mmol), and KCO (2.89 g, 20.89 mmol) was suspended in a 1:1 mixture of DMSO (20 mL) and HO (20 mL) and stirred at 60 °C for 16 h under an argon atmosphere. The reaction mixture was diluted with saturated NH Cl (30 mL) and extracted with EtOAc (30 mL × 3). The combined organics were washed with HO (30 mL × 4), brine (30 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [SiO gel (40 g), eluted with EtOAc (0–50%) in hexanes] to give 2-amino-5-(trifluoromethyl)-1H-indole-3-carbonitrile (11b) (1.24 g, 53% yield) as an orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.12 (s, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -58.93; MS (ES+): 226 (M+1); (ES-): 224 (M-1).

[0208] Step 2: Preparation of 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (11c) Compound 11c was prepared from 2-amino-5-(trifluoromethyl)-1H-indole-3-carbonitrile (11b) (1.24 g, 5.51 mmol) using trimethyl orthoformate (18.12 mL, 165 mmol), AcOH (1.575 mL, 27.5 mmol), and NHOAc (2.122 g, 27.5 mmol) according to the procedure reported in Scheme 6, Step 1. This afforded, after workup and purification [SiO gel (24 g), eluted with MeOH (0–5%) in DCM], 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (11c) (1.13 g, 4.48 mmol) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 7.66 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.46 (s, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -58.13; MS (ES+): 253 (M+1); (ES-): 251 (M-1).

[0209] Step 3: Preparation of tert-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (11d) Compound 11d was prepared from 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (11c) (0.75 g, 2.97 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.580 g, 2.97 mmol), CsCO (1.163 g, 3.57 mmol), and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (11d) (0.89 g, 82% yield) as a pale orange solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.36 (s, 1H), 7.84 - 7.70 (m, 2H), 7.60 (s, 2H), 5.21 (s, 2H), 1.41 (s, 9H).

[0210] Step 4: Preparation of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) Compound 11e was prepared from tert-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate 11d (0.89 g, 2.429 mmol) using TFA (4.43 g, 38.9 mmol) in DCM (7 mL) and stirring at room temperature for 16 hours according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid 11e (1.26 g) TFA salt as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.57 (s, 1H), 8.43 (s, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.84 (dd, J = 8.6, 1.7 Hz, 1H), 5.31 (s, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -58.51, -74.65; MS (ES+): 311 (M+1); (ES-): 309 (M-1).

[0211] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (11f) Compound 11f was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (2 mL) using the HCl salt of (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10a) (40.9 mg, 0.118 mmol), HATU (67.2 mg, 0.177 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (11f) (55 mg, 77% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H, D2O exchangeable), 8.99 (s, 1H), 8.59 (m, 3H, 2H D2O exchangeable), 7.84 (d, J = 2.1 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 5.73 (d, J = 17.4 Hz, 1H), 5.45 (d, J = 17.3 Hz, 1H), 4.36 (dd, J = 9.2, 5.2 Hz, 1H), 3.67 (dd, J = 5.4, 2.5 Hz, 1H), 2.60 - 2.54 (m, 1H), 2.09 - 2.02 (m, 1H), 2.00 (s, 3H), 1.34 (s, 3H), 1.06 (t, J = 5.3 Hz, 1H), 0.99 (dd, J = 5.4, 2.4 Hz, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -58.51;MS (ES+): 602.0 (M+1), 623.9 (M+Na);(ES-): 600.0 (M-1);C 26 H 23 Analysis calculated for BrF3N7O2.2.5H2O.1HCl: C, 45.66; H, 4.27; Cl, ​​5.18; N, 14.34; Found: C, 45.66; H, 4.02; Cl, ​​5.29; N, 14.26.

[0212] Scheme 12 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (12a) Compound 12a was prepared from the TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (50 mg, 0.14 mmol) in DMF (2 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10a) (48.7 mg, 0.14 mmol), HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (12a) (47 mg, 63% yield) as a white solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H, D2O exchangeable), 8.77 (s, 2H, D2O exchangeable), 8.66 (s, 1H), 8.55 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.45 (dd, J = 7.9, 6.0 Hz, 2H), 5.72 (d, J = 17.3 Hz, 1H), 5.42 (d, J = 17.3 Hz, 1H), 4.37 (dd, J = 9.2, 5.3 Hz, 1H), 3.68 (dd, J = 5.6, 2.4 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.09 - 2.01 (m, 1H), 2.00 (s, 3H), 1.34 (s, 3H), 1.06 (t, J = 5.4 Hz, 1H), 0.99 (dd, J = 5.3, 2.4 Hz, 1H). MS (ES+): 534.0 (M+1), 556.0 (M+Na);(ES-): 532.0 (M-1);C 25 H 24 Analysis calculated for BrNO.2.5H.sub.2O.1.1HCl: C, 48.47; H, 4.90; Cl, ​​6.29; N, 15.83; Found: C, 48.70; H, 4.84; Cl, ​​6.26; N, 15.63.

[0213] Scheme 13 [ka] Preparation of (S)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (13b) Compound 13b was prepared from the TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (50 mg, 0.14 mmol) in DMF (2 mL) using the TFA salt of (S)—N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (13a) [(53.9 mg, 0.140 mmol); Wiles, Jason A. et al., PCT International Application (2017), WO2017035353A1 20170302], HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol), and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (S)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (13b) (42 mg, 61% yield) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)]. 1 H NMR (300 MHz, DMSO-d6) δ 11.23 and 10.80 (2s, 1H D2O exchangeable), 8.63 - 8.50 (m, 3H, 2H D2O exchangeable), 8.45 (d, J = 7.9 Hz, 1H), 8.11 and 7.93 (2d, J = 8.1 Hz, 1H), 7.64 (q, J = 8.2 Hz, 2H), 7.55 - 7.44 (m, 1H), 7.40 - 7.31 (m, 1H), 7.24 (d, J = 7.7 Hz, 1H), 5.45 - 5.28 (m, 2H), 4.46 (dd, J = 8.3, 4.3Hz, 1H), 3.80 (tt, J = 9.7, 5.3 Hz, 2H), 2.23 - 1.76 (m, 4H);MS (ES+): 494.0 (M+1);(ES-): 492.0 (M-1);C 22 H 20Analysis calculated for BrNO.2.75H.sub.2O.1HCl: C, 45.53; H, 4.60; Cl, ​​6.11; N, 16.89; Found: C, 45.78; H, 4.22; Cl, ​​6.37; N, 16.65.

[0214] Scheme 14 [ka] Preparation of (2S,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (14a) Compound 14a was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (2 mL) using the HCl salt of (2S,4R)—N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (3a) (39.9 mg, 0.118 mmol), HATU (67.2 mg, 0.177 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-60%) in water (containing 0.1% HCl)], (2S,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (14a) (40 mg, 57% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (two rotor mix) 10.89 and 10.46 (2s, 1H, DO interchangeable), 8.96 (s, 1H), 8.55 (s, 1H), 8.44 (s, 2H, DO interchangeable), 7.90 - 7.69 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.76 - 5.33 (m, 3H), 4.57 (t, J = 8.6 Hz, 1H), 4.33 (dd, J = 21.8, 12.7 Hz, 1H), 4.18 - 3.95 (m, 1H), 2.73 (s, 1H), 2.30 - 2.11 (m, 1H), 1.93 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -58.47, -58.75, -176.20;MS (ES+): 594.0 (M+1);(ES-): 592.0 (M-1);C 24 H 20 Analysis calculated for BrF4N7O2.1.75H2O.1HCl: C, 43.52; H, 3.73; Cl, ​​5.35; N, 14.80; Found: C, 43.54; H, 3.24; Cl, ​​4.96; N, 14.54.

[0215] Scheme 15 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (15a) Compound 15a was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (2 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (1d) (39.2 mg, 0.118 mmol), HATU (67.2 mg, 0.177 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (15a) (47 mg, 68% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H, DO exchangeable), 9.00 (s, 1H), 8.70 - 8.54 (m, 3H, 2H DO exchangeable), 7.93 - 7.80 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 5.78 (d, J = 17.4 Hz, 1H), 5.51 (d, J = 17.3 Hz, 1H), 4.38 (dd, J = 9.2, 5.1 Hz, 1H), 3.90 (td, J = 6.3, 5.4, 2.3Hz, 1H), 2.46 - 2.18 (m, 2H), 2.03 - 1.86 (m, 4H), 1.11 (dt, J = 9.4, 5.3 Hz, 1H), 0.83 (dt, J = 7.1, 3.4 Hz, 1H);19 F NMR (282 MHz, DMSO-d6) δ -58.52;MS (ES+): 587.9 (M+1);(ES-): 586.0 (M-1);C 25 H 21 Analysis calculated for BrF3N7O2.HCl.1.75H2O: C, 45.75; H, 3.92; Cl, ​​5.40; N, 14.94; Found: C, 45.96; H, 3.65; Cl, ​​4.95; N, 14.71.

[0216] Scheme 16 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (16e) Step 1: Preparation of 7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (16b) Compound 16b was prepared from 2-amino-6-(trifluoromethyl)-1H-indole-3-carbonitrile (16a) (1.95 g, 8.66 mmol; CAS# 1242140-69-7) using trimethyl orthoformate (18.95 mL, 173 mmol), AcOH (2.476 mL, 43.3 mmol), and NHOAc (3.34 g, 43.3 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, the acetate salt of 7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (16b) (2.08 g, 77% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 11.98 (s, 1H), 8.52 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.76 - 7.65 (m, 1H), 7.58 - 7.47 (m, 1H), 7.43 (s, 2H), 1.91 (s, 3H); MS (ES+): 253.10 (M+1).

[0217] Step 2: Preparation of tert-butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (16c) Compound 16c was prepared from 7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (16b) (2 g, 7.93 mmol) in DMF (50 mL) using CsCO (3.10 g, 9.52 mmol) according to the procedure reported in Scheme 1, Step 1. This afforded, after workup and purification by flash column chromatography [silica gel (40 g), eluting with 0–100% EtOAc in hexanes], tert-butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (16c) (0.93 g, 32% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 8.2 Hz, 1H), 8.36 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.65 - 7.51 (m, 3H), 5.25 (s, 2H), 1.40 (s, 9H);MS (ES+): 367.10 (M+1).

[0218] Step 3: Preparation of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (16d) Compound 16d was prepared from tert-butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (16c) (0.92 g, 2.51 mmol) using TFA (14.41 mL, 37.7 mmol; 20% TFA in DCM) and stirring at room temperature for 16 h, following the procedure reported in Step 2 of Scheme 1. This afforded, after workup, the TFA salt of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (16d) (0.9 g, 84% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J = 8.3 Hz, 1H), 8.47 (s, 1H), 8.21 (s, 1H), 8.02 (s, 2H), 7.67 (d, J = 8.3 Hz, 1H), 5.31 (s, 2H);MS (ES+): 311.00 (M+1).

[0219] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (16e) Compound 16e was prepared from the TFA salt of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (16d) (75 mg, 0.177 mmol) in DMF (2 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (70.0 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol), DIPEA (0.154 mL, 0.884 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (16e) (62 mg, 61% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.73 (d, J = 8.1 Hz, 3H, 2H D2O exchangeable), 8.65 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.30 (d, J = 7.7 Hz, 1H), 5.87 (d, J = 17.4 Hz, 1H), 5.51 (d, J = 17.3 Hz, 1H), 4.42 (dd, J = 9.0, 5.5 Hz, 1H), 3.91 (ddd, J = 7.4, 5.4, 2.3 Hz, 1H), 2.41 - 2.13 (m, 2H), 1.92 (t, J = 6.4 Hz, 1H), 1.09 (dt, J = 8.7, 5.5 Hz, 1H), 0.77 (td, J = 5.2, 2.3 Hz, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -59.33;MS (ES+): 574.0 (M+1);(ES-): 572.0 (M-1);C 24 H 19 Analysis calculated for BrF3N7O2.1.5H2O.1HCl: C, 45.19; H, 3.63; Cl, ​​5.56; N, 15.37; Found: C, 45.06; H, 3.61; Cl, ​​5.38; N, 15.36.

[0220] Scheme 17 [ka] Preparation of tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-7-yl)carbamate (17f) Step 1: Preparation of 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (17b) Compound 17b was prepared from 2-amino-6-bromo-1H-indole-3-carbonitrile (17a) (2 g, 8.47 mmol; CAS# 1427028-36-1) using trimethyl orthoformate (18.54 mL, 169 mmol), AcOH (2.423 mL, 42.4 mmol), and NHOAc (3.27 g, 42.4 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (17b) (2.29 g, 84% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 2H), 8.27 (t, J = 4.2 Hz, 2H), 7.58 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 7.26 (s, 2H), 1.92 (s, 3H).

[0221] Step 2: Preparation of tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (17c) Compound 17c was prepared from 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (17b) (2.2 g, 6.81 mmol) in DMF (75 mL) using tert-butyl 2-bromoacetate (1.056 mL, 7.15 mmol), CsCO (4.88 g, 14.98 mmol), and stirring at room temperature for 15 h, following the procedure reported in Step 2 of Scheme 16. Additional tert-butyl 2-bromoacetate (1.006 mL, 6.81 mmol) and KCO (0.941 g, 6.81 mmol) were required for completion of the reaction. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc (0–100%) in hexanes], tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (17c) (1.25 g, 49% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (t, J = 4.2 Hz, 2H), 7.91 (d, J = 1.7 Hz, 1H), 7.46 - 7.36 (m, 3H), 5.14 (s, 2H), 1.41 (s, 9H).

[0222] Step 3: Preparation of tert-butyl 2-(4-amino-7-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (17d) To a solution of tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (17c) (200 mg, 0.530 mmol) in degassed toluene (10 mL) was added XPhos (50.5 mg, 0.106 mmol), t-butyl carbamate (93 mg, 0.795 mmol), Pd(dba) (48.5 mg, 0.053 mmol), and cesium carbonate (173 mg, 0.530 mmol), flushed with nitrogen, and heated at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), dried, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with DMA-80 (0-50%) in DCM] to give tert-butyl 2-(4-amino-7-(tert-butoxycarbonylamino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (17d) (92 mg, 42% yield) as a yellow solid. MS (ES+): 414.20 (M+1).

[0223] Step 4: Preparation of 2-(4-amino-7-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (17e) To a stirred solution of tert-butyl 2-(4-amino-7-(tert-butoxycarbonylamino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (17d) (90 mg, 0.218 mmol) in THF / MeOH (4 mL; 1:1 ratio), lithium hydroxide hydrate (1.088 mL, 1.088 mmol) was added and stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo, diluted with water (1 mL), acidified to pH 5-7 using 1 M HCl, and concentrated to dryness to give 2-(4-amino-7-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (17e) (67 mg, 86% yield). 1 H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.63 - 8.45 (m, 4H), 8.38 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.36 (dd, J = 8.7, 1.8 Hz, 1H), 5.19 (s, 2H), 1.51 (s, 9H); MS (ES+): 358.10 (M+1); (ES-): 356.10 (M-1).

[0224] Step 5: Preparation of tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-7-yl)carbamate (17f) Compound 17f was prepared from the TFA salt of 2-(4-amino-7-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (17e) (60 mg, 0.168 mmol) in DMF (1 mL) using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (66.5 mg, 0.168 mmol), HATU (96 mg, 0.252 mmol), DIPEA (0.146 mL, 0.839 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0–100%) in DCM], tert-butyl 4-amino-9-(2-((1R,3S,5R)-3-(6-bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-7-ylcarbamate (17f) (48 mg, 46% yield). 10 mg of this compound was purified by reverse-phase column chromatography [C18 column (50 g), eluted with ACN (0-100%) in water (containing 0.1% HCl)] to give tert-butyl 4-amino-9-(2-((1R,3S,5R)-3-(6-bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-7-ylcarbamate (17f) (6 mg) HCl salt as a white solid. 1H NMR (300 MHz, MeOD-d4) δ 8.46 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.7, 1.9 Hz, 1H), 7.24 (dd, J = 7.8, 0.7 Hz, 1H), 5.74 (d, J = 17.2 Hz, 1H), 5.53 (d, J = 17.1 Hz, 1H), 4.56 (t, J = 7.1 Hz, 1H), 3.89 (ddd, J = 7.4, 5.4, 2.4 Hz, 1H), 2.46 (dd, J = 7.9, 3.6 Hz, 2H), 2.04 (d, J = 6.4 Hz, 1H), 1.56 (s, 9H), 1.24 (dt, J = 8.6, 5.5 Hz, 1H), 1.00 (dt, J = 7.6, 3.7 Hz, 1H). MS (ES+): 621.2 (M+1);(ES-): 619.1 (M-1).

[0225] Scheme 18 [ka]

[0226] Preparation of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,7-diamino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (18a) Compound 18a was prepared from tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-7-yl)carbamate (17f) (35 mg, 0.056 mmol) in DCM (1 mL) using 2,2,2-trifluoroacetic acid (0.087 mL, 1.126 mmol) and stirring at room temperature for 16 h according to the procedure reported in Scheme 1, Step 3. This gave, after workup and two purifications by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0–100%) in water (containing 0.1% HCl)], (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,7-diamino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (17 mg, 58% yield) (18a) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H, D2O exchangeable), 8.45 (s, 1H), 8.29 (s, 2H, D2O exchangeable), 8.18 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 7.0 Hz, 2H), 5.58 (d, J = 17.4 Hz, 1H), 5.22 (d, J = 17.4 Hz, 1H), 4.36 (dd, J = 9.0, 5.4 Hz, 1H), 3.89 - 3.76 (m, 1H), 2.34 - 2.06 (m, 2H), 1.85 (d, J = 7.7 Hz, 1H), 1.10 - 0.92 (m, 1H), 0.68 (d, J = 5.9 Hz, 1H). MS (ES+): 521.1 (M+1);(ES-): 519.1 (M-1).

[0227] Scheme 19 [ka] Preparation of (2S,4R)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (19a) Compound 19a was prepared from the TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (150 mg, 0.421 mmol) in DMF (5 mL) using the TFA salt of (2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5d) (169 mg, 0.421 mmol), HATU (192 mg, 0.505 mmol), DIPEA (272 mg, 2.105 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (2S,4R)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (19a) (62 mg, 61% yield) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ (two rotors mixed) 11.37 (s) and 10.98 (s) (2s, 1H, DO interchangeable), 8.80 - 8.56 (m, 3H, 2H DO interchangeable), 8.51 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.75 - 7.63 (m, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.50 - 7.37 (m, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.64 (d, J = 3.5 Hz, 1H), 5.60 - 5.45 (m, 1H). 5.40 (d, J = 17.3 Hz, 1H), 4.71 - 4.57 (m, 1H), 4.43 - 4.21 (m, 1H), 4.18 - 3.96 (m, 1H), 2.74 - 2.50 (m, 1H), 2.29 - 2.02 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -175.73, -176.14;MS (ES+): 512.0 (M+1), (ES-): 510.0 (M-1);C 22 H 19 Analysis calculated for BrFN7O2.HCl.2.5H2O: C, 44.50; H, 4.24; Cl, ​​5.97; N, 16.51; Found: C, 44.36; H, 4.10; Cl, ​​5.76; N, 16.25.

[0228] Scheme 20 [ka] Preparation of (2S,4R)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (20a) Compound 20a was prepared from the TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1c) (200 mg, 0.561 mmol) in DMF (10 mL) using the TFA salt of (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (218 mg, 0.561 mmol), HATU (256 mg, 0.674 mmol), DIPEA (0.490 mL, 2.81 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (2S,4R)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (20a) (121 mg, 43% yield) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0–3%) in DCM] followed by reverse-phase column chromatography [C-18 column, 100 g, eluting with 0.1% aqueous HCl (0–100%) in HO and MeCN]. 1 H NMR (300 MHz, DMSO-d6) (two rotor mix) δ 9.15 (t, J = 5.8 Hz) and 8.79 - 8.64 (m, 3H, DO interchangeable), 8.61 (d, J = 3.0 Hz, 1H), 8.59 - 8.50 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.58 - 7.34 (m, 4H), 7.21 - 7.11 (m, 1H), 6.92 - 6.79 (m, 1H), 5.72 - 5.53 (m, 1H), 5.54 - 4.76 (m, 2H), 4.56 - 4.14 (m, 4H), 4.14 - 3.92 (m, 1H), 2.62 - 2.40 (m, 1H), 2.22 - 1.95 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.24, -121.76, -176.25, -176.47; MS (ES+): 499 / 501 (M+1).

[0229] Scheme 21 [ka] Preparation of (2S,4R)-1-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (21a) Compound 21a was prepared from the TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using the TFA salt of (2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5d) (54.3 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (2S,4R)-1-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (21a) (35 mg, 49% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (mixed rotors) 11.35 (s) and 10.97 (s, 1H, D2O exchangeable), 8.76 - 8.52 (m, 3H, 2H D2O exchangeable), 8.35 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.71 - 5.25 (m, 3H), 4.62 (t, J = 8.5 Hz, 1H), 4.37 - 4.23 (m, 1H), 4.16 - 3.96 (m, 1H), 2.66 - 2.43 (m, 4H), 2.30 - 1.95 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -175.73, -176.15;MS (ES+): 526.0 (M+1), (ES-): 524.0 (M-1);C 23 H 21 Analysis calculated for BrFN7O2.1.1HCl.2.25H2O: C, 45.51; H, 4.42; Cl, ​​6.42; N, 16.15; Found: C, 45.21; H, 4.47; Cl, ​​6.40; N, 15.88.

[0230] Scheme 22 [ka] Preparation of (1R,3S,5R)-2-((-)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22c) and (1R,3S,5R)-2-((+)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22d) Step 1: Preparation of tert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoate (22a) Compound 22a was prepared from 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b) (200 mg, 1.009 mmol) in DMF (10 mL) using (R)-tert-butyl 2-bromopropanoate (253 mg, 1.211 mmol; CAS#54631-38-8), CsCO (657 mg, 2.018 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 1. This afforded, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0–3%) in DCM], a mixture of two enantiomers of tert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoate (22a) (250 mg, 76% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J = 6.0 Hz, 1H), 8.23 ​​- 8.15 (m, 1H), 7.40 (dd, J = 7.4, 3.1 Hz, 1H), 7.30 - 7.07 (m, 3H), 5.81 - 5.63 (m, 1H), 2.46 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H), 1.30 (d, J = 5.7 Hz, 9H); MS (ES+): 327 (M+1).

[0231] Step 2: Preparation of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoic acid (22b) Compound 22b was prepared from tert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoate (22a) (250 mg, 0.766 mmol) in DCM (20 mL) using TFA (0.879 mL, 11.49 mmol) and stirring at room temperature for 16 h, following the procedure reported in Step 2 of Scheme 1. This afforded, after workup, a mixture of the two enantiomers of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoic acid (22b) (304 mg) TFA salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.49 - 8.36 (m, 2H), 8.36 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.6, 1.6 Hz, 1H), 5.86 (q, J = 7.1 Hz, 1H), 1.75 (d, J = 7.2 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -74.15; MS (ES+): 271 (M+1), (ES-): 269 (M-1).

[0232] Step 3: Preparation of (1R,3S,5R)-2-((-)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22c) and (1R,3S,5R)-2-((+)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22d) Compounds 22c and 22d were prepared from the TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoic acid (22b) (50 mg, 0.130 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.5 mg, 0.130 mmol), HATU (59.4 mg, 0.156 mmol), DIPEA (84 mg, 0.651 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by purification using reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)]: 1. (1R,3S,5R)-2-((-)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22c) (17 mgs, 25%) HCl salt as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H, D2O exchangeable), 8.64 (s, 1H), 8.62 - 8.50 (m, 2H, D2O exchangeable), 8.40 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 7.9, 2.6 Hz, 2H), 6.28 (q, J = 6.8 Hz, 1H), 4.27 (t, J = 7.2 Hz, 1H), 3.27 - 3.24 (m, 1H), 2.04 - 1.95 (m, 2H), 1.61 (m, 3H), 1.57 - 1.47 (m, 1H), -0.36 (m, 1H), -1.03 (m, 1H); MS (ES+): 534 / 536 (M+1), (ES-): 532 / 534 (M-1); Chiral HPLC: AD-H column 80 / 20 [(0.1% DEA in n-hexane in 0.1% DEA in ethanol)] 1.0 mL / min, UV detection 245 nm, run time 30 min (temperature 40 °C). t = 10.54 (Peak 1 (22c), 98.0742%); R t =19.473(Peak 2;(22d)1.388%)97.4084%ee;Optical rotation [α] D =-224(c=0.1, MeOH) 2. (1R,3S,5R)-2-((+)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22d) (22 mgs, 32%) HCl salt as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H, D2O exchangeable), 8.62 (s, 1H), 8.59 - 8.46 (m, 2H, D2O exchangeable), 8.36 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.22 (q, J = 7.0 Hz, 1H), 4.53 (dd, J = 9.1, 5.6 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.30 - 2.17 (m, 1H), 2.07 (m, 1H), 1.68 (m, 4H), 0.88 (m, 1H), 0.77 (m, 1H); MS (ES+): 534 / 536 (M+1), (ES-): 532 / 534 (M-1); Chiral HPLC: AD-H column 80 / 20 [(0.1% DEA in n-hexane in 0.1% DEA in ethanol)] 1.0 mL / min, UV detection 245 nm, run time 30 min (temperature 40 °C); R t = 10.54 (Peak 1 (22c) 0%); R t =19.427(Peak 2;(22d)100%)>99.99%ee;Optical rotation [α] D =+92.632(c=0.095, MeOH).

[0233] Scheme 23 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (23f) Step 1: Preparation of 2-amino-6-methyl-1H-indole-3-carbonitrile (23b) Compound 23b was prepared from 2,2,2-trifluoro-N-(2-iodo-5-methylphenyl)acetamide (23a) (7.03 g, 21.36 mmol) in DMSO (20 mL) using malononitrile (1.694 g, 26.6 mmol), L-proline (0.492 g, 4.27 mmol), CuI (0.407 g, 2.136 mmol), and KCO (5.91 g, 42.7 mmol) under argon atmosphere and heated at 60 °C for 16 h, according to the procedure reported in Scheme 11, Step 1. This afforded 2-amino-6-methyl-1H-indole-3-carbonitrile (23b) (2.65 g, 73% yield) as a brown solid after workup and purification [SiO gel (40 g), eluted with 0–40% EtOAc in hexane]. 1 H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.78 (dd, J = 8.3, 1.5 Hz, 1H), 6.63 (s, 2H), 2.31 (s, 3H);MS (ES+): 172 (M+1);(ES-): 170 (M-1).

[0234] Step 2: Preparation of 7-methyl-9H-pyrimido[4,5-b]indol-4-amine (23c) Compound 23c was prepared from 2-amino-6-methyl-1H-indole-3-carbonitrile (23b) (2.65 g, 15.48 mmol) using triethyl orthoformate (51.5 mL, 310 mmol), AcOH (4.43 mL, 77 mmol), and NHOAc (5.97 g, 77 mmol) according to the procedure reported in Scheme 6, Step 1. This afforded 7-methyl-9H-pyrimido[4,5-b]indol-4-amine (23c) (1.45 g) as a tan solid after workup and purification [SiO gel (24 g), eluted with MeOH (0–5%) in DCM]. 1H NMR (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 7.15 - 6.96 (m, 3H), 2.45 (s, 3H);MS (ES+): 199 (M+1);(ES-): 197 (M-1).

[0235] Step 3: Preparation of tert-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (23d) Compound 23d was prepared from 7-methyl-9H-pyrimido[4,5-b]indol-4-amine (23c) (1.45 g, 7.31 mmol) in DMF (25 mL) using tert-butyl 2-bromoacetate (1.427 g, 7.31 mmol), CsCO (2.86 g, 8.78 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (23d) (0.84 g, 37% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.19 (s, 2H), 7.14 - 7.06 (m, 1H), 5.07 (s, 2H), 2.48 (s, 3H), 1.41 (s, 9H); MS (ES+): 313 (M+1).

[0236] Step 4: Preparation of 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) Compound 23e was prepared from tert-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (23d) (0.84 g, 2.69 mmol) using TFA (6.13 g, 53.8 mmol) in DCM (20 mL) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) (1.01 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.24 (s, 2H), 7.59 (s, 1H), 7.26 (d, 1H), 5.21 (s, 2H), 2.49 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -74.09; MS (ES+): 257 (M+1), (ES-): 255 (M-1).

[0237] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (23f) Compound 23f was prepared from the TFA salt of 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) (50 mg, 0.135 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (43.0 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (23f) (44 mg, 63% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.57 (s, 1H), 8.44 (s, 2H, D2O exchangeable), 8.37 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.29 - 7.23 (m, 1H), 5.71 (d, J = 17.3 Hz, 1H), 5.38 (d, J = 17.3 Hz, 1H), 4.42 (dd, J = 9.1, 5.6 Hz, 1H), 3.96 - 3.87 (m, 1H), 2.49 (s, 3H), 2.40 - 2.27 (m, 1H), 2.27 - 2.11 (m, 1H), 2.00 - 1.85 (m, 1H), 1.12 - 1.02 (m, 1H), 0.82 - 0.73 (m, 1H);MS (ES+): 520.0 (M+1), 518.0 (M-1);C 24 H 22 Analysis calculated for BrNO.1.2HCl.2.5H.sub.2O: C, 47.32; H, 4.67; Cl, ​​6.98; N, 16.10; Found: C, 47.10; H, 4.59; Cl, ​​6.75; N, 15.97.

[0238] Scheme 24 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (24a) Compound 24a was prepared from the TFA salt of 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) (50 mg, 0.135 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (44.9 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (24a) (36 mg, 50% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.61 (s, 3H, 2H D2O exchangeable), 8.39 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 5.68 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 17.3 Hz, 1H), 4.37 (dd, J = 9.1, 5.9 Hz, 1H), 3.69 (dd, J = 5.5, 2.4 Hz, 1H), 2.55 - 2.41 (m, 4H), 1.98 (dd, J = 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.97 (m, 1H), 0.97 - 0.89 (m, 1H);MS (ES+) 534.0 (M+1), 532.0 (M-1);C 25 H 24 Analysis calculated for BrNO.HCl.2.25H.sub.2O: C, 49.11; H, 4.86; Cl, ​​5.80; N, 16.04; Found: C, 48.98; H, 4.79; Cl, ​​6.02; N, 15.90.

[0239] Scheme 25 [ka] Preparation of (2S,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (25a) Compound 25a was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (10 mL) using the TFA salt of (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (45.8 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (2S,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (25a) (28 mg, 42% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ (mixture of two rotors) 8.98 (d, J = 3.6 Hz, 1H), 8.71 - 8.52 (m, 4H, 2H D2O exchangeable), 7.88 (d, J = 8.6 Hz, 1H), 7.75 (dd, J = 8.7, 1.7 Hz, 1H), 7.45 - 7.31 (m, 1H), 7.17 - 7.08 (m, 1H), 6.80 (t, J = 7.9 Hz, 1H), 5.64 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.54 - 4.26 (m, 3H), 4.23 (d, J = 5.8 Hz, 1H), 4.19 - 4.05 (m, 1H), 3.96 (dd, J = 12.3, 2.9 Hz, 1H), 2.62 - 2.41 (m, 1H), 2.23 - 1.91 (m, 1H); 19F NMR (282 MHz, DMSO) δ -58.53, -121.26, -121.72, -176.26, -176.42; MS (ES+): 567.0 (M+1), (ES-): 565.0 (M-1).

[0240] Scheme 26 [ka] Preparation of (2S,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (26a) Compound 26a was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (5 mL) using the TFA salt of (2S,4R)—N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5d) (47.4 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (2S,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (26a) (33 mg, 48% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H, D2O exchangeable), 8.95 (s, 1H), 8.64 - 8.38 (m, 3H, 2H D2O exchangeable), 7.98 (d, J = 8.2 Hz, 1H), 7.84 (dd, J = 8.4, 5.0 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.71 - 5.57 (m, 1H), 5.51 - 5.39 (m, 1H), 4.62 (dd, J = 9.7, 7.5 Hz, 1H), 4.32 (dd, J = 22.1, 12.6 Hz, 1H), 4.18 - 4.08 (m, 1H), 4.01 (dd, J = 12.8, 3.0 Hz, 1H), 2.68 - 2.33 (m, 1H), 2.30 - 1.97 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -58.51, -175.70;MS (ES+): 580.0 (M+1), (ES-): 578.0 (M-1);C 23 H 18 Analysis calculated for BrF4N7O2.HCl.2.5H2O: C, 41.74; H, 3.66; Cl, ​​5.36; N, 14.81; Found: C, 41.66; H, 3.49; Cl, ​​5.10; N, 14.74.

[0241] Scheme 27 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (27a) Compound 27a was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (10 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (37.5 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (27a) (42 mg, 62% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H, D2O exchangeable), 8.96 (s, 1H), 8.59 (s, 1H), 8.52 (s, 2H, D2O exchangeable), 8.00 (d, J = 8.2 Hz, 1H), 7.85 (s, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.80 (d, J = 17.4 Hz, 1H), 5.46 (d, J = 17.3 Hz, 1H), 4.41 (dd, J = 9.1, 5.5 Hz, 1H), 3.95 - 3.88 (m, 1H), 2.40 - 2.28 (m, 1H), 2.28 - 2.13 (m, 1H), 1.99 - 1.82 (m, 1H), 1.14 - 1.00 (m, 1H), 0.81 - 0.74 (m, 1H); 19F NMR (282 MHz, DMSO-d6) δ -58.47;MS (ES+): 574.0 (M+1);(ES-): 572.0 (M-1);C 24 H 19 Analysis calculated for BrF3N7O2.HCl.2H2O: C, 44.56; H, 3.74; Br, 12.35; Cl, ​​5.48; N, 15.16; Found: C, 44.27; H, 3.69; Cl, ​​5.59; N, 14.75.

[0242] Scheme 28 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (28a) Compound 28a was prepared from the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (39.2 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (28a) (50 mg, 72% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.96 (s, 1H), 8.71 - 8.43 (m, 3H, 2H D2O exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.91 - 7.80 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.76 (d, J = 17.4 Hz, 1H), 5.41 (d, J = 17.3 Hz, 1H), 4.36 (dd, J = 9.1, 6.0 Hz, 1H), 3.69 (dd, J = 5.5, 2.4 Hz, 1H), 2.52 - 2.39 (m, 1H), 1.98 (dd, J = 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.07 - 0.98 (m, 1H), 0.98 - 0.87 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -58.53;MS (ES+): 588.0 (M+1), (ES-): 586.0 (M-1);C 25 H 21 Analysis calculated for BrF3N7O2.1.1HCl.1.75H2O: C, 45.49; H, 3.91; Cl, ​​5.91; N, 14.86; Found: C, 45.32; H, 3.90; Cl, ​​5.87; N, 14.62.

[0243] Scheme 29 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (29f) Step 1: Preparation of 2-amino-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (29b) To NaH (2.55 g, 63.7 mmol) cooled to 0 °C was added a solution of malononitrile (4.21 g, 63.7 mmol) in THF (40 mL) in portions. The resulting cloudy mixture was stirred at 0 °C for 1 h, followed by the slow addition of 4-chloro-3-nitropyridine (29a) (5.00 g, 31.5 mmol) in THF (10 mL). The mixture was then heated at 60 °C under argon for 3 h. The cooled mixture was quenched with HO (30 mL) and extracted with EtOAc (50 mL × 5). The combined organic extracts were washed with HO (50 mL × 2), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give 2-(3-nitropyridin-4-yl)malononitrile (8.77 g) as an orange-red solid, which was used directly in the next reaction. MS (ES+) 189 (M+1), (ES-) 187 (M-1). To 2-(3-nitropyridin-4-yl)malononitrile (4.40 g, 23.39 mmol) suspended in DMF (20 mL) at room temperature was added a solution of NaHCO (9.82 g, 117 mmol) in HO (20 mL), followed by solid NaSO (12.22 g, 70.2 mmol). The resulting mixture was stirred at room temperature for 16 hours and filtered. The filtrate was extracted with EtOAc (50 mL × 4). The combined organic extracts were washed with HO (30 mL × 4), brine (30 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO (40 g), eluted with DMA-80 (0–20%) in DCM) to give 2-amino-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (29b) (0.673 g, 18% yield) as a beige solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.27 (s, 2H), 7.14 (d, J = 5.3 Hz, 1H);MS (ES+): 159 (M+1), (ES-): 157 (M-1).

[0244] Step 2: Preparation of 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (29c) To a suspension of 2-amino-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (29b) (0.46 g, 2.91 mmol) in EtOH (10 mL) in a pressure vessel, formamidine acetate (2.422 g, 23.27 mmol) was added. The cloudy, pale yellow mixture was heated at 80 °C for 16 h, during which time the cloudy mixture turned into a clear solution, and then a precipitate formed. The resulting cloudy, pale yellow mixture was filtered hot. The filter cake was thoroughly washed with boiling ethanol to give the product, 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (29c) (0.35 g, 65.0% yield), as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.78 (s, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.49 (s, 2H);MS (ES+): 186 (M+1), (ES-): 184 (M-1).

[0245] Step 3: Preparation of tert-butyl 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (29d) Compound 29d was prepared from 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (29c) (0.35 g, 1.890 mmol) in DMF (25 mL) using tert-butyl 2-bromoacetate (0.369 g, 1.890 mmol), CsCO (1.232 g, 3.78 mmol), and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (29d) (0.27 g, 48% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–7%) in DCM]. 1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 8.39 (s, 1H), 8.38 - 8.34 (m, 1H), 7.66 (s, 2H), 5.22 (s, 2H), 1.41 (s, 9H);MS (ES+): 300 (M+1), (ES-1): 298 (M-1).

[0246] Step 4: Preparation of 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (29e) Compound 29e was prepared from tert-butyl 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (29d) (270 mg, 0.902 mmol) according to the procedure reported in Step 2 of Scheme 1 in DCM (10 mL) using TFA (1029 mg, 9.02 mmol) and stirring at room temperature for 16 h, which gave, after workup, 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (29e) (0.53 g) TFA salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.96 (d, J = 6.2 Hz, 1H), 8.78 (d, J = 6.2 Hz, 1H), 8.56 (s, 1H), 5.35 (s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -74.66.; MS (ES+): 244 (M+1), (ES-): 242 (M-1).

[0247] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (29f) Compound 29f was prepared from the TFA salt of 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (29e) (50 mg, 0.140 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (70.0 mg, 0.177 mmol), HATU (63.9 mg, 0.168 mmol), DIPEA (90 mg, 0.7 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (29f) (57 mg, 80% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.53 (s, 1H), 9.13 (d, J = 6.3 Hz, 1H), 8.94 (s, 2H), 8.80 (d, J = 6.3 Hz, 1H), 8.69 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.96 (d, J = 17.4 Hz, 1H), 5.53 (d, J = 17.3 Hz, 1H), 4.47 - 4.44 (m, 1H), 3.91 - 3.86 MS (ES+): 507 / 509 (M+1), (ES-): 505 / 507 (M-1).

[0248] Scheme 30 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (30f) Step 1: Preparation of 2-amino-7-methyl-1H-indole-3-carbonitrile (30b) Compound 30b was prepared from N-(2-bromo-6-methylphenyl)-2,2,2-trifluoroacetamide (30a) (7.45 g, 26.4 mmol; CAS# 2007409-96-1) in DMSO (20 mL) using a solution of malononitrile (2.094 g, 31.7 mmol), L-proline (0.608 g, 5.28 mmol), CuI (0.503 g, 2.64 mmol), and KCO (7.30 g, 52.80 mmol) in water (20 mL) and heated at 60 °C under argon atmosphere for 16 h. This gave, after workup and purification [SiO2 gel (40 g), elution with EtOAc (0-40%) in hexanes], 2-amino-7-methyl-1H-indole-3-carbonitrile (30b) (2.35 g, 52% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.3 Hz, 1H), 6.49 (s, 2H), 2.33 (s, 3H);MS (ES+): 172 (M+1);(ES-): 170 (M-1).

[0249] Step 2: Preparation of 8-methyl-9H-pyrimido[4,5-b]indol-4-amine (30c) Compound 30c was prepared from 2-amino-7-methyl-1H-indole-3-carbonitrile (30b) (4.28 g, 25 mmol) using trimethyl orthoformate (26.5 g, 250 mmol), AcOH (4.50 g, 75 mmol), and NHOAc (5.78 g, 75 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 8-methyl-9H-pyrimido[4,5-b]indol-4-amine (30c) (4.24 g, 86% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.26 (s, 1H), 8.10 (dd, J = 7.4, 1.8 Hz, 1H), 7.21 - 7.02 (m, 4H), 2.54 (s, 3H). MS (ES+): 199 (M+1).

[0250] Step 3: Preparation of tert-butyl 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (30d) Compound 30d was prepared from 8-methyl-9H-pyrimido[4,5-b]indol-4-amine (30c) (3.07 g, 15.49 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (3.02 g, 15.49 mmol), CsCO (6.06 g, 18.59 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (30d) (3.52 g, 73% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.19 (dd, J = 5.8, 3.4 Hz, 1H), 7.26 (s, 2H), 7.17 (d, J = 2.6 Hz, 1H), 7.15 (s, 1H), 5.34 (s, 2H), 2.64 (s, 3H), 1.43 (s, 9H);MS (ES+): 313 (M+1);(ES-): 311 (M-1).

[0251] Step 4: Preparation of 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e) Compound 30e was prepared from tert-butyl 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (30d) (0.12 g, 0.384 mmol) using TFA (438 mg, 3.84 mmol) in DCM (5 mL) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e) (0.190 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.87 - 8.66 (m, 2H), 8.64 (s, 1H), 8.36 (dd, J = 5.8, 3.4 Hz, 1H), 7.40 - 7.25 (m, 2H), 5.47 (s, 2H), 2.70 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -74.60; MS (ES+): 257 (M+1), (ES-): 255 (M-1).

[0252] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (30f) Compound 30f was prepared from the TFA salt of 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e) (50 mg, 0.135 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (43.0 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-4%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (30f) (44 mg, 63% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H, D2O exchangeable), 8.82 - 8.54 (m, 3H, 2H D2O exchangeable), 8.42 - 8.28 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.38 - 7.24 (m, 3H), 5.93 (d, J = 18.0 Hz, 1H), 5.65 (d, J = 17.9 Hz, 1H), 4.42 (dd, J = 9.0, 5.7 Hz, 1H), 3.96 - 3.90 (m, 1H), 2.71 (s, 3H), 2.43 - 2.28 (m, 1H), 2.25 - 2.12 (m, 1H), 1.99 - 1.83 (m, 1H), 1.14 - 0.99 (m, 1H), 0.74 - 0.59 (m, 1H);MS (ES+): 520.0 (M+1), (ES-): 518.0 (M-1);C 24 H 22 Analysis calculated for BrNO.sub.2.1.1HCl.sub.2.5H.sub.2O: C, 47.60; H, 4.68; Cl, ​​6.44; N, 16.19; Found: C, 47.64; H, 4.48; Cl, ​​6.39; N, 16.14.

[0253] Scheme 31 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (31f) Step 1: Preparation of 2-amino-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) NaH (1.990 g, 49.8 mmol) was added portionwise to a solution of malononitrile (3.29 g, 49.8 mmol) in cold THF (40 mL) at 0 °C. The resulting cloudy mixture was stirred at 0 °C for 1 h, followed by the slow addition of 2-bromo-3-nitropyridine (31a) (5.00 g, 24.63 mmol) in THF (10 mL). The mixture was then heated at 60 °C under argon for 3 h. The cooled mixture was quenched with HO (30 mL) and extracted with EtOAc (50 mL × 5). The combined organic extracts were washed with HO (50 mL × 2), brine (50 mL), dried, filtered, and concentrated to give 2-(3-nitropyridin-2-yl)malononitrile (8.62 g) as an orange-red solid, which was used directly in the next reaction. MS (ES+) 189 (M+1), (ES-) 187 (M-1). A suspension of 2-(3-nitropyridin-2-yl)malononitrile (4.315 g, 22.93 mmol), zinc (7.50 g, 115 mmol) in acetic acid (27.5 g, 459 mmol) was heated at 60 °C for 2 hours and filtered hot. The filter cake was thoroughly washed with boiling EtOH. The filtrate was concentrated to dryness. The concentrate was suspended in H2O (50 mL) and neutralized to pH 7 with 3 M aqueous NaOH, then extracted with EtOAc (50 mL × 3). The combined extracts were washed with H2O (30 mL × 2), brine (30 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO, 40 g, eluted with DMA-80 (0–20%) in DCM) to afford 2-amino-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) (320 mg, 9% yield) as a beige solid. 1 H NMR (300 MHz, DMSO- d6 ) δ 10.82 (s, 1H), 8.04 (dd, J = 5.0, 1.4 Hz, 1H), 7.36 (dd, J = 7.8, 1.4 Hz, 1H), 7.16 (s, 2H), 6.86 (dd, J = 7.8, 4.9 Hz, 1H);MS (ES+): 159 (M+1), (ES-): 157 (M-1).

[0254] Step 2: Preparation of 9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (31c) Compound 31c was prepared from 2-amino-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) (0.31 g, 1.960 mmol) using trimethyl orthoformate (4.16 g, 39.2 mmol), AcOH (0.589 g, 9.80 mmol), and NHOAc (0.755 g, 9.80 mmol) according to the procedure reported in Scheme 6, Step 1. This afforded 9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (31c) (100 mg, 28% yield) as a pale yellow solid after workup and purification [silica gel (12 g), eluted with DMA-80 (0-30%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 12.02 (d, J = 2.0 Hz, 1H), 8.49 (dd, J = 4.8, 1.4 Hz, 1H), 8.34 (s, 1H), 7.83 (dd, J = 8.1, 1.4 Hz, 1H), 7.37 (dd, J = 8.2, 4.8 Hz, 1H); MS (ES+): 186 (M+1), (ES-): 184 (M-1).

[0255] Step 3: Preparation of tert-butyl 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (31d) Compound 31d was prepared from 9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (31c) (80 mg, 0.432 mmol) in DMF (2.5 mL) using tert-butyl 2-bromoacetate (0.077 mL, 0.518 mmol), CsCO (282 mg, 0.864 mmol), and stirred at room temperature under a nitrogen atmosphere for 1.5 hours, followed by quenching with the addition of water. The separated solid was filtered and dried to give tert-butyl-2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (31d) (109 mg, 84% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (dd, J = 4.9, 1.3 Hz, 1H), 8.39 (s, 1H), 8.04 (dd, J = 8.3, 1.3 Hz, 1H), 7.43 (dd, J = 8.2, 4.8 Hz, 1H), 5.17 (s, 2H), 1.40 (s, 9H); MS (ES+): 300.1 (M+1).

[0256] Step 4: Preparation of 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (31e) Compound 31e was prepared from tert-butyl 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (31d) (80 mg, 0.267 mmol) using 20% ​​TFA in DCM (1534 μL, 4.01 mmol) and stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 2. This afforded, after workup, 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (31e) (64 mg, 98% yield) TFA salt as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (dd, J = 4.9, 1.3 Hz, 1H), 8.55 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.3, 4.9 Hz, 1H), 5.28 (s, 2H);MS (ES+): 244.10 (M+1).

[0257] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (31f) Compound 31f was prepared from the TFA salt of 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid 31e (60 mg, 0.247 mmol) in DMF (2 mL) using the TFA salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 4a (98.0 mg, 0.247 mmol), HATU (141 mg, 0.370 mmol), DIPEA (0.215 mL, 1.233 mmol) and stirring at room temperature for 1 hour. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (31f) (79 mg, 63% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.97 (s, 1H, D2O exchangeable), 8.75 - 8.64 (m, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.75 - 7.61 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H), 5.84 (d, J = 17.4 Hz, 1H), 5.47 (d, J = 17.3 Hz, 1H), 4.45 - 4.37 (m, 1H), 3.89 (ddd, J = 7.5, 5.4, 2.4 Hz, MS (ES+): 507.1 (M+1);(ES-): 505.0 (M-1);C 22 H 19 Analysis calculated for BrNO 1.75H 2 O. 1.2HCl: C, 45.35; H, 4.10; Cl, ​​7.30; N, 19.23; Found: C, 45.38; H, 4.02; Cl, ​​7.16; N, 18.95.

[0258] Scheme 32 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (32f) Step 1: Preparation of 2-amino-5-fluoro-1H-indole-3-carbonitrile (32b) Compound 32b was prepared from 2,2,2-trifluoro-N-(4-fluoro-2-iodophenyl)acetamide (32a) (7.03 g, 21.1 mmol; CAS#784183-55-7) in DMSO (30 mL) using malononitrile (1.673 g, 25.3 mmol), L-proline (0.486 g, 4.22 mmol), CuI (0.402 g, 2.110 mmol), KCO (5.83 g, 42.2 mmol) and heating at 60 °C under argon atmosphere for 15 h. This gave, after workup and purification [SiO gel (80 g), elution with 0-50% EtOAc in hexanes], 2-amino-5-fluoro-1H-indole-3-carbonitrile (32b) (2.657 g, 72% yield) as a brown solid. MS (ES+): 176.05 (M+1).

[0259] Step 2: Preparation of 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32c) Compound 32c was prepared from 2-amino-5-fluoro-1H-indole-3-carbonitrile (32b) (1.2 g, 6.85 mmol) in ethanol (30 mL) using formamidine acetate (5.76 g, 54.8 mmol) and refluxing for 40 h according to the procedure reported in Step 2 of Scheme 29. This gave, after workup, 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32c) as a brown solid (2.706 g), which was used directly in the next step. MS (ES+): 203.00 (M+1).

[0260] Step 3: Preparation of tert-butyl 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (32d) Compound 32d was prepared from 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32c) (346 mg, 1.71 mmol) in DMF (10 mL) using tert-butyl 2-bromoacetate (0.252 mL, 1.71 mmol), cesium carbonate (1.337 g), and stirring at room temperature for 47 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (32d) (160 mg, 30% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (40 g), eluting with hexane / 10% methanol in ethyl acetate (1:0 to 1:1)]. 1H NMR (300 MHz, DMSO-d6) δ 8.32 - 8.22 (m, 2H), 7.57 (dd, J = 8.9, 4.5 Hz, 1H), 7.38 (s, 2H), 7.26 (td, J = 9.2, 2.5 Hz, 1H), 5.12 (s, 2H), 1.39 (s, 9H); 19 F NMR (282 MHz, DMSO-d6) δ -122.42; MS (ES+): 317.10 (M+1).

[0261] Step 4: Preparation of 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (32e) Compound 32e was prepared from tert-butyl 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (32d) (140 mg, 0.443 mmol) in DCM (10 mL) using TFA according to the procedure reported in Step 2 of Scheme 1. The reaction mixture was concentrated to dryness to give 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (32e), which was used directly in the next step. MS (ES+): 261.10 (M+1); (ES-): 259.00 (M-1).

[0262] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (32f) Compound 32f was prepared from the TFA salt of 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (32e) (0.443 mmol, from Step 4 above) in DMF (15 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (141.0 mg, 0.443 mmol), HATU (337 mg, 0.886 mmol), DIPEA (0.386 mL, 2.215 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This afforded, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0–5%) in DCM], followed by treatment of the resulting product with acetonitrile (2 mL) and 50 mM aqueous HCl (8 mL) and lyophilization, (1R,3S,5R)-2-(2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (32f) (53 mg, 23% yield) HCl salt as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.73 (s, 2H, D2O exchangeable), 8.63 (s, 1H), 8.47 (dd, J = 9.8, 2.5 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.79 - 7.65 (m, 2H), 7.45 (td, J = 9.2, 2.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 17.3 Hz, 1H), 4.41 (dd, J = 9.0, 5.5 Hz, 1H), 4.02 - 3.82 (m, 1H), 2.41 - 2.12 (m, 2H), 1.99 - 1.79 (m, 1H), 1.16 - 0.97 (m, 1H), 0.82 - 0.71 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -119.89;MS (ES+): 524.10 & 526.10 (M+1);MS (ES-): 522.00 & 524.00 (M-1);C 23 H 19 Analysis calculated for BrFN7O2.1.2HCl.2.75H2O: C, 44.73; H, 4.19; N, 15.87; Cl, ​​6.89; Found: C, 44.84; H, 4.13; N, 15.51; Cl, ​​6.81.

[0263] Scheme 33 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (33e) Step 1: Preparation of 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b) Compound 33b was prepared from 2-amino-6-fluoro-1H-indole-3-carbonitrile (33a) (1.2 g, 6.85 mmol; CAS#378236-80-7) in ethanol (30 mL) using formamidine acetate (5.76 g, 54.8 mmol) and refluxing for 20 h according to the procedure reported in Scheme 29, Step 2. This gave, after workup, 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b) as a brown solid (2.62 g), which was used directly in the next step. 1 H NMR(300 MHz, DMSO-d6) δ 8.29 (dd, J = 8.7, 5.4 Hz, 1H), 8.23 ​​(s, 1H), 7.78 (s, 1H), 7.22 (dd, J = 9.7, 2.4 Hz, 1H), 7.10 - 7.01 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -116.72; MS (ES+): 203.10 (M+1).

[0264] Step 2: Preparation of tert-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (33c) Compound 33c was prepared from 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b) (346 mg, 1.71 mmol) in DMF (10 mL) using tert-butyl 2-bromoacetate (0.252 mL, 1.71 mmol), cesium carbonate (1.337 g), and stirring at room temperature for 46 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (33c) (151 mg, 28% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (40 g), eluting with hexane / 10% methanol in ethyl acetate (1:0 to 1:1)]. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (dd, J = 8.7, 5.4 Hz, 1H), 8.28 (s, 1H), 7.53 (dd, J = 10.2, 2.4 Hz, 1H), 7.31 (s, 2H), 7.17 - 7.04 (m, 1H), 5.11 (s, 2H), 1.40 (s, 9H); 19 F NMR (282 MHz, DMSO-d6) δ -116.10; MS (ES+): 317.20 (M+1).

[0265] Step 3: Preparation of 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (33d) Compound 33d was prepared from tert-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (33c) (145 mg, 0.458 mmol) in DCM (10 mL) using TFA according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (33d), which was used directly in the next step. MS (ES+): 261.10 (M+1); (ES-): 259.00 (M-1).

[0266] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (33e) Compound 33e was prepared from the TFA salt of 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (33d) (119 mg, 0.458 mmol) in DMF (15 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (146.0 mg, 0.458 mmol), HATU (348 mg, 0.916 mmol), DIPEA (0.399 mL, 2.29 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], followed by purification using flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM], dissolution of the product in acetonitrile (3 mL) and 0.1% aqueous HCl (20 mL), followed by lyophilization, (1R,3S,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (33e) (31 mg, 13% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.76 - 8.66 (m, 3H, D2O exchangeable), 8.63 (s, 1H), 8.56 (dd, J = 8.8, 5.2 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.75 - 7.63 (m, 2H), 7.37 - 7.25 (m, 2H), 5.76 (d, J = 17.4 Hz, 1H), 5.40 (d, J = 17.3 Hz, 1H), 4.42 (dd, J = 9.1, 5.5 Hz, 1H), 3.95 - 3.84 (m, 1H), 2.42 - 2.12 (m, 2H), 2.02 - 1.76 (m, 1H), 1.12 - 0.99 (m, 1H), 0.89 - 0.75 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -113.65;MS (ES+): 524.10 & 526.10 (M+1);MS (ES-): 522.10 & 524.00 (M-1);C 23 H 19 Analysis calculated for BrFNO.sub.2.1.1HCl.2.0H.sub.2O: C, 46.00; H, 4.05; Cl, ​​6.49; N, 16.33; Found: C, 46.28; H, 4.10; Cl, ​​6.44; N, 15.96.

[0267] Scheme 34 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (34e) Step 1: Preparation of 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b) Compound 34b was prepared from 2-amino-5-bromo-1H-indole-3-carbonitrile (34a) (2.20 g, 9.32 mmol; CAS#1242140-64-2) using triethyl orthoformate (31.0 mL, 186 mmol), AcOH (2.66 mL, 46.6 mmol), and NHOAc (3.59 g, 46.6 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b) (1.58 g, 64% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.26 (s, 1H), 7.48 (dd, J = 8.6, 1.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.30 (s, 2H); MS (ES+): 263 / 265 (M+1).

[0268] Step 2: Preparation of tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (34c) Compound 34c was prepared from 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b) (1.58 g, 6.01 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (1.171 g, 6.01 mmol), CsCO (2.348 g, 7.21 mmol), and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (34c) (2.265 g, 72% yield) as a pale orange solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.31 (s, 1H), 7.56 (s, 2H), 7.44 (s, 2H), 5.13 (s, 2H), 1.40 (s, 9H);MS (ES+): 377 / 379 (M+1), (ES-): 375 / 377 (M-1).

[0269] Step 3: Preparation of 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) Compound 34d was prepared from tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (34c) (0.300 g, 0.795 mmol) in DCM (10 mL) using TFA (0.907 g, 7.95 mmol) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) (0.387 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.70 - 8.44 (m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.7, 1.8 Hz, 1H), 5.26 (s, 2H);MS (ES+): 321 / 323 (M+1), (ES-): 319 / 321 (M-1).

[0270] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (34e) Compound 34e was prepared from the TFA salt of 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) (50 mg, 0.115 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (36.6 mg, 0.115 mmol), HATU (52.4 mg, 0.138 mmol), DIPEA (74.3 mg, 0.575 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (34e) (26 mg, 39% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H, D2O exchangeable), 8.76 (d, J = 3.1 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.38 (s, 2H, D2O exchangeable), 8.00 (d, J = 8.1 Hz, 1H), 7.75 - 7.58 (m, 3H), 7.32 (d, J = 7.7 Hz, 1H), 5.73 (dd, J = 17.7, 1.8 Hz, 1H), 5.39 (d, J = 17.4 Hz, 1H), 4.40 (dd, J = 9.2, 5.5Hz, 1H), 3.94 - 3.86 MS (ES+) 584.0 (M+1);(ES-): 582.0 (M-1);C 23 H 19 Analysis calculated for Br2N7O2.HCl.2.25H2O: C, 41.71; H, 3.73; Cl, ​​5.35; N, 14.81; Found: C, 41.55; H, 3.58; Cl, ​​5.49; N, 14.65.

[0271] Scheme 35 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (35f) Step 1: Preparation of 2-amino-7-bromo-1H-indole-3-carbonitrile (35b) Compound 35b was prepared from N-(2,6-dibromophenyl)-2,2,2-trifluoroacetamide (35a) (7.79 g, 22.45 mmol; CAS#340034-49-3) in DMSO (20 mL) using malononitrile (1.780 g, 26.9 mmol), L-proline (0.517 g, 4.49 mmol), CuI (0.428 g, 2.245 mmol), KCO (6.21 g, 44.9 mmol) and heating at 60 °C under argon atmosphere for 16 h. This gave, after workup and purification [SiO gel (40 g), elution with EtOAc (0–40%) in hexanes], 2-amino-7-bromo-1H-indole-3-carbonitrile (35b) (4.18 g, 18% yield) as a pale orange solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.15 (dd, J = 7.7, 1.0 Hz, 1H), 7.11 (dd, J = 7.9, 0.9 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.69 (s, 2H);MS (ES+): 236 ;(ES-): 234 (M-1).

[0272] Step 2: Preparation of 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35c) Compound 35c was prepared from 2-amino-7-bromo-1H-indole-3-carbonitrile (35b) (4.18 g, 17.71 mmol) using trimethyl orthoformate (37.6 mg, 354 mmol), AcOH (5.06 mL, 89 mmol), and NHOAc (6.82 g, 89 mmol) according to the procedure reported in Scheme 6, Step 1. This afforded, after workup, 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35c) as a pale yellow solid residue, which was used directly in the next step. 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.32 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.30 (s, 2H), 7.17 (t, J = 7.8 Hz, 1H).

[0273] Step 3: Preparation of tert-butyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (35d) Compound 35d was prepared from 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35c) (4.11 g, 15.62 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (3.05 g, 15.62 mmol), CsCO (6.62 g, 20.31 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (35d) (4.11 g, 88% yield) as a pale orange solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 8.39 (d, J = 7.8 Hz, 1H), 8.34 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.48 (s, 2H), 7.21 (t, J = 7.8 Hz, 1H), 5.44 (s, 2H), 1.43 (s, 9H).

[0274] Step 4: Preparation of 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (35e) Compound 35e was prepared from tert-butyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (35d) (0.250 g, 0.663 mmol) using TFA (1.511 g, 13.25 mmol) in DCM (20 mL) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (35e) (0.356 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 8.49 - 8.24 (m, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 5.54 (s, 2H).

[0275] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (35f) Compound 35f was prepared from the TFA salt of 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (35e) (50 mg, 0.115 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (36.6 mg, 0.115 mmol), HATU (52.4 mg, 0.138 mmol), DIPEA (74.3 mg, 0.575 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Scheme 1, Step 3. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (35f) (38 mg, 57% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.59 (s, 1H), 8.55 - 8.32 (m, 3H, 2H D2O exchangeable), 8.00 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 7.4 Hz, 2H), 7.30 (dt, J = 7.9, 4.0 Hz, 2H), 5.98 (d, J = 17.7 Hz, 1H), 5.84 - 5.72 (m, 1H), 4.41 (dd, J = 9.0, 5.7 Hz, 1H), 3.91 - 3.87 (m, 1H), 2.40 - 2.25 (m, MS (ES+): 584.0 (M+1), (ES-): 582.0 (M-1);C23 H 19 Analysis calculated for Br2N7O2.HCl.2H2O: C, 42.00; H, 3.68; Cl, ​​5.39; N, 14.91; Found: C, 41.98; H, 3.61; Cl, ​​5.08; N, 14.77.

[0276] Scheme 36 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36e) Step 1: Preparation of 7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (36b) Compound 36b was prepared from 2-amino-6-methoxy-1H-indole-3-carbonitrile (36a) (2.50 g, 13.35 mmol; CAS number 1016680-93-5) using triethyl orthoformate (44.4 mL, 267 mmol), AcOH (3.82 mL, 66.8 mmol), and NHOAc (5.15 g, 66.8 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (36b) (0.89 g, 31% yield) as a tan solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.17 (d, J = 9.9 Hz, 2H), 7.01 (s, 2H), 6.93 (d, J = 2.3 Hz, 1H), 6.82 (dd, 1H), 3.83 (s, 3H).

[0277] Step 2: Preparation of tert-butyl 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (36c) Compound 36c was prepared from 7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (36b) (0.89 g, 4.15 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.81 g, 4.15 mmol) and CsCO (1.624 g, 4.99 mmol) with stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (36c) (0.83 g, 61% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 7.5 Hz, 2H), 7.22 - 7.07 (m, 3H), 6.89 (dd, J = 8.6, 2.3 Hz, 1H), 5.10 (s, 2H), 3.85 (s, 3H), 1.41 (s, 9H).

[0278] Step 3: Preparation of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) Compound 36d was prepared from tert-butyl 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (36c) (0.83 g, 2.53 mmol) in DMF (20 mL) using TFA (5.76 g, 50.6 mmol) and stirring at room temperature for 16 hours according to the procedure reported in Step 2 of Scheme 1. The reaction mixture was concentrated in vacuo to give 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (1.18 g) TFA salt as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.59 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.8, 2.2 Hz, 1H), 5.28 (s, 2H), 3.89 (s, 3H).

[0279] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36e) Compound 36e was prepared from the TFA salt of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (50 mg, 0.129 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.2 mg, 0.129 mmol), HATU (59.1 mg, 0.155 mmol), DIPEA (84 mg, 0.647 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36e) (52 mg, 75% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H, D2O exchangeable), 8.48 (s, 1H), 8.35 (dd, J = 12.4, 6.2 Hz, 3H, 2H D2O exchangeable), 7.94 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.7, 2.2 Hz, 1H), 5.64 (d, J = 17.3 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 4.40 - 4.29 (m, 1H), 3.88 - 3.80 (m, 4H), 2.34 - 2.23 (m, 1H), 2.23 - 2.10 (m, 1H), 1.92 - 1.80 (m, 1H), 1.06 - 0.95 (m, 1H), 0.74 - 0.64 (m, 1H);MS (ES+): 536.0 (M+1), (ES-): 534.0 (M-1);C 24 H 22 BrN7O3.1.2HCl.2.25H2O: C, 46.44;H, 4.50;Cl, 6.85;N, 15.80;Actual value:C, 46.47;H, 4.50;Cl, 6.46;N, 15.867.

[0280] Scheme 37 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (37a) Compound 37a was prepared from the TFA salt of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (100 mg, 0.259 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (86 mg, 0.259 mmol), HATU (118 mg, 0.311 mmol), DIPEA (167 mg, 1.294 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (37a) (85 mg, 60% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H, D2O exchangeable), 8.55 (s, 1H), 8.46 (s, 2H, D2O exchangeable), 8.39 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 8.7, 2.3 Hz, 1H), 5.67 (d, J = 17.3 Hz, 1H), 5.37 (d, J = 17.3 Hz, 1H), 4.37 (dd, J = 9.2, 5.9 Hz, 1H), 3.87 (s, 3H), 3.69 (dd, J = 5.5, 2.3 Hz, 1H), 2.54 - 2.47 (m, 1H), 1.99 (dd, J = 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.07 - 0.97 (m, 1H), 0.96 - 0.83 (m, 1H);MS (ES+): 550.0 (M+1);(ES-): 548.0 (M-1).

[0281] Scheme 38 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (38e) Step 1: Preparation of 6-methoxy-9H-pyrimido[4,5-b]indol-4-amine (38b) Compound 38b was prepared from 2-amino-5-methoxy-1H-indole-3-carbonitrile (38a) (3.10 g, 16.56 mmol; CAS#1304143-87-0) using trimethyl orthoformate (35.1 g, 331 mmol), AcOH (4.74 mL, 83 mmol), and NHOAc (6.38 g, 83 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 6-methoxy-9H-pyrimido[4,5-b]indol-4-amine (38b) (2.78 g, 78% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.20 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.17 (s, 2H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 3.85 (s, 3H). MS (ES+): 215 (M+1), (ES-): 213 (M-1).

[0282] Step 2: Preparation of tert-butyl 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (38c) Compound 38c was prepared from 6-methoxy-9H-pyrimido[4,5-b]indol-4-amine (38b) (0.59 g, 2.75 mmol) in DMF (25 mL) using tert-butyl 2-bromoacetate (0.537 g, 2.75 mmol), CsCO (1.077 g, 3.30 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 1, Step 1. This afforded tert-butyl 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (38c) (0.56 g, 62% yield) as a pale yellow solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.31 (s, 2H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 5.07 (s, 2H), 3.87 (s, 3H), 1.40 (s, 9H).;MS (ES+): 329 (M+1), (ES-): 327 (M-1).

[0283] Step 3: Preparation of 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d) Compound 38d was prepared from tert-butyl 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (38c) (0.56 g, 1.705 mmol) in DCM (20 mL) using TFA (1.945 g, 17.05 mmol) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d) (0.68 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 - 8.44 (m, 3H), 8.05 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 5.23 (s, 2H), 3.89 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -74.16; MS (ES+): 273 (M+1), (ES-): 271 (M-1).

[0284] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (38e) Compound 38e was prepared from the TFA salt of 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d) (50 mg, 0.129 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.2 mg, 0.0.129 mmol), HATU (59.1 mg, 0.155 mmol), DIPEA (84 mg, 0.647 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (38e) (41 mg, 59% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.81 (s, 2H), 8.60 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 5.71 (d, J = 17.3 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.40 (dd, J = 9.0, 5.5 Hz, 1H), MS (ES+): 536 / 538 (M+1), (ES-): 534 / 536 (M-1);C 24 H 22 Analysis calculated for BrNO.HCl.2.75H.sub.2O: C, 46.31; H, 4.62; Cl, ​​5.70; N, 15.75; Found: C, 46.48; H, 4.40; Cl, ​​5.45; N, 15.18.

[0285] Scheme 39 [ka] Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39f) Step 1: Preparation of methyl 2-amino-3-cyano-1H-indole-5-carboxylate (39b) Compound 39b was prepared from methyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate (39a) (6.61 g, 17.72 mmol; CAS#848485-43-8) in DMSO (20 mL) using malononitrile (1.405 g, 21.26 mmol), L-proline (0.408 g, 3.54 mmol), CuI (0.337 g, 1.772 mmol), KCO (4.90 g, 35.4 mmol) and heating at 60 °C under argon atmosphere for 16 h. This gave, after workup and purification [SiO gel (40 g), elution with EtOAc (0–40%) in hexanes], methyl 2-amino-3-cyano-1H-indole-5-carboxylate (39b) (2.94 g, 77% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.2, 1.7 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.06 (s, 2H), 3.83 (s, 3H); MS (ES+): 216, (ES-): 214 (M-1).

[0286] Step 2: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylate (39c) Compound 39c was prepared from methyl 2-amino-3-cyano-1H-indole-5-carboxylate (39b) (2.94 g, 13.66 mmol) using trimethyl orthoformate (29.0 g, 273 mmol), AcOH (3.91 mL, 68.3 mmol), and NHOAc (5.27 g, 68.3 mmol) according to the procedure reported in Step 1 of Scheme 6. The pale yellow solid residue obtained after workup was used directly in the next step. 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.95 (s, 1H), 8.30 (s, 1H), 7.99 (dd, J = 8.5, 1.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.42 (s, 2H), 3.89 (s, 3H).

[0287] Step 3: Preparation of methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39d) Compound 39d was prepared from methyl 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylate (39c) (2.68 g, 11.06 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (2.158 g, 11.06 mmol), CsCO (4.33 g, 13.28 mmol), and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 1. This afforded methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39d) (2.50 g, 63% yield) as a pale orange solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J = 8.6, 1.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.54 (s, 2H), 5.18 (s, 2H), 3.91 (s, 3H), 1.40 (s, 9H).

[0288] Step 4: Preparation of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (39e) Compound 39e was prepared from methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39d) (2.50 g, 7.02 mmol) using TFA (16 g, 140 mmol) in DCM (20 mL) and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 2. This gave, after workup, 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (39e) (3.70 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.16 (d, J = 1.6 Hz, 1H), 8.65 (s, 2H), 8.60 (s, 1H), 8.13 (dd, J = 8.6, 1.6 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 3.93 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -74.65.

[0289] Step 5: Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39f) Compound 39f was prepared from the TFA salt of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (39e) (50 mg, 0.121 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (38.5 mg, 0.121 mmol), HATU (55.1 mg, 0.145 mmol), DIPEA (78 mg, 0.603 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39f) (53 mg, 78% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 9.13 (s, 1H), 8.59 (s, 1H), 8.54 (s, 2H, D2O exchangeable), 8.12 (dd, J = 8.7, 1.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.79 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 17.4 Hz, 1H), 4.41 (dd, J = 8.9, 5.5 Hz, 1H), 3.92 (s, 4H), 2.38 - 2.28 (m, 1H), 2.28 - 2.14 (m, 1H), 1.99 - 1.84 (m, 1H), 1.14 - 0.97 (m, 1H), 0.84 - 0.74 (m, 1H);MS (ES+): 564.0 (M+1), (ES-): 562.0 (M-1);C 25 H 22 Analysis calculated for BrNO.HCl.2.75H.sub.2O: C, 46.17; H, 4.42; Cl, ​​5.45; N, 15.08; Found: C, 46.19; H, 4.27; Cl, ​​5.68; N, 14.87.

[0290] Scheme 40 [ka] Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (40a) Compound 40a was prepared from the TFA salt of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (39e) (100 mg, 0.241 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (80 mg, 0.241 mmol), HATU (110 mg, 0.290 mmol), DIPEA (156 mg, 1.207 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (40a) (53 mg, 78% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 9.14 (s, 1H), 8.79 - 8.52 (m, 3H, 2H D2O exchangeable), 8.13 (dd, J = 8.7, 1.6 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.75 (d, J = 17.3 Hz, 1H), 5.39 (d, J = 17.3 Hz, 1H), 4.37 (dd, J = 9.0, 5.9 Hz, 1H), 3.92 (s, 3H), 3.69 (dd, J = 5.7, 2.4 Hz, 1H), 2.56 - 2.42 (m, 1H), 1.98 (dd, J = 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.05 - 0.97 (m, 1H), 0.97 - 0.90 (m, 1H);MS (ES+): 578.0 (M+1), (ES-): 576.0 (M-1);C 26 H 24 Analysis calculated for BrNO.HCl.2.25H.sub.2O: C, 47.65; H, 4.54; Cl, ​​5.41; N, 14.96; Found: C, 47.54; H, 4.50; Cl, ​​5.29; N, 14.92.

[0291] Scheme 41 [ka] Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41f) Step 1: Preparation of methyl 2-amino-3-cyano-1H-indole-6-carboxylate (41b) Compound 41b was prepared from methyl 4-iodo-3-(2,2,2-trifluoroacetamido)benzoate (41a) (6.73 g, 18.04 mmol; CAS#494799-11-0) in DMSO (20 mL) using malononitrile (1.430 g, 21.65 mmol), L-proline (0.415 g, 3.61 mmol), CuI (0.344 g, 1.804 mmol), KCO (4.99 g, 36.1 mmol) and heating at 60 °C under argon atmosphere for 16 h. This gave, after workup and purification [SiO gel (40 g), elution with EtOAc (0–50%) in hexanes], methyl 2-amino-3-cyano-1H-indole-6-carboxylate (41b) (1.32 g, 34% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.2, 1.5 Hz, 1H), 7.26 - 7.12 (m, 3H), 3.81 (s, 3H);MS (ES+): 216 (M+1), (ES-): 214 (M-1).

[0292] Step 2: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-7-carboxylate (41c) Compound 41c was prepared from methyl 2-amino-3-cyano-1H-indole-6-carboxylate (41b) (1.32 g, 6.13 mmol) using trimethyl orthoformate (13.02 g, 123 mmol), AcOH (1.754 mL, 30.7 mmol), and NHOAc (2.364 g, 30.7 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, methyl 4-amino-9H-pyrimido[4,5-b]indole-7-carboxylate (41c) (0.83 g, 56% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.82 (dd, J = 8.3, 1.5 Hz, 1H), 7.41 (s, 2H), 3.90 (s, 3H); MS (ES+): 243 (M+1), (ES-): 241 (M-1).

[0293] Step 3: Preparation of methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41d) Compound 41d was prepared from methyl 4-amino-9H-pyrimido[4,5-b]indole-7-carboxylate (41c) (0.83 g, 3.43 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.668 g, 3.43 mmol), CsCO (1.340 g, 4.11 mmol), and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 1. This afforded methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41d) (0.67 g, 55% yield) as a pale orange solid after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–3%) in DCM]. 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 8.3 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.89 (dd, J = 8.2, 1.4 Hz, 1H), 7.54 (s, 2H), 5.23 (s, 2H), 3.91 (s, 3H), 1.41 (s, 9H); MS (ES+): 357 (M+1), (ES-): 355 (M-1).

[0294] Step 4: Preparation of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (41e) Compound 41e was prepared from methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41d) (0.67 g, 1.880 mmol) using TFA (4.29 g, 37.6 mmol) in DCM (20 mL) and stirring at room temperature for 16 h, according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (41e) (3.70 g) TFA salt as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.71 - 8.47 (m, 4H), 8.36 (d, J = 1.4 Hz, 1H), 7.99 (dd, J = 8.3, 1.4 Hz, 1H), 5.36 (s, 2H), 3.93 (s, 3H);MS (ES+): 301 (M+1), (ES-): 299 (M-1).

[0295] Step 5: Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41f) Compound 41f was prepared from the TFA salt of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (41e) (50 mg, 0.121 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (38.5 mg, 0.121 mmol), HATU (55.1 mg, 0.145 mmol), DIPEA (78 mg, 0.603 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41f) (48 mg, 71% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.59 (d, J = 8.5 Hz, 1H), 8.57 (s, 1H), 8.45 (s, 2H, D2O exchangeable), 8.28 (s, 1H), 8.05 - 7.92 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.86 (d, J = 17.4 Hz, 1H), 5.49 (d, J = 17.3 Hz, 1H), 4.42 (dd, J = 9.1, 5.6 Hz, 1H), 3.92 (s, 4H), 2.39 - 2.29 (m, 1H), 2.29 - 2.16 (m, 1H), 2.01 - 1.87 (m, 1H), 1.15 - 1.03 (m, 1H), 0.76 - 0.69 (m, 1H);MS (ES+): 564 / 566 (M+1), (ES-): 562 / 564 (M-1);C 25 H 22 Analysis calculated for BrNO4.1.1.HCl.2.75.H2O: C, 45.91; H, 4.41; Cl, ​​5.96; N, 14.99; Found: C, 45.90; H, 4.21; Cl, ​​5.98; N, 14.69.

[0296] Scheme 42 [ka] Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (42a) Compound 42a was prepared from the TFA salt of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (41e) (100 mg, 0.241 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (80 mg, 0.241 mmol), HATU (110 mg, 0.290 mmol), DIPEA (156 mg, 1.207 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (42a) (82 mg, 59% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.70 - 8.41 (m, 4H, 2H D2O exchangeable), 8.29 (d, J = 1.4 Hz, 1H), 8.06 - 7.92 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.83 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 17.3 Hz, 1H), 4.38 (dd, J = 9.0, 5.9 Hz, 1H), 3.92 (s, 3H), 3.73 - 3.70 (m, 1H), 2.54 - 2.44 (m, 1H), 1.99 (m, 1H), 1.32 (s, 3H), 1.09 - 1.01 (m, 1H), 0.93 - 0.85 (m, 1H);MS (ES+): 578 / 580 (M+1), (ES-): 576 / 578 (M-1);C 26 H 24 Analysis calculated for BrNO.HCl.2.5.H2O: C, 47.32; H, 4.58; Cl, ​​5.37; N, 14.86; Found: C, 47.48; H, 4.28; Cl, ​​5.23; N, 14.68.

[0297] Scheme 43 [ka] Preparation of 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylic acid (43a) Compound 43a was prepared from methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (41f) (78 mg, 0.138 mmol) in THF (1 mL) and water (2 mL) using 2 M aqueous lithium hydroxide hydrate (0.138 mL, 0.276 mmol) and stirring at room temperature for 16 h. This gave, after work-up and purification by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxylic acid (43a) (34 mg, 45% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (two rotor mixture) 10.85 (s) and 10.77 (s) (2s, 1H, DO interchangeable), 8.93 (s, 2H, DO interchangeable), 8.69 (d, J = 4.9 Hz, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.67 (q, J = 7.7 Hz, 1H), 7.29 (dd, J = 7.7, 4.7 Hz, 1H), 5.87 (dd, J = 17.4, 11.5 Hz, 1H), 5.50 (dd, J = 17.3, 7.3 Hz, 1H), 4.42 (dd, J = 9.0, 5.5 Hz, 1H), 3.95 - 3.92 (m, 1H), 2.39 - 2.28 (m, 1H), 2.26 - 2.14 (m, 1H), 2.01 - 1.86 (m, 1H), 1.28 - 1.17 (m) and 1.16 - 1.04 (m) (2m, 1H), 1.02 - 0.83 (m) and 0.79 - 0.67 (m) (2m, 1H); MS (ES+): 550 / 552 (M+1), (ES-): 548 / 550 (M-1); C 24 H 20 Analysis calculated for BrNO4.1.1HCl.3H2O: C, 44.72; H, 4.24; Cl, ​​6.05; N, 15.21; Found: C, 44.67; H, 4.12; Cl, ​​6.07; N, 15.23.

[0298] Scheme 44 [ka] Preparation of 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylic acid (44a) Compound 44a was prepared from the TFA salt of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (39f) (156 mg, 0.276 mmol) in THF (2 mL) and water (4 mL) using 2 M aqueous lithium hydroxide hydrate (0.553 mL, 0.553 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in step 4 of scheme 17. This gave, after workup and purification by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0–100%) in water (containing 0.1% HCl)], 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylic acid (44a) (31 mg yield, 20%) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) (two rotor mix) δ 12.98 (s, 1H, DO exchangeable), 10.86 and 10.77 (2s, 1H, DO exchangeable), 9.11 (s, 1H), 8.60 and 8.58 (2s, 1H), 8.48 (s, 2H, DO exchangeable), 8.11 (dt, J = 8.6, 2.1 Hz, 1H), 8.01 and 7.96 (2d, J = 8.3 Hz, 1H), 7.78 - 7.62 (m, 2H), 7.38 - 7.22 (m, 1H), 5.79 (d, J = 17.3 Hz, 1H), 5.44 (d, J = 17.4 MS (ES+): 550.1 (M+1);(ES-): 548.0 (M-1);C 24 H 20Analysis calculated for BrNO2.25H2O.0.95HCl: C, 46.08; H, 4.10; Cl, ​​5.38; N, 15.67; Found: C, 46.42; H, 4.03; Cl, ​​4.94; N, 15.29.

[0299] Scheme 45 [ka] Preparation of ethyl 3-(4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)propanoate (45d) Step 1: Preparation of (E)-ethyl 3-(4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)acrylate (45a) A mixture of tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (34c) (200 mg, 0.53 mmol), ethyl acrylate (80 mg, 0.795 mmol), Pd(PPh)Cl (37.2 mg, 0.053 mmol), and KCO (220 mg, 1.591 mmol) was suspended in DMF (4 mL) in a sealed scintillation vial. The vial was flushed with nitrogen, and the yellow mixture was heated at 100 °C for 16 h. The resulting black mixture was filtered. The filtrate was diluted with H2O (25 mL) and extracted with EtOAc (25 mL × 3). The combined extracts were washed with H2O (25 mL × 4), brine (25 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel (24 g), eluting with EtOAc (0-60%) in hexanes) to give (E)-ethyl 3-(4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)acrylate (45a) (102 mg, 49% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.32 (s, 1H), 7.79 (d, J = 15.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.48 (s, 2H), 6.86 (d, J = 15.9 Hz, 1H), 5.15 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H);MS (ES+): 397 (M+1), (ES-): 395 (M-1).

[0300] Step 2: Preparation of ethyl 3-(4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)propanoate (45b) To a solution of (E)-ethyl 3-(4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)acrylate (45a) (100 mg, 0.252 mmol) in THF / ethanol (15 mL, 1:2) was added palladium hydroxide on carbon (7 mg) and heated at 100° C. under a hydrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with MeOH (0–3%) in DCM] to give ethyl 3-(4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)propanoate (45b) (80 mg, 80% yield) as a white semisolid. 1H NMR (300 MHz, DMSO-d6) δ 8.25 (d, J = 9.1 Hz, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.36 - 7.14 (m, 3H), 5.08 (s, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.01 (t, J = 7.8 Hz, 2H), 2.75 (t, J = 7.8 Hz, 2H), 1.40 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H); MS (ES+): 399 (M+1).

[0301] Step 3: Preparation of 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (45c) Compound 45c was prepared from ethyl 3-(4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)propanoate (45b) (78 mg, 0.196 mmol) in DCM (5 mL) using TFA (223 mg, 1.96 mmol) and stirring at room temperature for 16 h, according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (45c) TFA salt as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.41 (d, J = 10.5 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H), 4.06 (q, J = 7.1 Hz, 3H), 3.04 (t, J = 7.7 Hz, 2H), 2.76 (t, J = 7.8 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -74.25; MS (ES+): 343 (M+1), (ES-): 341 (M-1).

[0302] Step 4: Preparation of ethyl 3-(4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)propanoate (45d) Compound 45d was prepared from the TFA salt of 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (45c) (96 mg, 0.21 mmol) in DMF (5 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (67.0 mg, 0.210 mmol), HATU (96 mg, 0.252 mmol), DIPEA (136 mg, 1.05 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], ethyl 3-(4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)propanoate (45d) (44 mg, 35% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H, D2O exchangeable), 8.58 (s, 1H), 8.53 (s, 2H, D2O exchangeable), 8.39 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.3, 1.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.73 (d, J = 17.3 Hz, 1H), 5.39 (d, J = 17.3 Hz, 1H), 4.41 (dd, J = 9.0, 5.5 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.96 - 3.86 (m, 1H), 3.03 (t, J = 7.7 Hz, 2H), 2.74 (t, J = 7.8 Hz, 2H), 2.39 - 2.26 (m, MS (ES+): 606 / 608 (M+1), (ES-): 604 / 606 (M-1);C 28 H 28 Analysis calculated for BrNO.sub.1.25.HCl.1.75.H.sub.2O: C, 49.20; H, 4.83; Cl, ​​6.48; N, 14.34; Found: C, 49.16; H, 4.63; Cl, ​​6.68; N, 14.22.

[0303] Scheme 46 [ka] Preparation of ethyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46 g) Step 1: Preparation of methyl 2-bromo-3-(2,2,2-trifluoroacetamido)benzoate (46b) To a solution of methyl 3-amino-2-bromobenzoate (46a) (4.5 g, 19.56 mmol; CAS number 106896-48-4) and triethylamine (6.82 mL, 48.9 mmol) in DCM (30 mL), trifluoroacetic anhydride (4.08 mL, 29.3 mmol) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane (75 mL), washed with water (50 mL), dried, filtered, and concentrated in vacuo to give methyl 2-bromo-3-(2,2,2-trifluoroacetamido)benzoate (46b) as a yellow gum (8.17 g), which was used directly in the next step. MS (ES+): 325.90 (M+1); (ES-): 323.90 (M-1).

[0304] Step 2: Preparation of methyl 2-amino-3-cyano-1H-indole-4-carboxylate (46c) Compound 46c was prepared from methyl 2-bromo-3-(2,2,2-trifluoroacetamido)benzoate (46b) (1594 g, 4.89 mmol) in DMSO (8 mL) using malononitrile (388 mg, 5.87 mmol), L-proline (0.113 g, 0.978 mmol), CuI (93 mg, 0.489 mmol), and KCO (1.352 g, 9.78 mmol) in water (8 mL) and heated at 60 °C for 13 h under an argon atmosphere, according to the procedure reported in Step 1 of Scheme 11. This afforded, after workup and purification [SiO gel (24 g), eluted with EtOAc (0–66%) in hexanes], methyl 2-amino-3-cyano-1H-indole-4-carboxylate (46c) (115 mg, 11% yield) as a brown solid. (ES-): 214.00 (M-1).

[0305] Step 3: Preparation of methyl / ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) Compound 46d was prepared from methyl 2-amino-3-cyano-1H-indole-4-carboxylate (46c) (105 mg, 0.488 mmol) in ethanol (10 mL) using formamidine acetate (513 mg, 4.88 mmol) and heating to 100 °C in a microwave, following the procedure reported in Scheme 29, Step 2. The reaction mixture was filtered, washed with ethanol, and dried in vacuo. The residue was purified by flash column chromatography [SiO2 gel (24 g), eluting with 0–100% EtOAc in hexanes, followed by hexane / 10% methanol in ethyl acetate (1:1)] to afford a mixture of methyl and ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylates (46d) (66 mg) as a brown solid, which was used directly in the next step. MS(ES+):243.10, 257.10 (M+1).

[0306] Step 4: Preparation of methyl / ethyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46e) Compound 46e was prepared from a mixture of methyl / ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) (65 mg) in DMF (5 mL) using tert-butyl 2-bromoacetate (0.048 mL, 0.322 mmol), CsCO (219 mg, 0.671 mmol) and stirring at room temperature for 14 h, according to the procedure reported in Scheme 1, Step 1. This gave, after workup and purification by flash column chromatography [SiO gel (24 g), elution with 10% methanol (0–100%) in ethyl acetate in hexanes], methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (7 mg, 7%) (MS (ES+): 357.10 (M+1)); ethyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46e) (16 mg, 9% yield) as white solids (MS (ES+): 371.20 (M+1); (ES−): 369.00 (M−1)).

[0307] Step 5: Preparation of 2-(4-amino-5-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (46f) Compound 46f was prepared from ethyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46e) (16 mg, 0.043 mmol) using TFA (0.20 mL, 2.59 mmol) in DCM (5 mL) and stirring at room temperature for 17 hours according to the procedure reported in Scheme 1, Step 2. This gave, after workup, 2-(4-amino-5-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (46f), which was used directly in the next step 6 without further purification. MS (ES+): 315.10 (M+1).

[0308] Step 6: Preparation of ethyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46 g) Compound 46g was prepared from 2-(4-amino-5-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (46f) (13.51 mg, 0.043 mmol) in DMF (7 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (54.8 mg, 0.172 mmol), HATU (65.4 mg, 0.172 mmol), DIPEA (0.045 mL, 0.258 mmol) and stirring at room temperature for 19 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with hexanes / 10% MeOH (0–100%) in EtOAc], followed by conversion to the HCl salt by dissolving the product in acetonitrile (1.5 mL) and 0.1% aqueous HCl (6 mL), and lyophilization, ethyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46 g) (6.5 mg, 26% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H,), 8.57 (s, 1H), 8.14 - 7.93 (m, 4H,), 7.77 - 7.60 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 17.4 Hz, 1H), 5.49 (d, J = 17.3 Hz, 1H), 4.55 - 4.33 (m, 3H), 3.98 - 3.88 (m, 1H), 2.43 - 2.12 (m, 2H), 2.01 - 1.85 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.15 - 1.02 (m, 1H), 0.84 - 0.73 (m, 1H); MS (ES+): 578.10 & 580.10 (M+1).

[0309] Scheme 47 [ka] Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-8-carboxylate (47 g) Step 1: Preparation of methyl 3-bromo-2-(2,2,2-trifluoroacetamido)benzoate (47b) Compound 47b was prepared from methyl 2-amino-3-bromobenzoate (47a) (5 g, 21.73 mmol; CAS# 104670-74-8) in DCM (30 mL) using triethylamine (7.57 mL, 54.3 mmol), trifluoroacetic anhydride (4.53 mL, 32.6 mmol), and stirring at room temperature for 43 h, following the procedure reported in Step 1 of Scheme 46. This afforded, after workup and purification by flash column chromatography [SiO gel (120 g), EtOAc in hexanes (0–14%)], methyl 3-bromo-2-(2,2,2-trifluoroacetamido)benzoate (47b) as a yellow solid (5.27 g, 74% yield), which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.03 (dd, J = 8.1, 1.4 Hz, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 3.80 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -74.44; MS (ES-): 323.90 & 325.90 (M-1).

[0310] Step 2: Preparation of methyl 2-amino-3-cyano-1H-indole-7-carboxylate (47c) Compound 47c was prepared from methyl 3-bromo-2-(2,2,2-trifluoroacetamido)benzoate (47b) (2 g, 6.13 mmol) in DMSO (12 mL) using a solution of malononitrile (0.486 g, 7.36 mmol), L-proline (0.141 g, 1.227 mmol), CuI (0.117 g, 0.613 mmol), KCO (1.695 g, 12.27 mmol) in water (12 mL) and heated at 60 °C under argon atmosphere for 13 h, according to the procedure reported in Scheme 11, Step 1. This gave, after workup and purification by flash column chromatography [SiO gel (24 g), eluting with EtOAc (0–33%) in hexanes], methyl 2-amino-3-cyano-1H-indole-7-carboxylate (47c) (305 mg, 23% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.51 (dd, J = 7.8, 1.1 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.93 (s, 2H), 3.91 (s, 3H);MS (ES+): 216.00.

[0311] Step 3: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-8-carboxylate (47d) Compound 47d was prepared from methyl 2-amino-3-cyano-1H-indole-7-carboxylate (47c) (300 mg, 1.394 mmol) in ethanol (10 mL) using formamidine acetate (1466 mg, 13.94 mmol) and heating under reflux for 45 h according to the procedure reported in Scheme 29, Step 2. This gave, after workup, a gray solid residue (268 mg) which was used directly in the next step. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (dd, J = 7.8, 1.2 Hz, 1H), 8.34 (s, 1H), 7.97 (dd, J = 7.8, 1.1 Hz, 1H), 7.41 - 7.28 (m, 3H), 3.97 (s, 3H);MS (ES+): 243.10.

[0312] Step 4: Preparation of methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-8-carboxylate (47e) Compound 47e was prepared from methyl 4-amino-9H-pyrimido[4,5-b]indole-8-carboxylate (47d) (240 mg, 0.991 mmol) in DMF (6 mL) using tert-butyl 2-bromoacetate (0.176 mL, 1.189 mmol), CsCO (807 mg, 2.477 mmol), and stirring at room temperature overnight, following the procedure reported in Scheme 1, Step 1. This afforded methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-8-carboxylate (47e) (353 mg, 25% yield) as an off-white solid after workup and purification by flash column chromatography [SiO gel (24 g), eluted with 10% methanol (0–100%) in ethyl acetate in hexanes]. 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (dd, J = 7.9, 1.2 Hz, 1H), 8.36 (s, 1H), 7.84 - 7.79 (m, 1H), 7.49 (s, 2H), 7.37 (t, J = 7.8 Hz, 1H), 5.35 (s, 2H), 3.90 (s, 3H), 1.36 (s, 9H);MS (ES+): 357.15.

[0313] Step 5: Preparation of 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (47f) Compound 47f was prepared from methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-8-carboxylate (47e) (80 mg, 0.224 mmol) using TFA in DCM (10 mL) and stirring at room temperature according to the procedure reported in Scheme 1, Step 2. This gave, after workup, 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (47f), which was used directly in the next step 6 without purification. MS (ES+): 301.10 (M+1).

[0314] Step 6: Preparation of methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-8-carboxylate (47 g) Compound 47g was prepared from 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (47f) (67.3 mg, 0.224 mmol) in DMF (10 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (71.4 mg, 0.224 mmol), HATU (170 mg, 0.448 mmol), DIPEA (0.195 mL, 1.12 mmol) and stirring at room temperature for 18 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0–5%) in DCM], followed by conversion to the HCl salt by dissolving the product in acetonitrile (2 mL) and 0.1% aqueous HCl (8 mL) and lyophilization, methyl 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-8-carboxylate (47 g) (38 mg, 30% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H, D2O exchangeable), 8.65 (d, J = 7.7 Hz, 1H), 8.51 (s, 1H), 8.17 - 7.91 (m, 3H, 2H D2O exchangeable), 7.82 (d, J = 7.7 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.95 (d, J = 17.5 Hz, 1H), 5.64 (d, J = 17.3 Hz, 1H), 4.39 - 4.27 (m, 1H), 3.92 (s, 3H), 3.87 - 3.72 (m, 1H), 2.37 - 2.09 (m, 2H), 1.97 - 1.78 (m, 1H), 1.16 - 0.99 (m, 1H), 0.83 - 0.65 (m, 1H);MS (ES+): 564.10 & 566.10 (M+1); MS (ES-): 562.10 & 564.10 (M-1).

[0315] Scheme 48 [ka] Preparation of tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)carbamate (48d) Step 1: Preparation of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) Compound 48a was prepared from 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b) (540 mg, 2.053 mmol) in DMF (10 mL) using ethyl 2-bromoacetate (0.228 mL, 2.053 mmol), CsCO (802 mg, 2.463 mmol), triethylamine (1.716 mL, 12.32 mmol), and stirring at room temperature for 27 h, according to the procedure reported in Scheme 16, Step 2. This afforded, after workup, 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (166 mg) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 8.7, 1.8 Hz, 1H), 7.45 (s, 2H), 5.23 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H); MS (ES+): 349.00 & 350.90 (M+1).

[0316] Step 2: Preparation of ethyl 2-(4-amino-6-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (48b) Compound 48b was prepared from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (150 mg, 0.430 mmol) in toluene (8 mL) using XPhos, t-butyl carbamate, Pd(dba), CsCO (140 mg, 0.43 mmol) and heating at 90 °C for 20 h according to the procedure reported in Scheme 17, Step 3. This gave, after workup and purification, ethyl 2-(4-amino-6-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (48b) (10 mg, 6% yield); MS (ES+): 386.20 (M+1).

[0317] Step 3: Preparation of 2-(4-amino-6-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (48c) Compound 48c was prepared from ethyl 2-(4-amino-6-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (48b) (10 mg, 0.026 mmol) in THF (2 mL) and MeOH (2 mL) using lithium hydroxide hydrate (6.67 mg, 0.156 mmol) and stirring at room temperature for 18 hours, following the procedure reported in Step 4 of Scheme 17. This gave, after workup, 2-(4-amino-6-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (48c), which was used directly in the next step 4. MS (ES+): 358.20 (M+1); (ES-): 356.10 (M-1).

[0318] Step 4: Preparation of tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)carbamate (48d) Compound 48d was prepared from 2-(4-amino-6-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (48c) (from Step 3 above, 0.026 mmol) in DMF (6 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (71 mg, 0.224 mmol), HATU (40 mg, 0.104 mmol), DIPEA (0.027 mL, 0.156 mmol) and stirring at room temperature for 14 h. This gave, after work-up and purification by flash column chromatography [silica gel (4 g), eluting with MeOH (0–5%) in DCM], followed by conversion to the HCl salt in acetonitrile (1 mL) using 0.1% aqueous HCl (5 mL) and lyophilization, tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)carbamate (48d) HCl salt (6 mg, 37% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 9.26 (s, 1H, D2O exchangeable), 8.54 (s, 1H), 8.38 (s, 1H), 8.29 (s, 2H, D2O exchangeable), 8.01 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.70 (d, J = 17.3 Hz, 1H), 5.37 (d, J = 17.2 Hz, 1H), 4.41 (dd, J = 9.1, 5.5 Hz, 1H), 3.96 - 3.85 (m, 1H), 2.44 - 2.07 (m, 2H), 1.98 - 1.81 (m, 1H), 1.49 (s, 9H), 1.13 - 0.98 (m, 1H), 0.85 - 0.62 (m, 1H);MS (ES+): 621.20 & 623.20 (M+1);MS (ES-): 619.10 & 621.10 (M-1).

[0319] Scheme 49 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (49c) Step 1: Preparation of ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) To a mixture of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (300 mg, 0.859 mmol) and dicyanozinc (303 mg, 2.58 mmol) in DMF (8 mL) was added Pd(PPh3)4 (149 mg, 0.129 mmol), degassed, filled with nitrogen, and heated at 100° C. for 13 h. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water (2×60 mL), brine (60 mL), dried, filtered, concentrated in vacuo, and triturated with ethyl acetate (20 mL). The resulting solid was collected by filtration and dried under vacuum to give ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (160 mg, 63% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.94-8.93 (m, 1H), 8.36 (s, 1H), 7.86-7.80 (m, 2H), 7.59 (s, 2H), 5.31 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H); MS (ES+): 296.10 (M+1); (ES-): 294.10 (M-1).

[0320] Step 2: Preparation of 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (49b) Compound 49b was prepared from ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (80 mg, 0.271 mmol) in THF (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide hydrate (69.6 mg, 1.625 mmol) in water (3 mL) and stirred at room temperature for 15 hours, following the procedure reported in Step 4 of Scheme 17. This afforded 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (49b) (72 mg, 100% yield) after workup, which was used directly in Step 3 without further purification. MS (ES+): 268.10 (M+1).

[0321] Step 3: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (49c) Compound 49c was prepared from 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (49b) (0.072 g, 0.271 mmol) in DMF (10 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (0.104 g, 0.325 mmol), HATU (0.206 g, 0.542 mmol), DIPEA (175 mg, 1.355 mmol) and stirring at room temperature for 22 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel (12 g), 10% MeOH in EtOAc (0–100%) in hexanes], followed by conversion to the HCl salt in acetonitrile (5 mL) using 0.1% aqueous HCl (30 mL) and lyophilization, (1R,3S,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (49c) HCl salt (54 mg, 38% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 9.09 (d, J = 1.5 Hz, 1H), 8.74 - 8.54 (m, 3H, 2H D2O exchangeable), 8.00 (d, J = 8.2 Hz, 1H), 7.94 (dd, J = 8.6, 1.4 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 17.4 Hz, 1H), 5.45 (d, J = 17.3 Hz, 1H), 4.42 (dd, J = 9.0, 5.5 Hz, 1H), 3.95 - 3.84 (m, 1H), 2.42 - 2.08 (m, 2H), 1.98 - 1.83 (m, 1H), 1.16 - 0.98 (m, 1H), 0.90 - 0.67 (m, 1H);MS (ES+): 531.10 & 533.10 (M+1);MS (ES-): 529.00 & 531.10 (M-1);C 24 H 19 Analysis calculated for BrNO.sub.2.0.85HCl.2.0H.sub.2O: C, 48.17; H, 4.02; Cl, ​​5.04; N, 18.73; Found: C, 48.54; H, 4.17; Cl, ​​5.36; N, 18.40.

[0322] Scheme 50 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (50f) Step 1: Preparation of 2-amino-4-fluoro-1H-indole-3-carbonitrile (50b) Compound 50b was prepared from N-(2-bromo-3-fluorophenyl)-2,2,2-trifluoroacetamide (50a) (5 g, 17.48 mmol; CAS# 118313-91-0) in DMSO (20 mL) using malononitrile (1.386 g, 20.98 mmol), L-proline (0.403 g, 3.50 mmol), CuI (0.333 g, 1.748 mmol), KCO (4.83 g, 35.0 mmol) and heating at 60 °C under argon atmosphere for 16 h. This gave, after workup and purification by flash column chromatography [SiO gel (40 g), eluting with EtOAc (0–50%) in hexanes], 2-amino-4-fluoro-1H-indole-3-carbonitrile (50b) (0.3 g, 10% yield) as a brown solid. 1 MS (ES+): 176.0 (M+1), (ES-): 174.0 (M-1).

[0323] Step 2: Preparation of 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50c) Compound 50c was prepared from 2-amino-4-fluoro-1H-indole-3-carbonitrile (50b) (0.3 g, 1.713 mmol) using trimethyl orthoformate (3.64 g, 34.3 mmol), AcOH (0.490 mL, 8.56 mmol), and NHOAc (0.660 g, 8.56 mmol) according to the procedure reported in Scheme 6, Step 1. This afforded 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50c) (83 mg, 24% yield) as a tan solid after workup and purification by reverse-phase column chromatography [C18 column (30 g), eluted with ACN (0–100%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.60 (s, 1H), 7.61 - 7.38 (m, 2H), 7.23 (dd, J = 11.3, 7.8 Hz, 1H); MS (ES+): 203.04 (M+1).

[0324] Step 3: Preparation of tert-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d) Compound 50d was prepared from the HCl salt of 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50c) (80 mg, 0.335 mmol) in DMF (2.5 mL) using tert-butyl 2-bromoacetate (65.4 mg, 0.335 mmol), CsCO (218 mg, 0.670 mmol), and stirring at room temperature for 1.5 h, following the procedure reported in Step 2 of Scheme 16. The separated solid was collected by filtration and dried to give tert-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d) (83 mg, 78% yield) as a pale yellow solid. 1 MS (ES+): 317.10 (M+1).

[0325] Step 4: Preparation of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (50e) Compound 50e was prepared from tert-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d) (80 mg, 0.253 mmol) using 20% ​​TFA in DCM (1452 μL, 3.79 mmol) and stirring at room temperature for 16 h, following the procedure reported in Step 2 of Scheme 1. This afforded, after workup, the TFA salt of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (50e) (85 mg, 90% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.49 (td, J = 8.1, 5.5 Hz, 1H), 7.20 (dd, J = 11.3, 8.0 Hz, 1H), 5.22 (s, 2H);MS (ES+): 261.00 (M+1).

[0326] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (50f) Compound 50f was prepared from the TFA salt of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (50e) (50 mg, 0.134 mmol) in DMF (1.5 mL) using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (52.9 mg, 0.134 mmol), HATU (76 mg, 0.200 mmol), DIPEA (0.116 mL, 0.668 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Scheme 1, Step 3. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (50f) (53 mg, 76% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.68 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.35 - 7.20 (m, 2H), 5.79 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 17.3 Hz, 1H), 4.43 (dd, J = 9.1, 5.5 Hz, 1H), 3.91 (ddd, J = 7.4, 5.4, 2.3 Hz, 1H), 2.40 - 2.14 (m, 2H), 1.92 (dq, J = 13.3, 6.5, 6.0 Hz, 1H), 1.08 (dt, J = 8.7, 5.4 Hz, 1H), 0.79 (td, J = 5.2, 2.4 Hz, 1H); 19F NMR (282 MHz, DMSO-d6) δ -113.23;MS (ES+): 524.0 (M+1);546.0 (M+Na);(ES-): 522.0 (M-1);C 23 H 19 Analysis calculated for BrFN7O2.1.75H2O.1HCl: C, 46.64; H, 4.00; Cl, ​​5.99; N, 16.55; Found: C, 46.50; H, 3.71; Cl, ​​5.73; N, 16.29.

[0327] Scheme 51 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (51 g) Step 1: Preparation of 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (51b) Compound 51b was prepared from 2-fluoro-6-iodoaniline (51a) (5 g, 21.10 mmol; CAS#886762-73-8) in DCM (50 mL) using triethylamine (5 mL, 35.9 mmol), trifluoroacetic anhydride (4.40 mL, 6.65 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 46, Step 1. This afforded, after workup, 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (51b) (6.5 g, 93% yield) as a yellow solid, which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1H), 7.81 (dt, J = 8.0, 1.2 Hz, 1H), 7.43 (ddd, J = 9.6, 8.4, 1.3 Hz, 1H), 7.26 (td, J = 8.2, 5.6 Hz, 1H);MS (ES-): 331.80 (M-1).

[0328] Step 2: Preparation of 2-amino-7-fluoro-1H-indole-3-carbonitrile (51c) Compound 51c was prepared from 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (51b) (6.4 g, 19.22 mmol) in DMSO (20 mL) using malononitrile (1.452 mL, 23.06 mmol), L-proline (0.443 g, 3.84 mmol), CuI (0.366 g, 1.922 mmol), and KCO (5.31 g, 38.4 mmol) under argon atmosphere and heated at 60 °C for 16 h, according to the procedure reported in Scheme 11, Step 1. This gave, after workup and purification [SiO gel (40 g), eluted with 0–50% EtOAc in hexanes], 2-amino-7-fluoro-1H-indole-3-carbonitrile (51c) (1.535 g, 46% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.03 - 6.88 (m, 2H), 6.88 - 6.66 (m, 3H); MS (ES+): 176.0 (M+1), (ES-): 174.0 (M-1).

[0329] Step 3: Preparation of 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51d) Compound 51d was prepared from 2-amino-7-fluoro-1H-indole-3-carbonitrile (51c) (1.5 g, 8.56 mmol) using trimethyl orthoformate (18.74 mL, 171 mmol), AcOH (2.449 mL, 42.8 mmol), and NHOAc (3.30 g, 42.8 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51d) (1.54 g, 69% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 11.98 (s, 1H), 8.29 (s, 1H), 8.18 - 8.03 (m, 1H), 7.27 (s, 2H), 7.26 - 7.16 (m, 2H), 1.92 (s, 3H);MS (ES+): 203.10 (M+1).

[0330] Step 4: Preparation of tert-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (51e) Compound 51e was prepared from the AcOH salt of 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51d) (1.5 g, 5.72 mmol) in DMF (35 mL) using tert-butyl 2-bromoacetate (1.171 g, 6.01 mmol), CsCO (4.10 g, 12.58 mmol) and stirring at room temperature for 15 h, followed by the addition of KCO (0.791 g, 5.72 mmol), tert-butyl 2-bromoacetate (0.845 mL, 5.72 mmol) and stirring for an additional 3 h, according to the procedure reported in Scheme 16, Step 2. This gave, after workup, tert-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (51e) (1.15 g, 64% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.22 - 8.16 (m, 1H), 7.45 (s, 2H), 7.28 - 7.21 (m, 2H), 5.17 (d, J = 2.0 Hz, 2H), 1.42 (s, 9H);MS (ES+): 317.14 (M+1).

[0331] Step 5: Preparation of 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (51f) Compound 51f was prepared from tert-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (51e) (0.9 g, 2.85 mmol) using 20% ​​TFA in DCM (16.33 mL, 42.7 mmol) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (51f) (0.92 g, 86% yield) TFA salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.32 - 8.23 ​​(m, 1H), 8.07 (s, 2H), 7.40 - 7.27 (m, 2H), 5.25 (d, J = 1.9 Hz, 2H);MS (ES+): 261.10 (M+1).

[0332] Step 6: Preparation of (1R,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (51 g) Compound 51g was prepared from the TFA salt of 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (51f) (75 mg, 0.200 mmol) according to the procedure reported in Step 3 of Scheme 1 using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (79 mg, 0.200 mmol), HATU (114 mg, 0.301 mmol), DIPEA (0.175 mL, 1.002 mmol) in DMF (2 mL) and stirring at room temperature for 16 hours. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (51 g) (81 mg, 77% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H, D2O exchangeable), 8.60 (s, 1H), 8.45 (s, 2H, D2O exchangeable), 8.32 (dd, J = 5.8, 3.0 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.41 - 7.26 (m, 3H), 5.81 (d, J = 17.5 Hz, 1H), 5.57 - 5.38 (m, 1H), 4.44 (dd, J = 9.0, 5.6 Hz, 1H), 3.98 - 3.80 (m, 1H), 2.40 - 2.13 (m, 2H), 2.01-1.83 (m, 1H), 1.10 (dt, J = 9.3, 5.4 Hz, 1H), 0.64 (q, J = 3.8, 2.9 Hz, 1H). 19F NMR (282 MHz, DMSO-d6) δ -134.64. MS (ES+): 524.1 (M+1);(ES-): 522.1 (M-1);C 23 H 19 Analysis calculated for BrFN7O2.2H2O.0.9HCl: C, 46.57; H, 4.06; Cl, ​​5.38; N, 16.53; Found: C, 46.54; H, 3.90; Cl, ​​5.43; N, 16.32.

[0333] Scheme 52 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (52f) Step 1: Preparation of 2-amino-6-bromo-1H-indole-3-carbonitrile (52b) Compound 52b was prepared from N-(5-bromo-2-iodophenyl)-2,2,2-trifluoroacetamide (52a) (6.4 g, 16.25 mmol; CAS# 1870674-39-7) in DMSO (20 mL) using malononitrile (1.228 mL, 19.50 mmol), L-proline (0.374 g, 3.25 mmol), CuI (0.309 g, 1.625 mmol), KCO (4.49 g, 32.5 mmol) and heating at 60 °C under argon atmosphere for 16 h. This gave, after workup and purification [SiO gel (40 g), elution with EtOAc (0–50%) in hexanes], 2-amino-6-bromo-1H-indole-3-carbonitrile (52b) (2.06 g, 54% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.17 - 7.00 (m, 2H), 6.95 (s, 2H);MS (ES+): 236.0 (M+1), (ES-): 233.9 (M-1).

[0334] Step 2: Preparation of 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (52c) Compound 52c was prepared from 2-amino-6-bromo-1H-indole-3-carbonitrile (52b) (2 g, 8.47 mmol) using trimethyl orthoformate (17.98 g, 169 mmol), AcOH (2.54 g, 42.4 mmol), and NHOAc (3.27 g, 42.4 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (52c) (2.29 g, 84% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 2H), 8.27 (t, J = 4.2 Hz, 2H), 7.58 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 7.26 (s, 2H), 1.92 (s, 3H).

[0335] Step 3: Preparation of tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (52d) Compound 52d was prepared from the AcOH salt of 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (52c) (2.2 g, 6.81 mmol) in DMF (75 mL) using tert-butyl 2-bromoacetate (1.056 g, 7.15 mmol), CsCO (4.88 g, 14.98 mmol) and stirring at room temperature for 15 h, followed by the addition of KCO (0.941 g, 6.81 mmol), tert-butyl 2-bromoacetate (1.006 mL, 6.81 mmol) and stirring at room temperature for 3 h, according to the procedure reported in Scheme 16, Step 2. This gave, after workup, tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (52d) (1.25 g, 49% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.31 (t, J = 4.2 Hz, 2H), 7.91 (d, J = 1.7 Hz, 1H), 7.46 - 7.36 (m, 3H), 5.14 (s, 2H), 1.41 (s, 9H).

[0336] Step 4: Preparation of 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (52e) Compound 52e was prepared from tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (52d) (0.3 g, 0.795 mmol) using 20% ​​TFA in DCM (4.56 mL, 11.93 mmol) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (52e) (0.31 g, 90% yield) TFA salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 5.23 (s, 2H);MS (ES+): 321.00 (M+1).

[0337] Step 5: Preparation of (1R,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (52f) Compound 52f was prepared from the TFA salt of 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (52e) (75 mg, 0.172 mmol) in DMF (2 mL) using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (68.3 mg, 0.172 mmol), HATU (98 mg, 0.259 mmol), DIPEA (0.150 mL, 0.862 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Scheme 1, Step 3. This resulted in workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0–100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0–100%) in water (containing 0.1% HCl)] to afford (1R,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (52f) (79 mg, 78% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H, D2O exchangeable), 8.70 (s, 2H, D2O exchangeable), 8.64 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.08 - 7.97 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.60 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.79 (d, J = 17.4 Hz, 1H), 5.42 (d, J = 17.3 Hz, 1H), 4.43 (dd, J = 9.0, 5.5 Hz, 1H), 3.90 (ddd, J = 7.6, 5.4, 2.4 Hz, 1H), 2.39 - 2.10 (m, 2H), 2.01 - 1.83 (m, 1H), 1.08 (dt, J = 8.8, 5.5 Hz, 1H), 0.79 (td, J = 5.2, 2.4 Hz, 1H). MS (ES+): 586.0 (M+1);(ES-): 584.0 (M-1);C 23 H 19 Analysis calculated for Br2N7O2.2H2O.1HCl: C, 42.00; H, 3.68; Cl, ​​5.39; N, 14.91; Found: C, 42.08; H, 3.55; Cl, ​​5.18; N, 14.77.

[0338] Scheme 53 [ka] Preparation of (S)-5-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53d) Step 1: Preparation of (S)-tert-butyl 6-((6-bromopyridin-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (53b) To a stirred solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (53a) (0.5 g, 2.072 mmol) in DCM (15 mL) was added 1-methyl-1H-imidazole (0.413 mL, 5.18 mmol) under a nitrogen atmosphere at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 10 min, and methanesulfonyl chloride (0.192 mL, 2.487 mmol) was added, followed by stirring at 0-5 °C for 1 h. To this mixture was added 6-bromopyridin-2-amine (0.359 g, 2.072 mmol) and stirred at room temperature for 18 h. Water (30 mL) was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with DCM (3 × 30 mL). The combined organics were washed with 1N HCl (30 mL), saturated aqueous NaHCO3 (30 mL), brine (30 mL), dried, filtered, and concentrated in vacuo to give (S)-tert-butyl 6-((6-bromopyridin-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (53b) (0.8 g, 97% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.90 (d, J = 18.6 Hz, 1H), 8.11 (dd, J = 13.0, 8.1 Hz, 1H), 7.75 (q, J = 7.8 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 4.57 - 4.39 (m, 1H), 3.32 - 3.16 (m, 2H), 2.15 (ddd, J = 27.3, 12.8, 8.3 Hz, 1H), 1.83 (ddd, J = 35.1, 12.6, 5.2 Hz, 1H), 1.33 (d, J = 36.8Hz, 9H), 0.68 - 0.41 (m, 4H); MS (ES+): 396.00 (M+1).

[0339] Step 2: Preparation of (S)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53c) Compound 53c was prepared from (S)-tert-butyl 6-((6-bromopyridin-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (53b) (0.8 g, 2.019 mmol) using TFA (0.778 mL, 10.09 mmol) in DCM (7 mL) and stirring overnight at room temperature, following the procedure reported in Step 2 of Scheme 1. This gave, after workup, the TFA salt of (S)—N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53c) (0.55 g, 92% yield). 1 H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.71 (s, 1H), 8.90 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 4.63 - 4.47 (m, 1H), 3.20 (d, J = 5.2 Hz, 2H), 2.33 (dd, J = 13.1, 8.6 Hz, 1H), 2.03 (dd, J = 13.1, 7.0 Hz, 1H), 0.76 - 0.46 (m, 4H);MS (ES+): 295.93 (M+1).

[0340] Step 3: Preparation of (S)-5-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53d) Compound 53d was prepared from the TFA salt of (S)—N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53c) (72.5 mg, 0.177 mmol) in DMF (2 mL) using the TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (11e) (75 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol), DIPEA (0.154 mL, 0.884 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Scheme 1, Step 3. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (S)-5-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53d)) (89 mg, 86% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) (two rotor mix) δ 11.25 and 10.82 (2s, 1H, DO interchangeable), 8.96 (s, 1H), 8.59 and 8.57 (2s, 1H), 8.52 (s, 2H, DO interchangeable), 8.19 and 8.02 (2d, J = 8.2 Hz, 1H), 7.94 - 7.78 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.41 and 7.32 (2d, J = 7.7 Hz, 1H), 5.45 (d, J = 2.4 Hz, 2H), 4.65 (dd, J = 8.5, 5.0 Hz, 1H), 3.90 - 3.74 (m, 2H), 2.25 (dd, J = 12.7, 8.4 Hz, 1H), 1.89 (dd, J = 12.6, 4.9 Hz, 1H), 0.81 - 0.49 (m, 4H). 19F NMR (282 MHz, DMSO-d6) δ -58.70. MS (ES+): 588.1 (M+1);(ES-): 586.1 (M-1);C 25 H 21 Analysis calculated for BrF3N7O21.5H2O.1.1HCl: C, 45.81; H, 3.86; Cl, ​​5.95; N, 14.96; Found: C, 45.85; H, 3.73; Cl, ​​5.91; N, 14.70.

[0341] Scheme 54 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (54 g) Step 1: Preparation of N-(2-bromo-6-methoxyphenyl)-2,2,2-trifluoroacetamide (54b) Compound 54b was prepared from 2-bromo-6-methoxyaniline (54a) (5 g, 24.75 mmol; CAS#5473-01-8) in DCM (50 mL) using triethylamine (5.86 mL, 42.1 mmol), trifluoroacetic anhydride (5.16 mL, 37.1 mmol), and stirring at room temperature for 16 h according to the procedure reported in Scheme 46, Step 1. This afforded, after workup, N-(2-bromo-6-methoxyphenyl)-2,2,2-trifluoroacetamide (54b) (7.35 g, 100% yield) as a pale yellow solid, which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.40 - 7.26 (m, 2H), 7.18 (dd, J = 7.1, 2.5 Hz, 1H), 3.82 (s, 3H); MS (ES-): 295.9 (M-1).

[0342] Step 2: Preparation of 2-amino-7-methoxy-1H-indole-3-carbonitrile (54c) Compound 54c was prepared from N-(2-bromo-6-methoxyphenyl)-2,2,2-trifluoroacetamide (54b) (7.2 g, 24.16 mmol) in DMSO (20 mL) using malononitrile (1.826 mL, 29.0 mmol), L-proline (0.556 g, 4.83 mmol), CuI (0.460 g, 2.416 mmol), and KCO (6.68 g, 48.3 mmol) under argon atmosphere and stirring at 60 °C for 16 h, according to the procedure reported in Step 1 of Scheme 11. This afforded 2-amino-7-methoxy-1H-indole-3-carbonitrile (54c) (2.308 g, 51% yield) as a yellow solid after workup and purification [SiO gel (40 g), eluted with EtOAc (0–50%) in hexane]. 1 H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 6.92 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.37 (s, 2H), 3.86 (s, 3H);MS (ES+): 188.1 (M+1);(ES-): 186.0 (M-1).

[0343] Step 3: Preparation of 8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (54d) Compound 54d was prepared from 2-amino-7-methoxy-1H-indole-3-carbonitrile (54c) (2.3 g, 12.29 mmol) using trimethyl orthoformate (26.1 g, 246 mmol), AcOH (3.51 mL, 61.4 mmol), and NHOAc (4.74 g, 61.4 mmol) according to the procedure reported in Scheme 6, Step 1. This gave, after workup, 8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (54d) (2.7 g, 80% yield) as the AcOH salt as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.91 (s, 1H), 8.23 ​​(s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.08 (s, 2H), 6.98 (d, J = 7.9 Hz, 1H), 3.95 (s, 3H), 1.91 (s, 3H).

[0344] Step 4: Preparation of tert-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (54e) Compound 54e was prepared from the AcOH salt of 8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (54d) (2.6 g, 9.48 mmol) in DMF (75 mL) using tert-butyl 2-bromoacetate (1.471 mL, 9.95 mmol), CsCO (6.80 g, 20.86 mmol) and stirring at room temperature for 15 h, followed by the addition of tert-butyl 2-bromoacetate (1.401 mL, 9.48 mmol), KCO (1.31 g, 9.48 mmol) and stirring for 3 h, according to the procedure reported in Scheme 16, Step 2. The separated solid was filtered and dried to give tert-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (54e) (1.87 g, 60% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.26 (s, 2H), 7.20 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H), 3.89 (s, 3H), 1.42 (s, 9H).

[0345] Step 5: Preparation of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) Compound 54f was prepared from tert-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (54e) (0.9 g, 2.74 mmol) using 20% ​​TFA in DCM (15.73 mL, 41.1 mmol) and stirring at room temperature for 16 h according to the procedure reported in Step 2 of Scheme 1. This gave, after workup, the TFA salt of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) (0.46 g, 43% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.20 (s, 2H), 8.05 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 3.92 (s, 3H).

[0346] Step 6: Preparation of (1R,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (54 g) Compound 54g was prepared from the TFA salt of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) (75 mg, 0.194 mmol) in DMF (2 mL) using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (77 mg, 0.194 mmol), HATU (111 mg, 0.291 mmol), DIPEA (0.169 mL, 0.971 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (1R,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (54g) (85 mg, 82% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H, D2O exchangeable), 8.60 (s, 1H), 8.57 (s, 2H, D2O exchangeable), 8.08 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.40 - 7.24 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 17.0 Hz, 1H), 5.59 (d, J = 16.9 Hz, 1H), 4.43 (dd, J = 8.9, 5.6 Hz, 1H), 3.94 (s, 3H), 3.85 (td, J = 6.3, 5.3, 2.3 Hz, 1H), 2.42 - 2.14 (m, 2H), 2.06-1.88 (m, 1H), 1.12 (dt, J = 10.0, 5.5 Hz, 1H), 0.67 (td, J = 5.3, 2.4 Hz, 1H). MS (ES+): 536.1 (M+1);(ES-): 534.1 (M-1);C 24 H 22 Analysis calculated for BrNO.2H.sub.2O.1HCl: C, 47.34; H, 4.47; Cl, ​​5.82; N, 16.10; Found: C, 47.34; H, 4.40; Cl, ​​5.48; N, 15.94.

[0347] Scheme 55 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (55a) Compound 55a was prepared from the TFA salt of 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e) (50 mg, 0.135 mmol) in DMF (2 mL) using the HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (44.9 mg, 0.135 mmol), HATU (77 mg, 0.203 mmol), DIPEA (0.118 mL, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (55a) (47 mg, 65% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H, D2O exchangeable), 8.51 (s, 1H), 8.35 (s, 2H, D2O exchangeable), 8.24 (dd, J = 6.2, 3.0 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.27 - 7.14 (m, 3H), 5.81 (d, J = 18.0 Hz, 1H), 5.54 (d, J = 17.9 Hz, 1H), 4.31 (dd, J = 9.0, 6.1 Hz, 1H), 3.63 (dd, J = 5.6, 2.3 Hz, 1H), 2.62 (s, 3H), 2.48 - 2.45 (m, 1H), 1.91 (dd, J = 13.1, 6.1 Hz, 1H), 1.24 (s, 3H), 0.95 (t, J = 5.4 Hz, 1H), 0.77 (dd, J = 5.4, 2.4 Hz, 1H);MS (ES+): 534.1 (M+1);(ES-): 532.1 (M-1);C 25 H 24 Analysis calculated for BrNO 1.5H 2 O. 0.9HCl: C, 50.53; H, 4.73; Cl, ​​5.37; N, 16.50; Found: C, 50.38; H, 4.74; Cl, ​​5.68; N, 16.43.

[0348] Scheme 56 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (56 g) Step 1: Preparation of 2,2,2-trifluoro-N-(2-iodo-3-methylphenyl)acetamide (56b) Compound 56b was prepared from 2-iodo-3-methylaniline (56a) (5 g, 21.45 mmol; CAS#89938-16-9) in DCM (75 mL) using triethylamine (5.08 mL, 36.5 mmol), trifluoroacetic anhydride (4.47 mL, 32.2 mmol), and stirring at room temperature for 16 h according to the procedure reported in Scheme 46, Step 1. This afforded, after workup, 2,2,2-trifluoro-N-(2-iodo-3-methylphenyl)acetamide (56b) (6.9 g, 21% yield) as a pale yellow solid, which was used directly in the next step. 1 H NMR (300 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.43 - 7.24 (m, 2H), 7.17 (dd, J = 6.1, 3.3 Hz, 1H), 2.47 (s, 3H); MS (ES-): 327.90 (M-1).

[0349] Step 2: Preparation of 2-amino-4-methyl-1H-indole-3-carbonitrile (56c) Compound 56c was prepared from 2,2,2-trifluoro-N-(2-iodo-3-methylphenyl)acetamide (56b) (4.9 g, 14.89 mmol) in DMSO (15 mL) using malononitrile (1.125 mL, 17.87 mmol), L-proline (0.343 g, 2.98 mmol), CuI (0.284 g, 1.489 mmol), and KCO (4.12 g, 29.8 mmol) under argon atmosphere and heated at 60 °C for 16 h. This afforded, after workup and purification [SiO gel (80 g), elution with 0–50% EtOAc in hexane], 2-amino-4-methyl-1H-indole-3-carbonitrile (56c) (0.81 g, 32% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.70 (dt, J = 7.3, 1.0 Hz, 1H), 6.62 (s, 2H), 2.48 (s, 3H); MS (ES-): 170.10 (M-1).

[0350] Step 3: Preparation of 5-methyl-9H-pyrimido[4,5-b]indol-4-amine (56d) Compound 56d was prepared from 2-amino-4-methyl-1H-indole-3-carbonitrile (56c) (0.8 g, 4.67 mmol) in ethanol (30 mL) using formamidine acetate (3.93 g, 37.4 mmol) and refluxing for 22 h according to the procedure reported in Step 2 of Scheme 29. This gave 5-methyl-9H-pyrimido[4,5-b]indol-4-amine (56d) (114 mg, 12% yield) HCl salt as a pale yellow solid after workup and purification by reverse-phase column chromatography [C18 column (275 g), eluted with ACN (0–100%) in water (containing 0.1% HCl)]. 1 H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.65 (s, 1H), 8.03 (s, 2H), 7.49 - 7.32 (m, 2H), 7.22 - 7.05 (m, 1H), 2.94 (s, 3H);MS (ES+): 199.10 (M+1).

[0351] Step 4: Preparation of tert-butyl 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (56e) Compound 56e was prepared from the HCl salt of 5-methyl-9H-pyrimido[4,5-b]indol-4-amine (56d) (110 mg, 0.469 mmol) in DMF (3 mL) using tert-butyl 2-bromoacetate (0.076 mL, 0.516 mmol), CsCO (336 mg, 1.031 mmol), and stirring at room temperature for 1.5 h, according to the procedure reported in Scheme 16, Step 2. This afforded, after workup, tert-butyl 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (56e) (130 mg, 89% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.42 - 7.24 (m, 2H), 7.04 (d, J = 7.1 Hz, 1H), 6.79 (s, 2H), 5.11 (s, 2H), 2.96 (s, 3H), 1.41 (s, 9H);MS (ES+): 313.20 (M+1).

[0352] Step 5: Preparation of 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (56f) Compound 56f was prepared from tert-butyl 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (56e) (100 mg, 0.320 mmol) using 20% ​​TFA in DCM (1837 μL, 4.80 mmol) and stirring at room temperature for 16 hours, following the procedure reported in Step 2 of Scheme 1. This afforded, after workup, 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (56f) (115 mg, 97% yield) TFA salt as a white solid. MS (ES+): 257.10 (M+1).

[0353] Step 6: Preparation of (1R,3S,5R)-2-(2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (56 g) Compound 56g was prepared from the TFA salt of 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (56f) (50 mg, 0.135 mmol) in DMF (1.5 mL) using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (53.5 mg, 0.135 mmol), HATU (77 mg, 0.203 mmol), DIPEA (0.118 mL, 0.675 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (56 g) (34 mg, 48% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.60 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.79 - 7.65 (m, 3H, 2H D2O exchangeable), 7.52 - 7.37 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 5.74 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 17.3 Hz, 1H), 4.42 (dd, J = 9.1, 5.4 Hz, 1H), 3.94 - 3.86 (m, 1H), 2.96 (s, 3H), 2.36 - 2.13 (m, 2H), 1.99 - 1.84 (m, 1H), 1.07 (dt, J = 9.3, 5.3 Hz, 1H), 0.78 (dt, J = 5.5, 2.7 Hz, 1H). MS (ES+): 520.1 (M+1);542.1 (M+Na);(ES-): 518.0 (M-1).

[0354] Scheme 57 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (57 g) Step 1: Preparation of 2,2,2-trifluoro-N-(2-iodo-3-methoxyphenyl)acetamide (57b) Compound 57b was prepared from 2-iodo-3-methoxyaniline (57a) (5 g, 20.08 mmol; CAS#98991-09-4) in DCM (75 mL) using triethylamine (4.76 mL, 34.1 mmol), trifluoroacetic anhydride (4.19 mL, 30.1 mmol), and stirring at room temperature for 16 h, following the procedure reported in Scheme 46, Step 1. This afforded, after workup, 2,2,2-trifluoro-N-(2-iodo-3-methoxyphenyl)acetamide (57b) (6.8 g, 98% yield) as a dark oil, which was used directly in the next step. MS (ES-): 343.90 (M-1).

[0355] Step 2: Preparation of 2-amino-4-methoxy-1H-indole-3-carbonitrile (57c) Compound 57c was prepared from 2,2,2-trifluoro-N-(2-iodo-3-methoxyphenyl)acetamide (57b) (5.1 g, 14.78 mmol) in DMSO (15 mL) using malononitrile (1.117 mL, 17.74 mmol), L-proline (0.340 g, 2.96 mmol), CuI (0.281 g, 1.478 mmol), and KCO (4.12 g, 29.8 mmol) under argon atmosphere and heated at 60 °C for 16 h. This afforded 2-amino-4-methoxy-1H-indole-3-carbonitrile (57c) (1.35 g, 49% yield) as a gray solid after workup and purification by flash column chromatography [SiO gel (80 g), eluting with 0–50% EtOAc in hexane]. 1 H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.63 - 6.56 (m, 3H), 3.71 (s, 3H): 188.10 (M+1);(ES-): 186.10 (M-1).

[0356] Step 3: Preparation of 5-methoxy-9H-pyrimido[4,5-b]indol-4-amine (57d) Compound 57d was prepared from 2-amino-4-methoxy-1H-indole-3-carbonitrile (57c) (1.3 g, 6.94 mmol) in ethanol (45 mL) using formamidine acetate (5.84 g, 55.6 mmol) and refluxing for 22 h according to the procedure reported in Step 2 of Scheme 29. This gave 5-methoxy-9H-pyrimido[4,5-b]indol-4-amine (57d) (0.9 g, 61% yield) HCl salt as a pale yellow solid after workup and purification by reverse-phase column chromatography [C18 column (275 g), eluted with ACN (0–100%) in water (containing 0.1% HCl)]. 1 H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.60 (s, 2H), 8.55 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.7, 2.4 Hz, 1H), 3.87 (s, 3H); MS (ES+): 215.10 (M+1).

[0357] Step 4: Preparation of tert-butyl 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (57e) Compound 57e was prepared from the HCl salt of 5-methoxy-9H-pyrimido[4,5-b]indol-4-amine (57d) (810 mg, 3.23 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.525 mL, 3.55 mmol), CsCO (2316 mg, 7.11 mmol), and stirring at room temperature for 1.5 h, according to the procedure reported in Step 2 of Scheme 16. This afforded, after workup, tert-butyl 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (57e) (990 mg, 93% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.31 - 8.07 (m, 2H), 7.18 - 7.10 (m, 3H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H), 5.10 (s, 2H), 3.84 (s, 3H), 1.41 (s, 9H);MS (ES+): 329.20 (M+1).

[0358] Step 5: Preparation of 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) Compound 57f was prepared from tert-butyl 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (57e) (200 mg, 0.609 mmol) using 20% ​​TFA in DCM (3496 μL, 9.14 mmol) and stirring at room temperature for 16 h, following the procedure reported in Step 2 of Scheme 1. This afforded, after workup, the TFA salt of 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) (225 mg, 96% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.45 - 8.34 (m, 2H), 7.44 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.7, 2.2 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H); MS (ES+): 273.10 (M+1).

[0359] Step 6: Preparation of (1R,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (57 g) Compound 57g was prepared from the TFA salt of 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) (50 mg, 0.129 mmol) in DMF (1.5 mL) using the TFA salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (51.3 mg, 0.129 mmol), HATU (73.8 mg, 0.194 mmol), DIPEA (0.113 mL, 0.647 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (57 g) (35 mg, 50% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H, D2O exchangeable), 8.53 (s, 1H), 8.42 - 8.19 (m, 3H, 2H D2O exchangeable), 8.02 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 8.7, 2.2 Hz, 1H), 5.71 (d, J = 17.2 Hz, 1H), 5.42 (d, J = 17.2 Hz, 1H), 4.42 (dd, J = 9.0, MS (ES+): 536.1 (M+1);558.1 (M+Na);(ES-): 534.1 (M-1);C 24 H 22 Analysis calculated for BrNO.sub.7O.sub.31.5H.sub.2O.sub.1HCl: C, 48.05; H, 4.37; Cl, ​​5.91; N, 16.34; Found: C, 48.01; H, 4.33; Cl, ​​5.97; N, 16.16.

[0360] Scheme 58 [ka] Preparation of (1R,3S,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (58c) Step 1: Preparation of ethyl 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (58a) To a suspension of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in toluene (8 mL) was added tributyl(1-ethoxyvinyl)stannane (0.279 mL, 0.802 mmol), and the mixture was degassed and filled with nitrogen. Subsequently, Pd(PPh) (132 mg, 0.115 mmol) was added and heated at 120 °C for 14 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), treated with 1 N HCl (30 mL), water (30 mL), and subsequently stirred at room temperature for 15 min. The mixture was treated with 2 M KCO, extracted, and separated. The organic layer was washed with brine (60 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with methanol (0–5%) in DCM] to give ethyl 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (58a) (20 mg, 11% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.01 (dd, J = 8.6, 1.6 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.60 (s, MS (ES+): 313.10 (M+1).

[0361] Step 2: Preparation of 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (58b) Compound 58b was prepared from ethyl 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (58a) (18 mg, 0.058 mmol) in THF (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (14.81 mg, 0.346 mmol) in water (3 mL) and stirred at room temperature for 14 hours, following the procedure reported in Step 4 of Scheme 17. This gave, after workup, 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (58b) (17 mg, 100%), which was used directly in Step 3 without further purification. MS (ES+): 285.10 (M+1), (ES-): 283.0 (M-1).

[0362] Step 3: Preparation of (1R,3S,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (58c) Compound 58c was prepared from 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (58b) (17 mg, 0.058 mmol) in DMF (8 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (74 mg, 0.232 mmol), HATU (88 mg, 0.232 mmol), DIPEA (0.061 mL, 0.348 mmol) and stirring at room temperature for 20 hours, according to the procedure reported in Scheme 1, Step 3. This afforded, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-5%) in DCM], followed by conversion of the resulting product to its HCl salt by dissolving in acetonitrile (2 mL) and 0.1% aqueous HCl (15 mL), and lyophilization, (1R,3S,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (58c) HCl salt (27 mg, 85% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 9.09 (d, J = 1.6 Hz, 1H), 8.73 - 8.50 (m, 3H, 2H D2O exchangeable), 8.11 (dd, J = 8.7, 1.6 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.79 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 17.3 Hz, 1H), 4.41 (dd, J = 9.0, 5.6 Hz, 1H), 4.00 - 3.84 (m, 1H), 2.72 (s, 3H), 2.39 - 2.12 (m, 2H), 1.99 - 1.82 (m, 1H), 1.14 - 1.01 (m, 1H), 0.89 - 0.71 (m, 1H);MS (ES+): 548.10 & 550.10 (M+1);MS (ES-): 546.00 & 548.10 (M-1).

[0363] Scheme 59 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (59c) Step 1: Preparation of ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (59a) To a degassed solution of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (8 mL) was added a solution of potassium vinyltrifluoroborate (153 mg, 1.146 mmol), Pd(PPh) (132 mg, 0.115 mmol), and KCO (158 mg, 1.146 mmol) in water (2.3 mL) and heated under nitrogen at 80 °C for 20 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (25 g), eluting with 10% methanol (0–50%) in ethyl acetate in hexane] to give ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (59a) (82 mg, 48% yield) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.28 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.8, 1.5 Hz, 1H), 7.38 (s, 2H), 6.84 (dd, J = MS (ES+): 297.10 (M+1).

[0364] Step 2: Preparation of 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (59b) Compound 59b was prepared from ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (59a) (80 mg, 0.270 mmol) in THF (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (69.4 mg, 1.620 mmol) in water (3 mL) and stirred at room temperature for 20 hours, following the procedure reported in Step 4 of Scheme 17. This gave, after workup, 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (59b) (72 mg, 100%), which was used directly in Step 3 without further purification. MS (ES+): 269.10 (M+1), (ES-): 267.0 (M-1).

[0365] Step 3: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (59c) Compound 59c was prepared from 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (59b) (72 mg, 0.27 mmol) in DMF (12 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (172 mg, 0.540 mmol), HATU (308 mg, 0.810 mmol), DIPEA (0.235 mL, 1.350 mmol) and stirring at room temperature for 20 hours, according to the procedure reported in Scheme 1, Step 3. This afforded, after work-up and purification by flash column chromatography [silica gel (24 g), eluting with MeOH (0–5%) in DCM], followed by conversion of the resulting product to its HCl salt by dissolving in acetonitrile (5 mL) and 0.1% aqueous HCl (30 mL), and lyophilization, (1R,3S,5R)-2-(2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (59c) HCl salt (54 mg, 38% yield) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H, D2O exchangeable), 8.60 (s, 1H), 8.54 (s, 1H), 8.36 (s, 2H, D2O exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.63 (s, 2H), 7.32 (d, J = 7.7 Hz, 1H), 6.86 (dd, J = 17.8, 10.8 Hz, 1H), 6.01 (d, J = 17.7 Hz, 1H), 5.72 (d, J = 17.5 Hz, 1H), 5.39 (d, J = 17.1 Hz, 1H), 5.29 (d, J = 11.0 Hz, 1H), 4.47 - 4.36 (m, 1H), 3.96 - 3.85 (m, 1H), 2.43 - 2.13 (m, 2H), 2.00 - 1.83 (m, 1H), 1.14 - 0.99 (m, 1H), 0.85 - 0.67 (m, 1H);MS (ES+): 532.10 & 534.10 (M+1);MS (ES-): 530.05 & 532.10 (M-1);C 25 H 22 Analysis calculated for BrNO.1.0HCl.2.25H.sub.2O: C, 49.27; H, 4.55; Cl, ​​5.82; N, 16.09; Found: C, 49.02; H, 4.49; Cl, ​​5.61; N, 16.04.

[0366] Scheme 60 [ka] Preparation of 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxamide (60c) Step 1: Preparation of ethyl 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (60a) A suspension of ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (70 mg, 0.237 mmol) in ethanol (6 mL) was treated with concentrated NHOH (2.25 mL) followed by hydrogen peroxide (0.084 mL, 0.948 mmol) and stirred at room temperature for 48 h. The resulting solid was collected by filtration, washed with ethanol, and dried to give ethyl 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (60a) (40 mg, 54%) as a white solid residue, which was used directly in the next step. MS (ES+): 314.10 (M+1).

[0367] Step 2: Preparation of 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (60b) Compound 60b was prepared from ethyl 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (60a) (38 mg, 0.121 mmol) in THF (2 mL) and methanol (2 mL) using a solution of lithium hydroxide hydrate (31.2 mg, 0.728 mmol) in water (2 mL) and stirred at room temperature for 68 hours, following the procedure reported in Step 4 of Scheme 17. This gave, after workup, 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (60b) (35 mg, 100%), which was used directly in Step 3 without further purification. MS (ES+): 286.10 (M+1), (ES-): 284.0 (M-1).

[0368] Step 3: Preparation of 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxamide (60c) Compound 60c was prepared from 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (60b) (34.5 mg, 0.121 mmol) in DMF (8 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (77 mg, 0.242 mmol), HATU (92 mg, 0.242 mmol), DIPEA (0.105 mL, 0.605 mmol) and stirring at room temperature for 19 hours, according to the procedure reported in Scheme 1, Step 3. This gave, after work-up and purification by flash column chromatography [silica gel (4 g), eluting with MeOH (0-10%) in DCM] followed by reverse-phase column chromatography [C18 column, eluting with ACN (0-100%) in water (containing 0.1% HCl)], 4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxamide (60c) (12 mg, 18% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 8.36 (s, 2H, D2O exchangeable), 8.08 - 7.97 (m, 2H), 7.89 (s, 1H, D2O exchangeable), 7.78 - 7.63 (m, 2H), 7.47 (s, 1H, D2O exchangeable), 7.31 (d, J = 7.7 Hz, 1H), 5.76 (d, J = 17.3 Hz, 1H), 5.42 (d, J = 17.4 Hz, 1H), 4.42 (dd, J = 9.2, 5.5 Hz, 1H), 3.95 - 3.86 (m, 1H), 2.41 - 2.10 (m, 2H), 2.01 - 1.74 (m, 1H), 1.18 - 0.98 (m, 1H), 0.87 - 0.69 (m, 1H);MS (ES+): 549.10 & 551.10 (M+1);MS (ES-): 547.05 & 549.10 (M-1).

[0369] Scheme 61 [ka] Preparation of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,6-diamino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (61a) Compound 61a was prepared from tert-butyl (4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)carbamate (48d) (6 mg, 9.65 μmol) in DCM (5 mL) using TFA according to the procedure reported in Scheme 1, Step 2. This gave, after workup and purification by reverse-phase column chromatography [C18 column, elution with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,6-diamino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (61a) (3.9 mg, 77% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.09 (s, 2H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.32 (d, J = 7.6 Hz, 1H), 5.69 (d, J = 17.4 Hz, 1H), 5.37 (d, J = 17.4 Hz, 1H), 4.48 - 4.34 (m, 1H), 3.97 - 3.83 (m, MS (ES+): 521.10 & 523.10 (M+1).

[0370] Scheme 62 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (62c) Step 1: Preparation of ethyl 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (62a) A degassed solution of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (150 mg, 0.43 mmol) and phenylboronic acid (79 mg, 0.644 mmol) in dioxane (15 mL) was treated with cesium carbonate (210 mg, 0.644 mmol), Pd(PPh)Cl (60.3 mg, 0.086 mmol) in water (1.8 mL) and heated at 100 °C under nitrogen for 14 h. The reaction mixture was diluted with ethyl acetate / methanol (2:1, 75 mL), filtered, washed with ethyl acetate / methanol (2:1), and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography [SiO gel (25 g), eluting with MeOH (5–40%) in DCM] to give ethyl 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (62a) (86 mg, 58% yield) as an off-white solid. MS (ES+): 347.15.

[0371] Step 2: Preparation of 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b) Compound 62b was prepared from ethyl 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (62a) (80 mg, 0.231 mmol) in THF (2 mL) and methanol (2 mL) using a solution of lithium hydroxide hydrate (59.3 mg, 1.386 mmol) in water (2 mL) and stirred at room temperature for 19 hours, following the procedure reported in Step 4 of Scheme 17. This gave, after workup, 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b) (59 mg, 80%), which was used directly in Step 3 without further purification. MS (ES+): 319.10 (M+1).

[0372] Step 3: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (62c) Compound 62c was prepared from 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b) (59 mg, 0.185 mmol) in DMF (8 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (89 mg, 0.278 mmol), HATU (141 mg, 0.371 mmol), DIPEA (0.097 mL, 0.556 mmol) and stirring at room temperature for 21 hours, according to the procedure reported in Scheme 1, Step 3. This afforded, after work-up and purification by flash column chromatography [silica gel (12 g), eluting with 10% MeOH (0–100%) in hexanes / EtOAc in hexanes], followed by conversion to the HCl salt by dissolving the resulting product in acetonitrile (2 mL) and 0.1% aqueous HCl (15 mL) and lyophilization, (1R,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (62c) (51.5 mg, 48% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, D2O exchangeable), 8.77 (s, 1H), 8.56 (s, 1H), 8.43 (s, 2H, D2O exchangeable), 8.01 (d, J = 8.1 Hz, 1H), 7.90 - 7.80 (m, 3H), 7.79 - 7.66 (m, 2H), 7.55 - 7.47 (m, 2H), 7.42 - 7.36 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.77 (d, J = 17.3 Hz, 1H), 5.44 (d, J = 17.3 Hz, 1H), 4.42 (dd, MS (ES+): 582.10 & 584.20 (M+1);MS (ES-): 580.10 & 582.10 (M-1);C 29 H 24 Analysis calculated for BrNO.1.0HCl.1.5H.sub.2O: C, 53.92; H, 4.37; N, 15.18; Cl, ​​5.49; Found: C, 54.10; H, 4.48; N, 14.92; Cl, ​​5.28.

[0373] Scheme 63 [ka] Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(aminomethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (63d) Step 1: Preparation of ethyl / methyl 2-(4-amino-6-((tert-butoxycarbonylamino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (63a) To an ice / water-cooled solution of ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (100 mg, 0.339 mmol) in MeOH (8 mL) was added di-tert-butyl dicarbonate (299 mg, 1.355 mmol), nickel(II) chloride hexahydrate (40.2 mg, 0.169 mmol), followed by sodium borohydride (78 mg, 2.032 mmol) slowly over 5 min and stirred at room temperature for 1 h. The reaction mixture was treated with N-(2-aminoethyl)ethane-1,2-diamine (0.148 mL, 1.355 mmol), stirred at room temperature for 30 min, and concentrated to dryness. The resulting residue was purified by flash column chromatography [silica gel (25 g), 10% methanol in ethyl acetate in hexane (0-100%), followed by methanol in dichloromethane (0-33%) and DMA80] to give a mixture of ethyl / methyl 2-(4-amino-6-((tert-butoxycarbonylamino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (63a) (7 mg, 5%) as a colorless gum (MS (ES+): 400.20 (M+1); 386.20 (M+1)) and 2-(4-amino-6-(((tert-butoxycarbonyl)amino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (63b) (15 mg, 12%) as a colorless gum (MS (ES+): 372.20 (M+1), (ES-): 370.15 (M-1)).

[0374] Step 2: Preparation of 2-(4-amino-6-(((tert-butoxycarbonyl)amino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (63b) Compound 63b was prepared from a mixture of ethyl / methyl 2-(4-amino-6-((tert-butoxycarbonylamino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (63a) (7 mg, 0.018 mmol) in THF (2 mL) and methanol (2 mL) using a solution of lithium hydroxide hydrate (6 mg, 0.140 mmol) in water (2 mL) and stirring at room temperature for 19 hours, following the procedure reported in Step 4 of Scheme 17. This gave, after workup, 2-(4-amino-6-(((tert-butoxycarbonyl)amino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (63b), which was used directly in Step 3 without further purification. MS (ES+): 372.20 (M+1), (ES-): 370.10 (M-1).

[0375] Step 3: Preparation of tert-butyl ((4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)methyl)carbamate (63c) Compound 63c was prepared from 2-(4-amino-6-(((tert-butoxycarbonyl)amino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (63b) (21 mg, 0.057 mmol) in DMF (8 mL) using the HCl salt of (1R,3S,5R)—N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (55 mg, 0.171 mmol), HATU (65 mg, 0.171 mmol), DIPEA (0.05 mL, 0.285 mmol) and stirring at room temperature for 19 hours, according to the procedure reported in Step 3 of Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel (12 g), 10% MeOH in EtOAc in hexanes (0-100%)], tert-butyl ((4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)methyl)carbamate (63c) (8 mg) as an off-white solid. MS (ES+): 635.20 & 637.20 (M+1), (ES-): 633.10 & 635.10 (M-1).

[0376] Step 4: Preparation of (1R,3S,5R)-2-(2-(4-amino-6-(aminomethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (63d) Compound 63d was prepared from tert-butyl ((4-amino-9-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)methyl)carbamate (63c) (8 mg, 0.013 mmol) in DCM (5 mL) using TFA (0.097 mL, 1.259 mmol) and stirring at room temperature for 21 hours according to the procedure reported in Scheme 1, Step 2. This gave, after workup and purification by reverse-phase column chromatography [C18 column, elution with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-amino-6-(aminomethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (63d) (1.6 mg, 24% yield) HCl salt as a white solid. 1 H NMR (300 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.6, 1.7 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.26 (dd, J = 7.7, 0.7 Hz, 1H), 5.84 - 5.61 (m, 2H), 4.58 - 4.45 (m, 1H), 4.33 (s, 2H), 3.98 - 3.88 (m, 1H), 2.57 - 2.30 (m, MS (ES+): 535.10 & 537.10 (M+1).

[0377] Scheme 64 [ka] Preparation of (2S,4R)-1-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (64a) Compound 64a was prepared from the TFA salt of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (158 mg, 0.515 mmol) in DMF (5 mL) using the TFA salt of (2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (200 mg, 0.515 mmol), HATU (235 mg, 0.617 mmol), DIPEA (0.449 mL, 2.57 mmol) and stirring at room temperature for 16 hours, according to the procedure reported in Step 3 of Scheme 1. This gave (2S,4R)-1-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (64a) (115 mg, 50% yield) HCl salt as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)]. 1H NMR (300 MHz, DMSO-d6) (two rotor mix) δ 9.28 (bs, 1H, DO exchangeable), 9.14 and 8.70 (2t, J = 5.9 Hz, 1H), 8.54 (bs, 1H, DO exchangeable), 8.35 and 8.34 (2s, 1H), 7.55 - 7.34 (m, 2H), 7.21 (dt, J = 22.4, 7.6 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.95 (dd, J = 6.0, 3.4 Hz, 1H), 5.62 - 4.55 (m, 3H), 4.39 (td, J = 16.7, 6.9 Hz, 2H). 4.24 (dd, J = 15.9, 5.7 Hz, 1H), 4.16 - 3.99 (m, 1H), 3.87 (ddd, J = 37.7, 12.3, 3.0 Hz, 1H), 2.62 - 2.38 (m, 1H), 2.22-1.92 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.32, -121.65, -176.12, -176.32; MS (ES+): 449 / 451 (M+1).

[0378] Scheme 65 [ka] Preparation of (2S,4R)-1-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (65a) Compound 65a was prepared from the TFA salt of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetic acid (2c) (150 mg, 0.49 mmol) in DMF (5 mL) using the TFA salt of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (190 mg, 0.490 mmol), HATU (224 mg, 0.588 mmol), DIPEA (0.428 mL, 2.449 mmol) and stirring at room temperature for 16 h. This resulted in the workup. After purification by top-up and flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (2S,4R)-1-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (65a) (104 mg, 47.3% yield) HCl salt was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6) (two rotor mix) δ 9.81 (bs, 1H, DO exchangeable), 9.21 - 8.91 (m, 1H, DO exchangeable), 8.65 (t, J = 5.9 Hz, 1H), 8.14 and 8.12 (2s, 1H), 7.54 - 7.38 (m, 2H), 7.38 - 7.26 (m, 1H), 7.14 (dt, J = 15.6, 7.9 Hz, 1H), 6.78 and 6.66 (2d, J = 4.5 Hz, 1H), 5.56 - 5.20 (m, 1H), 4.51 - 4.22 (m, 3H), 4.18 - 3.34 (m, 4H), 2.63 - 2.38 (m, 1H), 2.19 - 1.88 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.27, -121.68, -176.19, -176.45;MS (ES+) 449 / 451 (M+1);C 20H 19 Analysis calculated for ClF2N6O2.HCl.1.75H2O: C, 46.48; H, 4.58; Cl, ​​13.72; N, 16.26. Found: C, 46.64; H, 4.31; Cl, ​​13.61; N, 15.94.

[0379] Scheme 66 [ka] Preparation of (1R,3S,5R)-2-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (66b) Following the procedure reported in Step 3 of Scheme 1, the TFA salt of (1R,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (66a) (125 mg, 0.327 mmol; Wiles, Jason A. et al., PCT International Application (2017), WO2017035349A1) was prepared. Compound 66b was prepared from the TFA salt of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetic acid (2c) (100 mg, 0.327 mmol) in DMF (5 mL) using 2c (prepared according to the procedure reported in [Journal of Chemical Industry], 20170302), HATU (149 mg, 0.392 mmol), DIPEA (0.285 mL, 1.633 mmol), and stirring at room temperature for 16 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH (0-3%) in DCM] followed by reverse-phase column chromatography [C18 column (100 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (66b) (59 mg, 40.8% yield) HCl salt as a white solid. 1H NMR (300 MHz, DMSO-d6) (mixture of two rotors) δ 9.93 (s, 1H, D2O exchangeable), 9.14 (s, 1H, D2O exchangeable), 8.46 (t, J = 5.9 Hz, 1H, D2O exchangeable), 8.17 (s, 1H), 7.55 - 7.41 (m, 2H), 7.25 (t, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H), 4.42 - 4.12 (m, 5H), 3.67 - 3.55 (m, 1H), 2.31 - 2.05 (m, 2H), 1.90 - 1.70 (m, 1H), 1.04 - 0.86 (m, 1H), 0.70 - 0.53 (m, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -121.74;MS (ES+): 443 / 445 (M+1);C 21 H 20 Analysis calculated for ClFN6O2.HCl.2.5H2O: C, 48.10; H, 5.00; Cl, ​​13.52; N, 16.03; Found: C, 48.08; H, 4.82; Cl, ​​13.96; N, 15.88.

[0380] Scheme 67 [ka] Preparation of (1R,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (67c) Compound 67c was prepared from 2-(6-amino-9H-purin-9-yl)acetic acid 67a (65 mg, 0.337 mmol) in DMF (1.5 mL) and DMSO (0.5 mL) using (1R,3S,5R)-N-(3-chloro-2-fluorobenzyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide 67b (114 mg, 0.404 mmol), HATU (96 mg, 0.252 mmol), DIPEA (0.293 mL, 1.683 mmol) and stirring at room temperature for 16 h, according to the procedure reported in Scheme 1, Step 3. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 (0-100%) in DCM] followed by reverse-phase column chromatography [C18 column (50 g), eluting with ACN (0-100%) in water (containing 0.1% HCl)], (1R,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (67c) (92 mg, 60% yield) HCl salt as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (t, J = 5.9 Hz, 1H, D2O exchangeable), 8.39 (s, 1H), 8.33 (s, 1H), 7.47 (td, J = 7.6, 1.7 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.13 (t, J = 7.9 Hz, 1H), 5.46 (d, J = 17.1 Hz, 1H), 5.20 (d, J = 17.0 Hz, 1H), 4.33 (d, J = 5.8 Hz, 2H), 4.24 (dd, J = 9.2, 4.7 Hz, 1H), 3.46 (dd, J = 5.5, 2.4 Hz, 1H), 2.40 (dd, J = 13.2, 9.2 Hz, 1H), 1.91 (dd, J = 13.2, 4.7 Hz, 1H), 1.25 (s, 3H), 1.00 (t, J = 5.3 Hz, 1H), 0.89 (dd, J = 5.3, 2.4Hz, 1H);19 F NMR (282 MHz, DMSO-d6) δ -121.57. MS (ES+): 458.1 (M+1), 480.1 (M+Na);(ES-): 456.7 (M-1), 492.5 (M+Cl);C 21 H 21 Analysis calculated for ClFN7O2.HCl.1.75H2O: C, 47.96; H, 4.89; Cl, ​​13.48; N, 18.64; Found: C, 47.91; H, 4.55; Cl, ​​13.17; N, 18.43.

[0381] Scheme 68 [ka] ...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 wherein, independently for each occurrence: X is a bond or C(R Ｘ ) ２ and Y is a bond, C(R Ｙ ) ２ , or -N(R ｂ ) - and G is S or C(R ３ ) ２ and R ａ and R ｂ are each independently H or (C １ -C ６ ) alkyl, R １ represents an optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl; R ２ represents an optionally substituted bicyclic or tricyclic heteroaryl; R ３ is independently for each occurrence H, halogen, —CN, —NH ２ , -CH ２ NH ２ , (C １ -C ６ ) alkoxy, or (C １ -C ６ ) alkyl, or R ３ two vicinal occurrences of, together with the carbon atoms to which they are attached, are optionally substituted fused (C ３ -C ７ ) cycloalkyl or (C ６ ) forming an aryl, or R ３ and two geminal occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted spiro (C ３ -C ７ ) forms a cycloalkyl, or R ３ Two homonymous occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted bridge (C ３ -C ７ ) forming a cycloalkyl, R Ｘ is independently expressed as H,(C １ -C ６ ) alkyl, or (C ３ -C ７ ) cycloalkyl; R Ｙ is independently expressed as H,(C １ -C ６ ) alkyl, or (C ３ -C ７ ) cycloalkyl or Or, R Ｙ The existence of R ２ and the above substituents together with the intervening atoms form a ring, R １ or R ２ The above optional substituents are each independently selected from halogen, —CN, and —NO. ２ , -OR １３ , -NR １３ R １４ , -C(O)R １３ , -C(O)OR １３ , —C(O)NR １３ R １４ , -OC(O)R １３ , -NR １３ C(O)R １４ , —OC(O)NR １３ R １４ , -OC(O)OR １３ , -NR １３ C(O)OR １４ , -NR １３ C(O)NR １３ R １４ , -OS(O) ｐ (R １３ ), -SR １３ , -NR １３ S (O) ｐ (R １４ ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; Or, R １ The above two substituents or R ２ two substituents form a ring together with the intervening atoms, R １３ and R １４ represents independently at each occurrence H or an optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; p is 0, 1, or 2.

2. Y is C(R Ｙ ) ２ 2. The compound of claim 1, wherein

3. Y is CH ２ 3. The compound according to claim 1 or 2, wherein

4. The compound of any one of claims 1 to 3, wherein X represents a bond.

5. X is CH ２ The compound according to any one of claims 1 to 3, wherein

6. R １ A compound according to any one of claims 1 to 5, wherein represents optionally substituted aryl or heteroaryl.

7. R １ A compound according to any one of claims 1 to 5, wherein represents optionally substituted heteroaryl.

8. R １ is optionally substituted phenyl (e.g., 3-halophenyl or 2,3-dihalophenyl), (C ３ -C ６ 6. A compound according to any one of claims 1 to 5, wherein R represents cycloalkyl, alkenyl, pyridinyl (eg 6-halopyridin-2-yl), or pyrazinyl (eg 6-halopyrazin-2-yl).

9. R １ The compound of any one of claims 1 to 8, wherein is mono-, di-, or tri-substituted.

10. R １ A compound according to any one of claims 1 to 7, wherein represents optionally substituted pyridinyl.

11. R １ A compound according to any one of claims 1 to 7 and 10, wherein represents optionally substituted 2-pyridinyl.

12. R １ but, 【Chemistry 2】 The compound according to any one of claims 1 to 7, 10 and 11, wherein

13. R １ A compound according to any one of claims 1 to 6, wherein represents optionally substituted phenyl.

14. R １ but, 【Transformation 3】 The compound according to any one of claims 1 to 6 and 13, wherein

15. R ２ but, 【Chemistry 4】 represents Z １ But N or CR １Ｚ represents Z ２ But N or CR ２Ｚ represents Z ３ represents N or C, Z ４ But N or CR ４Ｚ represents Z ５ But N or CR ５Ｚ represents Z ６ But N or CR ６Ｚ represents Z ７ But N or CR ７Ｚ represents Z ８ represents C, Z ９ represents N or C, k is an integer from 1 to 4, m is an integer from 1 to 3; R １Ｚ , R ２Ｚ , R ４Ｚ , R ５Ｚ , R ６Ｚ , R ７Ｚ , R ２Ａ each occurrence of is independently H, halogen, —CN, —NO ２ , -OR １３ , -NR １３ R １４ , -C(O)R １３ , -C(O)OR １３ , —C(O)NR １３ R １４ , -OC(O)R １３ , -NR １３ C(O)R １４ , —OC(O)NR １３ R １４ , -OC(O)OR １３ , -NR １３ C(O)OR １４ , -NR １３ C(O)NR １３ R １４ , -OS(O) ｐ (R １３ ), -SR １３ , -NR １３ S (O) ｐ (R １４ ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; R ６Ｚ The presence of R ７Ｚ The presence of forms a ring together with the intervening atoms, or R Ｙ The presence of R ２Ｚ The presence of forms a ring with the intervening atoms, The compound according to any one of claims 1 to 14.

16. Z ２ , Z ３ , Z ４ , and Z ６ 16. The compound of claim 15, wherein represents N.

17. Z ３ , Z ４ , and Z ６ 16. The compound of claim 15, wherein represents N.

18. Z ９ , Z ４ , and Z ６ 16. The compound of claim 15, wherein represents N.

19. Z ３ and Z ４ 16. The compound of claim 15, wherein represents N.

20. Z １ , Z ３ , Z ４ , and Z ６ 16. The compound of claim 15, wherein represents N.

21. R ２ but, 【Transformation 5】 16. The compound of claim 15, wherein

22. R ２ but, 【Transformation 6】 22. The compound of claim 21 , wherein

23. 23. A compound according to claim 21 or 22, wherein k represents 2.

24. R ２ but, 【Transformation 7】 16. The compound of claim 15, wherein

25. R ２ but, 【Transformation 8】 16. The compound of claim 15, wherein

26. R ２ but, 【Chemistry 9】 16. The compound of claim 15, wherein

27. R ２ but, 【Chemistry 10】 27. The compound of claim 26, wherein

28. R ２ but, 【Chemistry 11】 16. The compound of claim 15, wherein

29. R ２ but, 【Chemistry 12】 16. The compound of claim 15, wherein

30. R ２ but, 【Chemistry 13】 30. The compound of claim 29, wherein

31. R ７Ｚ But, -NR １３ R １４ The compound according to any one of claims 15 to 21, 24 to 26, 28 and 29, wherein

32. R ７Ｚ But -NH ２ The compound according to any one of claims 15 to 21, 24 to 26, 28 and 29, wherein

33. R ６Ｚ But -C(O)R １３ , -C(O)OR １３ , —C(O)NR １３ R １４ or hydroxyalkyl.

34. R ５Ｚ is alkyl, halo, or —NR １３ R １４ The compound according to any one of claims 15 to 21, 24 to 26, 28 and 29, wherein

35. R １Ｚ is —CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, —C(O)R １３ , -SR １３ , -NR １３ R １４ , -OR １３ , -C(O)OR １３ , —C(O)NR １３ R １４ , or -NR １３ C(O)R １４ The compound according to any one of claims 15 to 20, 25, 28 and 29, wherein

36. R ２Ａ each occurrence of is independently -CN, -NO ２ , halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, —C(O)R １３ , -C(O)OR １３ , -NR １３ C(O)OR １４ , -SR １３ , -NR １３ R １４ , -OR １３ , —C(O)NR １３ R １４ , or -NR １３ C(O)R １４ The compound according to any one of claims 15 to 24, wherein

37. G is C(R ３ ) ２ The compound according to any one of claims 1 to 36,

38. The compound of any one of claims 1 to 37, having the structure of formula (Ia): 【Chemistry 14】

39. R ３ two vicinal occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted fused C ３ -cycloalkyl.

40. R ３ 40. The compound of any one of claims 1 to 39, wherein at least one occurrence of is halo.

41. R ３ 40. The compound of any one of claims 1 to 39, wherein at least one occurrence of is fluoro.

42. R ３ 40. The compound of any one of claims 1 to 39, wherein at least one occurrence of is methyl.

43. R ３ two vicinal occurrences of, together with the carbon atoms to which they are attached, form an optionally substituted fused C ３ - forms a cycloalkyl, R ３ 40. The compound of any one of claims 1 to 39, wherein another occurrence of is methyl.

44. 2. A compound according to claim 1 selected from the table below, or a pharmaceutically acceptable salt thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55

45. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

46. 45. A method for treating or preventing a disease or condition characterized by abnormal complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

47. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is an immunological disorder.

48. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

49. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

50. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is a renal disease.

51. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

52. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is a cardiometabolic disease.

53. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposition disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

54. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of adult respiratory distress syndrome, myocardial infarction, pulmonary inflammation, sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ failure, Guillain-Barré syndrome, hemorrhagic shock, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, multiple sclerosis, platelet storage, and hemodialysis.

55. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

56. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is a hematological disorder.

57. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is an ocular disorder or eye disorder.

58. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascularization, corneal transplant rejection, corneal dystrophy, autoimmune dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye, Fuchs' endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

59. 47. The method of claim 46, wherein the disease or condition characterized by abnormal complement system activity is selected from the group consisting of obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, and neuropathy.

60. 47. The method of claim 46, wherein the disease or condition is angioedema.

61. 47. The method of claim 46, wherein the disease or condition is hereditary angioedema.

62. 47. The method of claim 46, wherein the disease or condition is acquired angioedema.

63. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy.

64. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of Alzheimer's disease, multiple sclerosis, neuromyelitis optica, generalized myasthenia gravis, Guillain-Barré syndrome, Parkinson's disease, and schizophrenia.

65. 47. The method of claim 46, wherein the disease or condition is periodontitis.

66. 47. The method of claim 46, wherein the disease or condition is Crohn's disease.

67. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.

68. 47. The method of claim 46, wherein the disease or condition is atherosclerosis.

69. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of age-related macular degeneration (AMD), uveitis, glaucoma, and wet AMD.

70. 47. The method of claim 46, wherein the disease or condition is myocardial infarction.

71. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of atypical hemolytic uremic syndrome, C3 nephropathy, lupus nephritis, IgA nephropathy, and membranous nephropathy.

72. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, and burns.

73. 47. The method of claim 46, wherein the disease or condition is hemodialysis.

74. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, and burns.

75. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of ischemia / reperfusion injury, acute kidney injury, and organ transplantation, e.g., kidney transplantation.

76. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of systemic inflammatory response syndrome, sepsis, septic shock, trauma, systemic lupus erythematosus, hereditary angioedema, and cancer.

77. 47. The method of claim 46, wherein the disease or condition is selected from the group consisting of antibody-mediated rejection, antiphospholipid syndrome, Buerger's disease, C3 glomerulonephritis, cold agglutinin disease, cardiopulmonary bypass, dense deposition disease, delayed onset of transplant renal function, geographic atrophy, granulomatosis with polyangiitis, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangiitis, pyoderma gangrenosum, Stargardt's disease 1, and warm autoimmune hemolytic anemia.

78. The disease or condition characterized by abnormal complement system activity is selected from the group consisting of obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, neuropathy, angioedema, e.g., hereditary angioedema or acquired angioedema, thrombotic microangiopathy, Parkinson's disease, schizophrenia, periodontitis, Crohn's disease, C3 nephropathy, membranous nephropathy, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, ischemia / reperfusion injury, acute kidney injury, and organ transplantation, e.g., kidney transplantation, systemic nephropathy, and the like.

47. The method of claim 46, wherein the disease is selected from the group consisting of: inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, Buerger's disease, delayed onset of renal transplant function, granulomatosis with polyangiitis, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangiitis, pyoderma gangrenosum, and Stargardt's disease 1.

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