Pyrrolopyrimidine amines as complement inhibitors

Abstract

Disclosed are compounds of formula (I), and pharmaceutically acceptable salts thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.

Description

PYRROLOPYRIMIDINE AMINES AS COMPLEMENT INHIBITORS RELATED APPLICATION This application claims the benefit of priority to U.S. Provisional Patent Application serial number 63 / 004,799, filed April 3, 2020 BACKGROUND OF THE INVENTION The complement system is a branch of an organism’s immune system that enhances the ability of antibodies and phagocytic cells to destroy and remove foreign particles (e.g. pathogens) from the organism. The complement system comprises a set of plasma proteins that act together to attack extracellular forms of pathogens and induce a series of inflammatory responses to help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to certain pathogens or by antibody binding to a pathogen. When complement proteins are activated a cascade 1s triggered by which one complement protein induces the activation of the next protein in the sequence. The activation of a small number of complement proteins at the start of the pathway is hugely amplified by each successive enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response. (Marrides, S. Pharmacological Reviews 1998, Vol. 50, pages 59-88). Tn healthy organisms there are regulatory mechanisms to prevent uncontrolled complement activation. ‘When activated. complement proteins can bind to a pathogen, opsonizing them for engulfiment by phagocytes bearing receptors for complement. Then, small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. Next, the complement proteins create holes or pores in the invading organisms, leading to their destruction. While complement plays an important role in protecting the body from foreign organisms, it can also destroy healthy cells and tissue. The inappropriate activation of complement is implicated in a long list of disease pathologies (Morgan, B. Eur J Clin Invest 1994, Vol. 24, pages 219-228) affecting the immune, renal, cardiovascular, and neurological systems. Accordingly, there exists a need to develop further complement inhibitors, which have therapeutic potential in the treatment of numerous disorders. SUMMARY OF THE INVENTION In certain aspects. the invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts thereof: R2 RS RS. 135 Rr? : R3 v JA - ™y - 0 R2 (I); wherein, independently for each occurrence: X is a bond or C(R®)1; Y is a bond. C(RY)a. or ~N(RP)-: Gis S or C(RY)2; R? and RY are each independently H or (C1-Ce)alkyl; R! represents optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl; R? represents optionally substituted bicyclic or tricyclic heteroaryl; R’ is independently for each occurrence H, halogen, ~CN, =NHz, ~CHzNHz, (Ci- Ce)alkoxy or (Ci-Cs)alkyl: or two vicinal occurrences of RY taken together with the carbon atoms to which they are bonded form an optionally substituted fused (Ci-Cr)eycloalkyl or (Ce)aryl: or two geminal occurrences of RY taken together with the carbon atom to which they are bonded form an optionally substituted spiro (Ca-Cr)eycloalkyl; or two hominal occurrences of R? taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C:-Cr)cveloalkyl; RX is independently for each occurrence H, (Ci-Ce)alkyl. or (Cs-Cr)eyeloalkyl: RY is independently for each occurrence H, (Ci-Cs)alkyl. or (C3-Cr)eycloalkyl: or an occurrence of RY and a substituent on R? taken together with the intervening atoms form a ring; optional substituents on R? or R? each independently represent halogen, ~CN, ~NQOa, ~0R!, ~NRURH, ~C(O)RS, -~C(O)ORE, ~C(O)NRI¥R™, ~QC(O)R 3, “NREC(O)RH, —OC(O)NRERM —0OC(OYORB, —-NREC(0)ORM, ~NRUYC(ONRIRY, —0S(0)(R1), -SR'3, ~NRS(0)p(R'), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cvcloalkoxyalkyl, aryloxyalkyl, aralkyl. heteroaralkvl. heteroarvl. aryl, aryloxy, cvcloalkyl, (cycloalkyl)alkyl, heterocyveloalkyl, or (heterocycloatkylalkyl; or wherein two substituents on R! or two substituents on R2, taken together with the intervening atoms, form a ring; R!* and R™, independently for each occurrence. represent H or optionally substituted alkyl, haloalkvl, alkenyl, alkynyl, arvl, or heteroaryl; and pis0, Lor2. In certain aspects. the invention provides a pharmaceutical composition. comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phamaceutically acceptable carrier. In certain aspects, the invention provides methods of treating a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound the invention. or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease or condition characterized by aberrant complement system activity is an immunological disorder. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system. Tn certain embodiments, the disease or condition characterized by aberrant complement system activity is a neurodegenerative disease or neurological disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a renal disease. In certain embodiments. the disease or condition characterized by aberrant complement system activity is a cardiovascular disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiometabolic disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal noctumal hemoglobinuria, atypical hemolytic aremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense-deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome. In certain other aspects, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of adult respiratory distress syndrome, myocardial infarct, lung inflammation, sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction, Guillain-Barré syndrome. hemorrhagic shock, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis. infertility, Alzheimer’s disease, multiple sclerosis, platelet storage, and hemodialysis. In certain other aspects, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, TgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis. In further aspects, the disease or condition characterized by aberrant complement system activity is a hematological disorder. In further aspects, the disease or condition characterized by aberrant complement system activity is an ocular disorder or an eye disorder. Tn still further aspects, the disease or condition characterized by aberrant 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, a comeal neovascularization disease, post-corneal transplant rejection, a corneal dystrophic disease, an autoimmune dry eye disease. Stevens-Johnson syndrome, Sjogren’s syndrome. an environmental dry eve disease, Fuchs” endothelial dystrophy, retinal vein occlusion, or post- operative inflammation. In certain other aspects, the disease or condition characterized by aberrant 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, Parkinsons disease, schizophrenia, periodontitis, Crohn's disease, C3 glomerulopathy, membranous nephropathy, osteoarthritis, bullous pemphigoid, psoriasis. hidradenitis suppurativa, of ischemia / reperfusion injury, acute kidney injury, and organ transplantation, e.g., kidney transplant, systemic inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, Berger's disease. delayed graft function, granulomatosis with polyangiitis, graft versus host disease. hematopoietic stem cell transplant-related thrombotic microangiopathy. immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangitis. pyoderma gangrenosum. and Stargardt Disease 1. DETAILED DESCRIPTION Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in treating disorders of the immune, renal, cardiovascular, and neurological systems. Provided herein are compounds of formula (I) and pharmaceutically acceptable salts thereof that are useful in treating or preventing a disease or condition characterized by aberrant activity of the complement system. Definitions 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. The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus. sulfur and selenium. and altematively oxygen, nitrogen or sulfur. The term “alkyl” as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloatkyl (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-Cao for straight chain, Ca-Cso for branched chain), and alternatively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a C:-Co alkyl group. In certain embodiments. the term “alkyl” refers to a C1-Cs alkyl group, for exarple a C1-Cs straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a Cs3-Ciz branched-chain alkyl group. Tn certain embodiments, the term “alkyl” refers to a C3-Cs branched-chain alkyl group. Representative examples of alkyl include. but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl. sec-butyl. iso- butyl, tert-butyl, n~pentyl, isopentyl. neopentyl, and n-hexyl. The term “cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably. cycloalkyl is (C3-Cr)eycloalkyl, which represents 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 contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e. a bridging group of the form -(CHz)w-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include. but are not limited to, bicyclo[3.1.1Theptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. bicyclo[3.2.2]nonane, bicyelo(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, ora monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted. Tn certain embodiments, the fused bicyclic cycloalkyl is a § or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a § or 6 membered monocyclic cycloalkyl, a § or 6 membered monocyclic cycloalkenyl, a 3 or 6 membered monocyclic heterocyelyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted. The term “(cycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of cycloalkylalkyl is cyclohexyimethyl group. The term “heterocycloalkyl™ as used herein refers to a radical of a non-aromatic ring system, including. but not limited to, monocyclic. bicyclic. and tricyclic rings. which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt. the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 ators including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1.3-dioxanyl. [,3-dioxolanyl, 1,3~ dithiolanyl, 1,3-dithianyl, imidazolidiny]. isothiazolinyl. isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, oxazolyl, thiazolyl. triazinyl, isothiazolyl, isoxazolyl, azepines. azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl. oxazolinyl. oxazolidinyl, oxopiperidinyl, oxopytrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pvrrolinyl, pyrrolidinyl, quinuclidiny!, thiomorpholinyl, tetrahydropyranyl. tetrahvdrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, and 2- azobicyclo[3.1.0}hexane. A heterocycloalkyl group is optionally substituted by one or more substituents as described below The term “(heterocycloalkyl)alkyl™ as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocvelvl) groups. The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 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) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 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- propvnyl, 2-propynvl, 3-butynyl, 2-pentvnyl, and 1-butynyl. The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment an alkylene refers to a disubstituted alkane, i.c.. an alkane substituted at two positions with 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, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties. fluoroalkyl (such as trifluromethyl), cyano, or the like. That is, in one erabodiment, a “substituted alkyl” is an “alkylene”. The term “amino” is a term of art and as used herein refers to both unsubstituted and substituted amines, ¢.g., a moiety that may be represented by the general formulas: Ra | 1+ ee NR, 5 bi \ 1 R, 7 a —N \ No Ry and R, wherein Ra, Ry, and Re each independently represent a hydrogen, an alkyl, an alkenyl. ~(CHz)x-Ra. or Ra and Re, taken together with the N ator to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rq represents an aryl, a heteroaryl, a cycloalkyl. a cycloalkenyl, a heterocyclyl or a polycyclyl: and x is zero or an integer in the range of | to 8. fn certain embodiments, only one of Ra or Re may be a carbonyl, e.g, Ra, Re, and the nitrogen together do not form an imide. In other embodiments, Ra and Re (and optionally Rc) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CHz)x-Ra. In certain embodiments, Ra and Ro are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl. heteroaryl, cycloalkyl, cycloalkenyl. heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which may be further substituted (e.g., by halogen, alkyl, alkoxy. hydroxy, and so forth). In certain embodiments. the term “amino” refers to -NHaz. Ta certain embodiments, the term “alkylamino™ refers to -NH(alkyl). In certain embodiments, the term “dialkylamino” refers to -N(alkyl)2. The term “amido”, as used herein, means -NHC(=Q)-, wherein the amido group is bound to the parent molecular moiety through the nitrogen. Examples of amido include alkylamido such as CH;C(=0)N(H)- and CH: CH2C(=0)N(H)-. The term “acyl” is a term of art and as used herein refers to anv group or radical of the form RCO- where R is any organic group, ¢.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl. The term “aminoalkyl™ as used herein refers to an alkyl group substituted with one or more one amino groups. In one embodiment, the term “aminoalkyl” refers to an aminomethyl group, i.¢., ~CH2NH:. The term “aminoacy]” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups. The term “aminothionyl” as used herein refers to an analog of an aminoacyl in which the QO of RC(0)- has been replaced by sulfur, hence is of the form RC(S)-. The term “phosphoryl” is a term of art and as used herein may in general be represented by the formula: Qs0 I a —— P I} OR5Y wherein Q50 represents S or O, and R39 represents hydrogen, a lower alkyl or an aryl; for example, -P(O)(OMe)- or -P(O)(OH)2. When used to substitute, ¢.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: Qs0 Q30 —Q5 i — —l ones 1 1 ORS59 ORS59 wherein Q50 and R39. cach independently, are defined above, and Q31 represents O, § or N; for example. -O-P(OYOH)OMe or -NH-P(O)(OH)2. When Q50 is S, the phosphoryl moiety is a “phosphorothioate.” 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)NMe:. The term “azide” or “azido™, as used herein, means an —Ns group. The term “carbonyl” as used herein refers to -C(=0)- The term “thiocarbonyl” as used herein refers to -C(=S)-. The term “alkylphosphoryl” as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O}OH)Me. The term “alkylthio” as used herein refers to alkyl-S-. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group. The term “carboxy”, as used herein, means a -CO:2H group. The term “aryl” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i... (Ce-Cro)aryl). The aromatic ring may 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. sulfonamido, ketone, aldehyde. ester, heterocyclyl, aromatic or heteroaromatic moieties. fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, ¢.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, arvls, heteroaryls, and / or heterocyclyls. In certain embodiments. the term “aryl” refers to a phenyl group. The term “heteroaryl” is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolvl. 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, thiazolvl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The “heteroaryl” may 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 moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings 1s an aromatic group having one or more heteroatoms in the ring structure, ¢.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Such heteroaryl groups may be connected to the rest of the molecule through either the aromatic group having one or more heteroatoms in the ring structure or the other cyclic group. For example, heteroaryl includes indole, which coruprises a benzene ring and a pyrrole ring that are fused together. An indole substituent may be attached to a parent structure through either the benzene ring or through the pyrrole ring of the indole. The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group. 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 the alkyl group The term “alkoxy” as used herein means an alkyl group. as defined herein. appended to the parent molecular moiety through an oxygen ator. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy The ten “alkoxvalkyl” refers to an alkyl group substituted by an alkoxy group. The term “alkoxycarbonyl” means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=0)-. as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and terf-butoxycarbonyl. The term “alkylcarbounyl”, 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-dimethyvl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term “arylcarbouyl”, 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, The term “alkylcarbonyloxy™ and “arylcarbonyloxy™, as used herein, means an alkylcarbonyl or arylearbonyl 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 rert-butylearbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to phenvlcarbounylosy. The term “alkenoxy™ or “alkenoxyl” means 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-propen-t-oxyl (i.e., CHz=CH-CHz-0-) and vinyloxy (i.e., CHa=CH-0-). The term “aryloxy™ as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term “carbocyclyl” as used herein means a monocyclic or multicyclic (e.g. bicyclic, tricyclic, ete.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (c.g., phenyl). Examples of carbocyclyl groups include L-cyclopropyl, L-cyclobutyl, 2-cyclopentyl, 1- cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl. The term “cyano” is a term of art and as used herein refers to ~CN. The term “halo” is a term of art and as used herein refers to —F, ~Cl, -Br, or ~I The terra “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms. The term “hydroxy” is a term of art and as used herein refers to ~OH. The term “hydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is 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-dibydroxypentyl, and 2-¢thyl-4- hvdroxyheptyl. The term “silyl”, as used herein, includes hydrocarbyl derivatives of the silyl (HsSi-) group (i.., (hydrocarbyl):Si-). wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups. such as trimethylsilyl (TMS). tert-butyldiphenylsilyl (TBDPS). tert- butyldimethylsilyl (TBS / TBDMS). tritsopropylsilyl (TIPS), and [2- (trimethylsilyl)ethoxy Jmethyl (SEM). The term “silyloxy™, as used herein, means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom, Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and frans-isomers, (R)- and (S)-enantiomers. diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof. are intended to be included in this invention. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary. where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino. or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base. followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction. The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyelic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. lllustrative substituents include. for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatorns such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. In certain embodiments, the optional substituents contemplated in this invention include halogen. azide. alkyl, alkenyl. alkynyl. aryl, arylalkyl. heteroaryl. heteroarylalkyl, cycloalkyl, (cycloalkylalkyl, beterocyelyl, (heterocyelyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g.. -alkvlene-O(alkyl)), alkylthio, sulfonyl, sulfonamido, ketone (e.g. ~ CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alky1)). haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano. As used herein, the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieities that follow are each substituted or unsubstituted. 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. The term “vicinal” describes 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.c., the two substituents, moicties, or functional groups are in a 1,2-relationship). The methyl groups in 3.4-dimethylheptane are vicinal. The term “geminal” describes the positional relationship between two substituents, moieties, or functional groups bonded to the same carbon atom (i.¢., the two substituents. moieties, or functional groups are in a 1,1-relationship). The methyl groups in 3,3~ dimethylheptane are geminal. 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 themselves are each bonded to a single carbon atom (i.c., the two substituents, moieties, or functional groups are in a 1.3-relationship). The methyl groups in 3,5-dimethylheptane are hominal. The phrase “protecting group”, as used herein, means temporary substituents which 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 and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, P.GM. Protective Groups in Organic Synthesis, 2" ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention. For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics. 67th Ed., 1986-87, inside cover. Other chemistry terms herein are used according to 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 pertains. The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glveolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example. the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid The tom “prodrug” as used herein refers 10 a compound that can be metabolized in vive to provide a compound of fornuda I Thas prodrags include compounds that can be prepared by modifving one or sore functional groups in a compound of formula 1 to provide a corresponding compound that can be metabolized i vivo to provide a compound of fornala L Such modifications are known in the art. For example, one or more hydroxy! QUOUPs Of Amine groups in a compound of fornwda § ean be acylated with alkyh- Ch groaps or with residues from amino acids to provide a prodrug. Prodrag forms of a compound bearfog vadous mitrogen-contabung functional groups {anuno, hydroxyamino, amide. ete.) may include the following types of derivatives, where wach Rp group mdividually may be hydrogen. substituted or nasabstituted alkyl, arvi, alkenyl alkenyl heteroovele, alkvlan, arvialbyvi, amlkenvl amalkinvl, eveloaliot or evcloalkenvl {a} Carboxamides, represented as — NHR, {by Carbarnates, represented as —NHC{OHOR, fo) {Aavioxylalint Carbamates. represented as NHOOOROCOR, £d) Enavdnes, represented as —NHURGCHUO:R) of —NHCRE&CHCONRR) {ec} Schiff Bases. represented as —N=UR, Ry {f} Mannich Bases {from carboximide compounds). represented as RUCONHCHNRGR, Preparations of such prodrug derivatives are discussed in various Hieratae sources {examples are: Alevander eval, I Med Chem. 1988, 31. 318, Aligas-Mastin etal, PCT WOO4133E 5 30) Prodrag forms of carboxy bbearing compounds include esters (—{0:Rm), wher the Ru group corresponds to any alcohol ahose refease mw the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels. Anather prodrag derived from a carboxyiie acid form of the disclosure may be a quaternary salt type of struct desorbed by Bodor et all, J Med, Chen, 1980, 23, 469. The terms “carrier” and “pharmaceutically acceptable carrier” as used herein refer to a diluent. adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia. gelatin, starch paste, tale, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety The term “treat” as used herein means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject. In one embodiment “treat” means halt or slow the progression of, or eliminate a disease or condition in a subject. In one embodiment, “treat” means reduce at least one objective manifestation of a disease or condition in a subject. The term “effective amount” as used herein refers to an amount that is sufficient to bring about a desired biological effect. The term “therapeutically effective amount” as used herein refers to an amount that is sufficient to bring about a desired therapeutic effect. The term “juhibit” as used herein means decrease by an objectively measurable amount or extent. In various embodiments “inhibit” means decrease by at least 5, 10. 20, 30, 40, 50, 60. 70, 80, 90, or 95 percent compared to relevant control. In one embodiment “inhibit” means decrease 100 percent, i.¢., halt or eliminate. The term “subject” as used herein refers to a mammal. In various embodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, a subject is a human. Compounds The present invention provides compounds having the structure of Formula (T), and pharmaceutically acceptable salts thereof: R2 oO ¥ HT 7 re “Few e SE IN ° R2 0; wherein, independently for each occurrence: X is a bond or C(RX):; Y is a bond. C(RY)a. or ~N(RP)-: Gis S or C(RY)2; R? and RY are each independently H or (C1-Ce)alkyl; R! represents optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl. or cycloalkenyl; R’ represents optionally substituted bicyclic or tricyclic heteroaryl; R? is independently for each occurrence H, halogen, ~CN, ~NHa, ~CHNH, (Ci- Cs)alkoxy or (Ci-Ce)alkvl; or two vicinal occurrences of R® taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C3-Cr)eycloalkyl or (Cs)aryl; or two geminal occurrences of R? taken together with the carbon atom to which they are bonded form an optionally substituted spiro (Ci-Cr)cycloalkyl; or two hominal occurrences of R? taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C3-C7)eveloalkyl: RX is independently for each occurrence H, (C1-Cealkyl, or (Ca-Cr)eveloalkyl; RY is independently for each occurrence H, (C:-Ce)alkyvl, or (C3-Cr)cyeloalkyl; or an occurrence of RY and a substituent on R* taken together with the intervening atoms form a ring; optional substituents on R! or R? each independently represent halogen, —CN, —NO», —QRY, =NR!'RM ~C(O)RY, ~C(O)ORY, =C(O)NRVR™, —~QC(O)RS, ~NRUEC(O)R!, ~OC(O)NRUERM, ~OC(Q)OR3, ~NRBC(0)ORM™, ~NREC(O)NR¥RM, ~0S(0)p(RY), -SR3, ~NRUES(0)p(RM). or optionally substituted alkvl, alkenyl, alkynyl, haloalkyl, hydroxvalkyl. alkoxyalkyl, cycloalkoxyalkyl, arvloxyalkyl, aralkyl. heteroaralkyl. heteroaryl. arvl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocveloalkyl, or (heterocycloalkyl)alkyl: or wherein two substituents on R! or two substituents on R?, taken together with the intervening atoms, form a ring; R¥ and R', independently for each occurrence. represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; and pis0, 1,0r2. In certain embodiments, Y represents C(RY)a, preferably CHa. In certain embodiments, X represents a bond. Alternatively, X may represent CHa. In certain embodiments, R’ represents optionally substituted aryl or heteroaryl. In some embodiments, R! is optionally substituted heteroaryl. Exemplary embodiments of R? include optionally substituted phenyl (e.g., 3-halophenyl, or 2,3-dihalophenyl), (Ca- Ce)cycloalkyl, alkenyl, pyridinyl (e.g.. 6-halopyridin-2-y1), or pyrazinyl (¢.g.. 6-halopyrazin- 2-yl). To certain embodiments, R! is mono-, di-, or tri~ substituted. In certain embodiments, R! represents optionally substituted pyridinyl, preferably WH NG Br | J optionally substituted 2-pyridinyl. For example, R! may represent Tn other embodiments, R! represents optionally substituted phenyl. For example, R! F hy + may represent “on pd 250-2 7 O 10.7 Inet sz! z ead i 257.550 y2 A In certain embodiments, R? represents 2" z! (REY), wan, J ’ \ pd lk “le z4 7a 27% | T PR Rm, 4 ~ 2 5 Hy, Ole eZ Re, ! JZ 75 IS BD 7 I 5 2 z 5 (Rm or oo, wl / 3 77h OW z8 “oF A) ov (Rr Z! represents N or CR; 77 represents N or CRY; Z? represents N or C; Z* represents N or CR*; 25 represents N or CR; 2° represents N or CR; 27 represents N or CR7Z; Z? represents C; 2° represents N or C; k is an integer from 1-4; m is an integer from 1-3; and cach occurrence of R'%. R¥, R#2, R¥ RY, R™, R* independently represents H, halogen, CN, -NO2, ~OR*, -NR¥RM, ~C(O)R*, ~C(0)OR", ~C(O)NRFRH, ~0C(O)RY, -NREC(O)R™, ~OC(OINRIR¥, ~OC(0)OR’?, ~NR*C(0)ORY, ~NRPC(O)NRPRY™, ~0S(0)u(R?), -SRY, ~NRU¥S(O)p(R'), or optionally substituted alkyl, alkenyl. alkynyl. haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, beteroaralkyl, heteroaryl, aryl, arvloxy, cycloalkyl, (cycloalkylalkyl. heterocycloalkyl. or (heterocycloalkyl)alkyl; or wherein an occurrence of R% and an occurrence of R72 taken together with the intervening atoms form a ring; or wherein an occurrence of RY and an occurrence of R* taken together with the intervening atoms form a ring. In certain embodiments, Z2, 2°, Z*, and Z° represent N. Tn certain embodiments, 2°, Z*, and Z° represent N. In certain embodiments, 2°, Z*, and Z° represent N. In certain embodiments, Z* and Z* represent N. In certain embodiments, Z, Z°, Z*, and Z° represent N. wh, ne R7Z = In certain embodiments, R? represents (R*)_ For example, R? may NH, represent N, ia (Y NA \ | , NH, 2A, nt (RT). In some embodiments. k is 2. wha, 52 Rid Epes AREA [0 In certain embodiments, R” represents RZ hy an, . RZ _N { “pF N, | \ Na MN R7Z RZ In certain embodiments, R? represents Aan, g: ne RZ _N 7 Yr N i. Va Naw N In certain embodiments, R? represents R72 , for example Noa, | NH, : RZ NI Za \ RZ Na 1Z In certain embodiments, R* represents RZ ® won, , for example wr 52. N 1’ hg N or R Nog Alf i; 72 RZ In certain embodiments, R? represents R + l Nn, N. N oY, Na NH; To certain embodiments, R™ represents —NR!*R!, for example -NHa. In certain embodiments, R% represents ~C(O)R', ~C(0)OR', ~C(O)NRVR™, or hydroxyalkyl. Tn certain embodiments, R** represents alkyl, halo, or “NR¥R!, In certain embodiments, R*Z represents ~CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, ~C(O)R*, -SR*, ~NRBRM_ ~QOR, ~C(O)ORY, ~C(OINR3R¥ or ~NRIBC(O)R, In certain embodiments, each occurrence of R** independently represents —CN. ~NO2, halo, haloalkyl, optionally substituted ary], optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, ~C(O)RY, ~C(Q)OR", -NREC(O)OR*, ~SR¥, -NRURM, ~ORY, —C(O)NR¥R!M, or -NRIC(O)R™, In certain embodiments, G is C(R)a. In certain embodiments, the compound of the invention has the structure of formula (la): R3 R3 Ra “iy Ns RR rl Noo R < i" RNY 1 0° EN R2 (Ta). In certain embodiments, two vicinal occurrences of R® taken together with the carbon atoms to which they are bonded form an optionally substituted fused Cz-cvcloalkyl. In certain embodiments, at least one occurrence of R? is halo, preferably fluoro. In certain embodiments, at least one occurrence of R¥ is methyl, In certain embodiments, two vicinal occurrences of R* taken together with the carbon atoms to which they are bonded form an optionally substituted fused Ca-cycloalkyl and another occurrence of R? is methyl In certain embodiments, the compound of formula (I) is selected from the following table of compounds. and pharmaceutically acceptable salts thereof: # Structure # Structure 75d ~~ 24a < } (5 ’ rd [SF N N Ng-Br STO | x NN CN | is NHCH, oo oY NH, rrr rf e F Er 50f 76b Oh A, f or Ne MN NHCH; Cry HN N (3H 0D NH: F I 776! ~~ 157a A A Gh N N, ATU N, ~N CNHs LT” r NN | > / OH NH, Ar | J NH; Se 78a pe N 158e ~~ A | Tx A, © F A K H 0 = N 0 if 5 - i "HD al N. N 7 I Ny i or CHa Na 4 N. =~ / * NH, NH, TT hE — — N rT 4 H ATCT 0 # Ny 0 f N i hy Noy Ht NH, by BAY pay oN © N Ty ( vo F NHz ie 80a dr 43a nH a BE H CAH UN Br AT N AN i ts N N. 2H NN / J \ NH; NH, - - 2 as 81a Pe BT Cn 35f 0 <5" ~~ CA, | rs 2 F No N 2x5 NH, NO 0 a 0 (IC Ni. oC NH; HH "oy Br LAH | Are” _N N °° 7 ro, # I nN NN iL 0 NHCH; N= Ny A 0 < N. 7d : NH. 83d 27 3 - | 47g - Cs wy i Ne NO A COOCH, ~ oN COOCH; N N. (30 Ness Aled 5 7 NH | HN 84a fs 48d 2 Ho Ne™ » N._Ny Br {ov J AG 0 N, 0 Xe Nog if ¢ SQ ok NH Ne ws 85b 2 fr 18e Oy PR J 2 K H 0 & N 0 N Co NH, TQ AN 4 “Y) Ny 3 NH, OMe 8 tins 6b Mees AN 51g A a. ° ~ 0 - N ol Aq © | (Jo O NH, = D N 2 \ Ne 3 NH, Ll _ FO es IR 5 a7 Pr Yo2f ey H N Br ”, “UJ \ Lo Js K H N N 7 Br LY N HaN UN, TX AJ NH, NH, 88f 2m dr— Ry 54g H 2 Bi Tok Tap ~~ | N_ _# NH, NH, ed, ER ies Foe zo = 8 / 3 Lr~ Yo 48a avr MH A % H CAH Na Br | YY Ao TO Ml de. | ae) COH 90d 2" 29f — Br k o EL Ns N. N, Br Ney atv ~~ g H CAN Ng er | YY ~o lot © 2 0 TL Ne NH, Nas == Nid NH, | 91a AN [aed | 22d Oy ~~ fe N TD 3 | £0 Ty N ¢ \ NH, N= “ NH (+) and (-) isomer a2b Pon 33a Lo HD oy K H 0 oF J oO CY J HNC NG oN, Le NH, oy AT fo NH; 1 i 93a £ 49¢ Van) H 2 H Naw Br A Nd H Yer! NN Hr vo CN NH; NH, 94b + 2 a 58¢c ae i / No-N, 'S Cx NH, Taw sac p— OH NBT “, N. oy yo av Fan 0 Oo a oA {Le he NH, ; 95¢ RI 59¢ Co ay a Br oA NNN wet (0 NH, he Nt ¢ y J Y Na = NH; Le effet le, —£—,,,,,,,——_———g 96e Tr a 17f 2 H Br 7 Ne Ns Ao 3 [a] “yA gi AN oe “Ye 0 i Tp TN £ i Ns N NA? \ — NHBoc NH 97k ya 18a I H Cpe— OH NL BT NS CA N N 4 J Y% © TF Ao 4 NaN, (Le No ZN NH, Ne N Ly 3 NH; 7 NH, 98b Pe 31f H Ss Ns A, © Ao i Ny N (Le APZ NH, NN, 0 NH, N= agp | Ar YY 80 KY 4 NNN AoC No 99h CA 60c 3 H Br ; N N “, N = . : Ao % Go pW wl 08 oN © i: pre (0 F Nr ¢ \ NH; » NH, NH, J 1006 | Dom 6la rm Ho Ne NH» I NN, SN Cx NH; ie = bw tm 7 101b YL es ef a H yO ay 0 r 7 noo 7s N Le Cx NH; \ NH, Le ee, rf, > 102b | Eva a6g lx Yes ad WNC Ee Ne. N, ¢ 3-0 NH COOCH,CH, ! Ne-N, x > N A N NH, Cl ci 62¢ 103b | Pa | ( 2 Cl ct I 4, oO Br Cy 7 > I NaN S {Le NH; i, rtp 104a f, 63d Br 1 wo oH Ne % A, A, © i a Ho Ne Br CD (OL NC NH, 4 Ny N 5 or NH, NH 105b | 8 al 53d H Toy” YL Ao / NaN N {Xe NH, | ot o- Nd CFy NH, 111b | Mr—~ OF ' 5%a le 111b 2 3 55 * an TEE a Yo. Br dm % "I N NA \ ay o iy LT \s Ny -N, '~ NH; NH; | 107b | PrN 56g 5 Ns” Jie * H CAH OCF, ey ZY N { Ne N, S {Le NH; 0g: N NGA OCH; “ L) a A, 8 I 1. © % F % H CAL ZN OCH; A o J N / Non 0 ZN NHa C 0 or NZ NH, O CHs 109e XT Fee To a 159a TT a Br | H XNA Cl \ ~~ Q £ / Ny -N 'S eo NH, N A I |. OMe NH, 110d | E 160a 110d | fy H 3 YY A LS Ns pai Ne oN 0 ON il Br {Xs NH; NN Ly N= Yn Br NH, =o NYY NNR on SY AD Ar ye Je) 7 roe N Ne Ao > Cr fv oo NN Na N / N ‘ RX {Le N ” Ne CF, | 112b | Lore 172a — % u x ye &, 0 LJ Noo N H New Br / Ng, Le N. A N NH, N N =» N C ! D O NH, O CH 119a Fe TTT ETA TE TTT ANT Sor oY f Cl ) A L) AD "Rope IN, a {Le i Nr Rec Nd NH, " RR i NH, = 120c «7 161a 1 . H <3 i Of Nae® vy A ~o a J / el TN No NY v - oo 7» Ne i 0 - NH, - - Nu COH NH, 121d | % Rn bo174g NPI oT 121d 3 17 i Br te ma ag ary HOON 2 oP £1 LO N Cl ry = 1 NgN 5 NN NH, NH, 122¢ El 175a Ful le . Sy a aR” H =. Ne = yA yO AY r i os N lL SF Ke (30 NH, Nf LE, i 176a 123g | ‘ Co 118a | % 169f wy HN N 820g Ce NH. / 0 Nn NH HN A gut nl 117d 7 7 177d NC, Sq Poy « 9... Br NC, 8 H r No Ms SN \ A o Q LL " < YT fe ef i on H Gyo Be aot ae) A g N. av Ne Ne, Br oo Ng —N as N 2 NH, : CF; a 115e £ ot 16: pe Br , 7 26 pr HO ON - Bi Ao > . ¢l Fp rT N . " N Ng 7 \ NLS SF NH, er. -~ OOOO Ty 114f E cl 163g “L ~My Ao? E cl 1 F. CAH ( “ N AT NN 0 NH, —=N 113a | E 164a Wy” N YL ~~ NNN , AY xy! A 0 0 NN 0 : Yoo OH ae | WL? N NH, NH; ie — Tr ET Pa re 66b me 22, 168a OL NH; x CY a N-~ Torr we N 0 F5N © | NY Ng Ng A HN NH; ( 7 LOH ~~ 124b NH 170¢ On HaN ~ 170¢ _ ] ; " N Br Ne ND) ~ CS 4 Oy ~~ 0 7 & NaN | {Je HoN NH, 7 hk Ea a Ty J 68a E ' 179d 1 i —— k 179d Fe, 4 N ~~ A H N NN Np . © = N\ Da a | me 68a E 179d % ar LA CY 3 N N NN 7 ~~, oe ar Ao 0 Non © > N mY» Na NAN € NH; B ¢ 2 NH, CFs LN 67¢ 7 180e 08 { LL N NL. ZH , a I ct 180e HN, Hon a ? A, 5 ATTY XY NN " Le Ho Wg Far Np wn sN Nr ir NA NH, CF; 65a fi nN 166a ang B wy Ms CF; 1668 | SQ. oo NN 0 Sy OH NH, 64a FE 167a 2 Ho Ne ® Iu A, | J i Ao = I ~~ A 4: oo Ne oN © A N | 0 x 7 OH NH, | | NH, | g aN 168g wr H ime eT he Hon = al CN Ao = IN ~~ vr o r N N No # hs n Ny | NH, CN Nn HN: ~ F & VON YY el a [oe Po NH NH ~ Ly yy hy E 132d | a Co 1ssg mea A 0 rE pl a 9 J HON N Lo NH w Ho Ne Br a ~C A N N NLL NO, NH, Dp CoS TA = oN % NN Nes, FN-OH NA A = NH, 20a £ £ 198a < Lor Ne® ~CT § 198a 3 Lf 9 Ho p= i - 7 a o “2 VY No ¢ © Ao ) NN, Hon x F yd y= * E ™ N= NH, 134b RR Co 199a » antl 134b fy 199a * AA 2 Ho Nsee® N \ N ay © F VY # FE he N. _~ CFs NH. he 135a K 200a Ye. Pas BN HN Br kK 200a Ly Clo y ® CNS 7 Oo Ny NHz 7 NH, 136a | Fr RN 194a © WS o © : 7 1 1 N N. (30 Na, == NL CF; NH, 137b | FE ' 201e 2 ie 137b F, 201e HoN, 3 aa ZN uu... Br A y= Ho NB N. 2 ~ OCS 1 8 AQ YY Arr 4 A I 0 0 7 - uv A N Ng { Ng [ N A \ NH; NH = NH CFs and 140a | = Cl 211e HoNHAC cl 211e HoNHC E NHC % 1 Z £ Cl AA ) N oh 1 I A Lo rv Ne N, Ng —N, fr i Nt N_ ~~ NH, #~NH, NH, o CF, 141a al 212¢ HaNH,C, E I | ZN ow «Bf 141 cl bo212e HyNH,C, ° | A E. © ve q NB" / M = N } SN \ J ) A o oh 0 3 0 oh 7 ; cl .¥ © ANN = © No. N he N Ad NH, NH, Aang fea la oo rt N. = NH, CF, E, Ao ® 0 1 | N. 30 Nes =N N 7 Nz NH, Nagra NH; NH, 139b | % 182a Co (s wd ay Re LY NN Lado Nn © 0 Fo NON ( Cr NAY No~d N oy NH, == N\NH 125d cl 183a F I Cl 3 F SA —, 8 fr NN 7 0 E z H Nas Br Pr Ne = NH © 7 a NH, I of i 126f FE nw I 207b pl H 142d £ 208d A ; Si Ny Hg BT 3 CAI, | = © F NH a H3C. N, | Honeiopt, N AY NH, 143d | = Cl 203a 143d FE E cl * F. H AN 0 ~~, © Br LI i! Tb | AN LN on oy “Neo NH, 1 TC HN Nz J O cl ag fo ed 20% pr HO NG Be > al Ppl £ Ny, N an LI2 O NH, * hd NH; ro 2 HN CH, 145a | 5 184g 3 VY LS Ao NO AT: a A No Me oy as, NH; CF; “ya5a | FE Tigsa TT N A 0 F a | 2s H y N ry OS Q 2, AD | on NH y £ NN C Na NH Fn ~ HN: CN 146a | c Cl 186a E Cl i F ANID 4 0 LHS SY (30 NH 1 po4 he 5 NH, (OCH; 147 © 206 3 | Fy e 1 ie fil Se 147a F T 206¢ 3 | cy eA Re ao i cl * F. S00) A, © = ay I or | woo LI2 Oo NH, 1 } ~3 a TE 148d Z 208b Fp HN Z 209b E, N N ~~ 0 o | ~ N o N N Nd = = NH, bah he 19a F 210d ~7 5 dr 1 A (No 7 r ~ Or Nv HN HN Yas 12 N a SN N= HN oe 3b £ 189g wr Ho NB Toy Aq ~ 1 A 7 N, N 0 O | SB { Lr $ Mr Non N= HN N N. J (30 N= Co Me NH, F 149b | 3 nN 193a H H SEN YY el NH, 433d =F H Ne Br I ~ " L(Y NN o | X Y, ATT Aa Br NH J NH i ap! Co wa a Br i 190a U wy = o e a Na NN, (FO Sug N x NL INI™ np NH, lv N ” i Na NH, COLE Se £ 191a H Va H hs . Sdihet La <Y Br NN Nr | YW Ny ON o G Or 5% 10 (30 NH; Nest’ Me NH; 150d | E 'o192g E 3 iL 150d F 19 ) Br 3 re 2g rH NG / . Br ay SGA 4, o F ata) LW Yoo Br NH; 4 rt {Xe NH, Me 69a E ' 196d F % oF N, BI ~5U \ id = EE NH, , 70a 2 197¢ 'e H ) ry ——————— —— “ar 70a Se “ 197¢ CQ Y NAN er | N / 4 TY 0 N % © = 0 ZN A . N a (30 N= a NH, _ NH He 2d Ly 214b * fs wy Arye \ HB ™ i TOR “7 o 2 tid Ao © An \ NN Nay Ay (SY pou NH, NH 71a | x 213d H ~~ N 0 er 0 LX A N, re 4 Br Salty HoN %, H Of Ne” yy NH; 1 2 CFy =~ 215g Nbr i - N o © A N FY A © Ny Ay 0 NH; N N NN NH; I mo ru Tm —— = 9 4 "216g H A 2 Br #108 CY . 0 A i TC N Me Crt Te CX N = FH Sd rN -* dd 1 Loo N __ N=! A N, Me | HN Ny NH; COMe ewe. 151a | E RN 217a A H AL, | o£ A aN ~ 5 be | vo LI & NH NE N ¢ LU Ns a NH. COMe NH; eV 152d f 220a ge— H 152d Pi +, $ r 4 [a N o N I oo {Loon A No COM Te Ny NH; 1e Co wn as BE 202a ” H * \ Ao Na (0 Ne? Nk H N 3 ‘NO; NH; NH, 2 ee ge— HN Br 205¢ ws — <r WU 8 a (3-0 NH; We: NH; 2 CH F, y H Y Cl N F 0 0 L (5 \ N \ oo Me COOH A NH; COH NH, Me 2 CO Ly NN yy sm F 21a F 236f 2 H Br = ’ NH, a or _ 3 ely i ~~ N Ia NS N 0 O i Nbr | N_. a | HaN Me 73a > 237a H re! | NH, 74a » ' 238g - i f NaN 0S | Nod NH, HX 153a 5 Ee 239a i. dH oNB oH 3 Cl yO N N LY 7 = NH; of | NH; OH 27a yg: H . Br 2 Loy" Ao lo] N 296a NH, £ N. 7 N Me Na NH, 2 CF3 H 25a E Zn 240g 5 "wo J NN r nT — H Cl N. SOY E 0 Ao Ny» 3 0 to N. Ne TN Yi CF; NH, CFs NH 26a FE 241g . ¥ N YL 1 oy A ~~ N NN 5 6 JNeer | N__ a | Hi CFs NH, 8h ~ n 242a Jung LS Ng N LES J Me ry Me A wg NH, Me NH, 28s - 1 28323 oe H oy "of Ae 1 oo | OT ir £1 PSO) ( NH, CFs NH, NO; aN hg IP New " (30 Nt NH, ita NH. 11f o oo 245a Ao hd [ “Ph oS i Ne 0 «7 NH, NH, CFa 1 | a lonls 12a » 42a . nN ul Ho Nae® - 0 Ls 0 NY \ LL 0 Av N be, ) ~ " (Feo b, ¥ 127d | fo, 16e al (Co Ns N NN NH, dh | NH, 127d rN 16e pry oH NE Cg 1 Br vw Sg) Posy oO Fe NN or Nt AN NH, 128a | Jee Hn Br | 36e N 5 7 0 we ~ wl [ | wo LL0 & SJ OMe 0 Nes NK NH, Nha 3 ov) Ho NB Br 39f H Nae 154 ery HONG TT Ne y Br Hoy Br 39f BY Cy % N = Sex AY a \ 7 Ao SMe / N he N Al NH, SM Wz A NH; ethel JUNG H 346 ames WW own BE 23f ~ z I. d Na. Br Ao LE MY NH, 4: NN i 7 \ NH, Br Se: 13b ~~ H Nu Br 40a ¥ oo - H Br av N NY o A N ne i 0 NL {FO IN AN | - he NaN N J CS ] V Ny NH, NH, CO;Me 14a F, 156e 2 " : “ H AY o J N © / 2 I N on JI2 H NH, NHa 15a a H ~ Br 45d 5 H ” Br ed $d Lye NT pt a NM . OY N \ Nt NLS CF, NH, ='s \ COE 155fF Lom 4a1f qo H oN * H N “Cr | o J ~~ aN 23 % 1 gl’. YT | J! A 0 0 | oy JI NN OH NH, (Feo NH, 37a _ 221¢ H W Ww oO Cy / _ OMe NH, Seg N. NH: ! HiCOCE 218a | 0H... Br 250b 218a pr H “Br Ho NBT 250b fy MN LE No oN IP N. N- 0 Na, aL NH, \ A COM NH, & a N. Me Na NH, CoH Fam em L(Y Lg AN COOCH- oN NH, NH; NY) \ A 5 = o COOCH; NN ¢ \ Na NH, N 224b ~ a 271c 224b TB 271c ” He Br 5 av HN n= \ oN 0 1 eso A; N $& \ N { COM NH, oY NN NH, >, CH Reg: 225¢ — HONE 249a ONY 24% | YW Oy : i i Na Br oY 1 16 oo) N N (30 OCH; NH vy 226c oN 252a | Co o=(_ x. HN NH I ¢ Co roy get 219a 1 a ew Br 253a 1 Bd a Br Ao rt LS Ns ° N CTY Nt Nd ) i N N (30 Fe NEE COzH NH; wey NH, 227¢ | nn HH « Br 254a a 227¢ Qf NB 254a VY TY wy 1 oO £ NN Sg O-0 NH, NH, 4 Ro Nsr® wy 1. 0 A Ao Me NN, 7 _ 4 NAY o NH, 251f | 0m Ho 272c LIN oO A ° CL NH, ! = of Co-L Vici. CFs NH, 233h 255¢ Br ey Cor jour 30 NH, ~~ NH AN irl fant NH 2 N FAG HN 229, | arm Hn 256m jo Br Ea NH; Ny oe Me er Ge N Ta, NH, », 230a CY wo. Br 273c¢ 7 Ho NB CS" YL) AF N £3 NH; 0 257g 231g Cy H . Br 257g N A 5 7 0 Ao NON “0 NH, N= Fv A N, Me Ng Ad NH, OMe CF, 246b | F 258a 246b £ ” 258a H j H ) Ho Ns Br NY A A Qa N H ~~ NY NS Oy | TN © © or | ov N___. a A N. Me LH | HN S CF, NH; OMe 247 HaCO 2 > d 5CQ 59d oN HCO 3 N- H N A Ore | 2 = RA N 0 © or <TR Nid oo HN | Han ~3 248d HCO 260a A Ary CFy HCO CQ 260a ¢ a . " N Ns " INA N gr Na No SN 0 0 3 N = N, == pe HN | ka CF; CFs 232a oq Ler 261d a - Br oN COM HuN oN COM NN (30 St NH. NH, 234a — TY" 2 © ¢ oy 62a ONY No N, N_ SY (2 s i z Yo NSC » CFy NH, 73 N= 4 Foes Tp Fa TL 267c A 264a Col. CY Br N, \ iad ~~ NaN pe TQ C) HN Ne CF, Sn 7 \ Lot <y Ao © 2 NN Me J \ HN N " 1 oy ¢ o- oo NG -N Me “ Na NH; ” MEY 269¢ ” J 266b oN H N: H A No 0 © 8r > Or oe HN # 2 Bs N, N° 0 0 J a | 5 Or I | HN IN J N © N= HN CF, 2" 275¢ 2 oN rg H ox ff hl Ia J oo CN F '® = XY + oo N HN HN a / A EE rere eee maa rere] ea 276g I | HN A N, JE Oy | 2840 Or & a ] N Me Ne? \ NH, N= o£ > Cn ww... Br 277a | 285g xo | (0 N= N= Me NH, H Br HON Br 2) H < {~~ ( or ou LY ER 278g Nex’ TN NH, = No _N | 0 NH, NSC Me Y . mnrenten x Br . H ” Cl We LX 5 mm | CT me £ ae N, Me Ny NH, CFy ne: fr \ Nt NH, ? HAGE I | I EL | av PRT 280 | NaS 288¢ NH, VE A N, Me Ny NH, 7 \ Co \e= / v = / TAS < bs” Fade Fai 281a | ae NL P- | 289 i Ge TS Ne xy A ®! N. b- N= A F + 1 NH NH, F 2 y Ce 1 N= NH, J N 2 H Nae Br Ye Aue | 282a | I He | 290g ONL N AI N= N= Br NH» (IQ a Yo. OH NH, 0 A N Qe (30 N= N= NH, re A N Me: | = Me, OY” oN Lz 292a 293a and 293b [9 No N LI \ NH, NSC Br fr y HN / - FLL wy Rr E, H Ao o N Me 294c | So - Lic | 295 a Ap © CL Ie Cl wn Jo) | ~ Yo NN Me a Na NH CFy NozN Ny City” oC N H LY, Yi | 207d | oe No or | 298 HN lag / NH, ¥™\ 0 N. ’ © F NN Ne HN id: 3 A NHCH. HN~( % 0 fromm de] a xo i q Na. Br ba: a Ao i’ Ci | 2993 | @N~N 3008 | MeN Me oo NaN, Me 'S i NH, CFs oo ee a , Br pe Ho NB YC pao ~ \ N J OS 0 | Ao He © I! 01a |. / 302a o 4, — i NBT SAY J o 0 hs N. Me Ra, NH; ‘ CF, So Ns N Me NA 3 NH, CF, uy H B ONY r N Ty Ws 2 H Na Br A. Owe Ao 3032 | NN Me 307¢ NH, Lr SU NS N Me N. ~# NH, CF3 QO Tm Lo “N \_ / Sn A 2042 | Ao © 08a | No Ao © " F, Br Ao © 30a | . [fv 305a hs { - N s 3053 | NH ; \ a { x = NH; CFs B CFy H N.S dH N IY By Ho Nee® ‘Me NN Me + 1 a rr % 2% 3092 Cy | AY N= Na NH, / SN NH, SN v= n= Me Me oO i aol | LI New Br Pa J 7 A © J 310 | ~~. WL 2X 311a I oo Il “ o A N Me A N Me de) aa | [7] NH, NH, 72 7) N N N= So = = Me A 2 i Me Lo S pre NS [ Oo rr Lv NaN 318c NaN ® es N N# NH, NH; CF3 CF3 H TY Ns” "DS Ne © rd 0 0] Nz 320¢ | NH, ; CF rnd NH, CFs E, i i Ne Br *. Br 7 Ea oY 1S N’ 3 of Ao Ao 322 | UN. 321d | J N [oe ryt No NH CF, re NN, FS LA Nr CF o=( 33a | _N » - {J 7 335¢ 0 Se HN a / NH, == i wy © FN Ne HN J. J ew. vd 2s YU = 0 Tye © N 334a | 2 N 335¢ | (3X p HN NH, OCF, oy H Br Sey | 0 2 Ho Na 314a | fe A oo | % Ns oN Me: | # N Me = MD 7 " H; NH, ee. NH; C Me Me rm E, Mi I~ Br a Ao © Fir) a HJ Na AY \ J ko © r © 312a | | = 323a | {% N Ao i 3 1 NH; 1 1 ¢ \ NZ Yoo CFa NH EG NN Me iS Na NH; 7 YN N=" Me S Br AC {AN A 0 i 0 0 324; A a | iY 306a | re 306: Ng ’ 324a | Nes N / a | Js N { / NA N CF; NH CFy NH, 3 2 we 1. e.g MH pe Ho ne 325¢ | r= 326c | Lo 4 / oC Nd NEL CFy 0 Nas Cl A New N ( \ 7 Sets CFs NH, Met's NH, H yo BT TY 327¢ | F ™ 328f $5 x? No N N ( Yi. CF NH; A Cra } NH, 1 . 1 i ee Bi RNs ONY VY J x TL Ao = | 0 3293 | 330f | i oT HN Br POO Nt ¢ NH, - - - NH, fs N N < F NZ NH, P hi. I o=(_ 331a | rf 336¢c TIN Na” HN [ A Ne NH, P I —— x Hone i j cl Wy LN o 337a | Cl 3153 | C09 NH, NH, fN . Ho Ne™ BP N. Raa NH; 2 © = Fant wh Ye ¢ § 7 3 Na NH; 2 JN a vie 316a | a NO 4 3433 Ff H NBM Dg NC Ney V5 Neo Ns Neo N r 343a | NN r 7 t 7 NH, AY NH; JN Ve La x > 2 H Br ‘ytd A Q. OMe le 344¢ | i Me WHS: 345¢ Now) sl i N Qe (30 (LC Yeti. CFy N vie N. ¢ 1 Fs Yo CFy NH, NH, te _ . 2 H Nox, Br 346g | J Me 347a N vie N ¢ LJ N Nex = INI CFs NH; NH. YH H Br | Tr : =N. N li Hn - | c “ ( Nf 338e | rs. HN Ae” HN ed IR ja i np - CF, 2 PE] 0 N 3a8c | A Ye set mde 1 Me N N ¢ \ a8e| irk CF; FE 348¢c | . gd ie 349c | A No Me FQ , hey NH, jv Bi x Ho Nee™ N L VV. A o W 30a | [© 351a LN ® : 359» | A N a 3512 | i 5 “Me NH N oF, y po 2 H % RNs z N- N \ ys N A 0 A 0 332 | ro 333c | ory ° N Br : HONS 4 N . oy 13 ~ © © 0 No asc | l 332¢ | ) . ” N " ee fe i CFy N CF, . NH, : eed E i 1 7% om F , oe Ne” } = vy AS 365¢ | E J 366¢c | ry N Ao ” i I E i - Ne Br SP pol No,” 0 do of HMR Ls. IF = N ! N Nog Noy | CFs Nori Fy NH; >: NH, 2 H Nas, Br rd Lid 0" LO <5" N \ \ o # N % J 0 0 N 352¢ | AN Me 53a | NON Me = NN Me 9 Ny, NH, \-0 8 H 0 <5" Ao © 384c | FT N / T" 3553 NH; i: NH, H o=( FN nN NC 30a | =NO . / OC 7 341¢ = 0 Oy Ne, > A HN NA oN 0 iL I Bg { HN o meee ee] " By Ait IN. N Me 2423 | oN - 356¢c | CT LJ te \ L3H N hy NH, Cy OCH; - Me au. va ty A wm AS Me Non N Me 358¢ | =a Ne — NH, SX CFs ¢ ’ \ a ee CFs I | 2 H ” Br Nl \ N Ae A 2359¢ | ZNN-N Me WB0c | 00 ZN-N Me oo No oN Me Fo NH, 2 4 Br LY 361la | NUN me 367g U & N l QO to LX Nd CFy NH; FE A N, Me Ny NH, frre | (eV My aa Ao ol 94 368 | Nn . / 369g NH, NN ry Nz NH, ¢ CF, ia - - H Ty" N NY Ls 362F | 1 Me 363a or Br N ie N (30Y Nix N= Nd CF3 nN AL 3 Se A Ge (33 Na N= Ni CFy NH; fal NH, H oO DO Nag” Id % Ch 364e | rr Yas 364d Ro 5 Qe N N. ¢Y Lo Nd CFy qT i Nae Br 0X ow Ne NL (IQ N=, NL CFa NH; TE NH, Fe) H iy N- H rey A O== o i" 3 7 C = F . . 4 ho 1 =r IN, Ty wy CO oe lig ) -N oi 382a | ~ od { 3 No HN Te F © v F Tr nH i asa | or Y Cy aig | oy Oy O=y NN Ng N = © YP amg | Ng 9 Fo 7 L '® Na 3 HN F oN F oN o=( o={_ N H Yh N° Oy A } NR Tey ; IN F F a 3 J NN Br oO - J ANN = 387a | A Ny J Ng J HN F HN F F F 2 A 0 N o r vy o=( 0 Oy 388a | ’ bal oe | 2rd F © F FE B B IN Ng ‘ Or 388a | 3 & { = _— a = i 8 0 ba HN oo’ HN o” F F oN f o= \ N_ 7 389% | ANN Sef 390a | =N_ k® DW So ¢ y= N = 3 7 HN FF HN w iq os Oo = y-N N HN F Br Br Br bo fmm] MA k Na 0 rs Br BA N, 376g = cL Nec OA YT NERS, A i N, i ~~ I» ° Or 377a | a J Ng J pF iL Nr HN W Br Br H ox H J, / . 9 A yr Hi \ AY o=x 0 Oy 2808 | ol =N N wn ’ | rl Br Br asad pV, TN 8 TN 8r o= J ° PSN " 0a | Ny { Nay J Ng J HN HN Br Br H mn. o=( N ‘ YC Oy N - Ig ZN Br j: © + Br —— N, ha § 7 NR Br O=x I 1 N, / N ; SN i 375a | 2S ng A Ne HN o” HN oo Br Br I I oo - - EF hy i Na. Br Se qT H ~~ F 391g | ® Lk PF 392a | YY pe Ne NL Ne Bn ow 0 A F N N ¢ \ (YN NH; . - NH, ied - — I ! 2 HN Br a, N. a av ° oN 3703 | wo Me 378¢ NH; NH, 7 LT N N. [a ( oN 2 v a Q NH; [) gw oe wy NU Me | 7 TN 372a N= Sr n ol Ho Ne Er Dey Ao © 3733 Pharmaceutical Compositions The invention provides pharmaceutical compositions, each comprising one or more compounds of the invention, or pharmaceutically acceptable salts thereof. and a pharmaceutically acceptable cartier. Tn certain embodiments, the pharmaceutical composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention, which may include pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of a disease or condition characterized by aberrant complement system activity. Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. Methods of Use The present invention provides compounds, and pharmaceutically acceptable salts thereof, that are useful for treating or preventing a disease or condition characterized by aberrant complement svstem activity. In certain aspects, the invention provides a compound of the invention, ora pharmaceutically acceptable salt thereof, for use as a medicament. In certain aspects, the invention provides methods of treating or preventing a disease or condition characterized by aberrant complement system activity. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. or a pharmaceutically acceptable salt thereof, thereby treating or preventing the disease or condition characterized by aberrant complement system activity. By reducing complement system activity in the subject, the disease or condition characterized by aberrant complement system activity is treated. Alternatively. in certain aspects, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition characterized by aberrant complement system activity. Alternatively, in certain aspects, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treatment of a disease or condition characterized by aberrant complement system activity. As used herein, a “disease or condition characterized by aberrant 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 the setting of inappropriate activation or hyperactivation of the complement system. In certain embodiments, the disease or condition characterized by aberrant complement system activity is an immunological disorder. In certain embodiments. the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a neurodegenerative disease or neurological disease. To certain embodiments, the disease or condition characterized by aberrant complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiovascular disease. To certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiometabolic disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hermolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuroryelitis optica, membranoproliferative glomerulonephritis, dense-deposit disease, cold agglutinin disease. and catastrophic antiphospholipid syndrome. Tn certain embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria. In certain embodiments, the disease or condition is atypical hemolytic uremic syndrome. In certain embodiments, the disease or condition is organ transplant rejection. In certain embodiments, the disease or condition is myasthenia gravis. In certain embodiments, the disease or condition is neuromyelitis optica. Tn certain embodiments, the disease or condition is membranoproliferative glomerulonephritis. In certain embodiments, the disease or condition is dense-deposit disease. In certain embodiments, the disease or condition is cold agglutinin disease. In certain embodiments. the disease or condition is catastrophic antiphospholipid syndrome. In other embodiments, the disease or condition characterized by aberrant complement system activity is adult respiratory distress syndrome, myocardial infarct, lung inflammation, hyperacute rejection (transplantation rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barré syndrome, hemorrhagic shock, paroxysmal noctumal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer’s disease, organ rejection (transplantation), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis. In other embodiments, the disease or condition characterized by aberrant 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 certain embodiments, the disease or condition characterized by aberrant complement system activity is a hematological disorder. To other embodiments, the disease or condition characterized by aberrant complement system activity is an ocular disorder or an eve disorder. In certain embodiments, the disease or condition characterized by aberrant 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. a corneal neovascularization disease, post-comeal transplant rejection, a comeal dystrophic disease, an autoimmune dry eye disease, Stevens-Tohnson syndrome, Sjogren’s syndrome, an environmental dry eve disease, Fuchs’ endothelial dystrophy, retinal vein occlusion, or post- operative inflammation. In certain embodiments. the disease or condition characterized by aberrant complernent system activity is angioedema, e.g., hereditary angioedema or acquired angioedema. In certain embodiments, the disease or condition characterized by aberrant complement system activity is obesity, insulin resistance. diabetes, dyslipidemia, nephropathy, or neuropathy. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), paroxysmal noctumal hemoglobinuria, and thrombotic microangiopathy. In certain embodiments, the disease or condition characterized by aberrant 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. In certain embodiments. the disease or condition characterized by aberrant complement system activity is periodontitis. In certain embodiments, the disease or condition characterized by aberrant complement system activity is Crohn's disease. To certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of asthma, chronic obstructive pulmonary disease. and acute respiratory distress syndrome In certain embodiments, the disease or condition characterized by aberrant complement system activity is atherosclerosis. To certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of age-related macular degeneration (AMD), uveitis, glaucoma, and wet AMD. In certain embodiments, the disease or condition characterized by aberrant complement svstem activity is myocardial infarction. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of atypical hemolytic uremic syndrome. C3 glomerulopathy, lupus nephritis. IgA nephropathy, and membranous nephropathy. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of rheumatoid arthritis, osteoarthritis, bullous pemphigoid, psoriasis. hidradenitis suppurativa. and burns, In certain embodiments, the disease or condition characterized by aberrant complement system activity is hemodialysis. Tn certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of ischemia / reperfusion injury, acute kidney injury, and organ transplantation, ¢.g., kidney transplant. In certain embodiments, the disease or condition characterized by aberrant 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. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antibody-mediated rejection, antiphospholipid syndrome, Berger's disease, C3 glomerulonephritis, cold agglutinin disease, cardiopulmonary bypass, dense-deposit disease. delayed graft function, geographic atrophy. granulomatosis with polyangiitis. graft versus host disease, hematopoietic stem cell transplant-related thrombotic microangiopathy, immune complex- mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy. idiopathic polypoidal choroidal vasculopathy, microscopic polyangitis, pyoderma gangrenosum, Stargardt Disease 1, and warm type autoimmune hemolytic anemia. Formulations, Routes of Administration, and Dosing The compounds of the 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 adapted to the chosen route of administration, e.g., orally or parenterally. by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the invention. Thus, the present compounds may be systemically administered, ¢.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. may be compressed into tablets, or may be incorporated directly with 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 active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between 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 obtamed. The tablets, troches, pills, capsules, and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like: a lubricant such as magnesium stearate: and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen. or cherry flavoring may be added. When the unit dosage form isa capsule, it may contain. in addition to materials of the above type, a liquid carrier, such asa vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin. wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dve and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition. the active compound may be incorporated into sustained-release preparations and devices. The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water or physiologically acceptable aqueous solution, optionally ruixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forras suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporancous preparation of sterile injectable or infusible solutions or dispersions. optionally encapsulated in liposomes. In all cases. the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable nuixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutancl, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, 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. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required. followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and the freeze drying techniques. which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. For topical administration, the present compounds may be applied in pure form, i.e. when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose. silica. alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glyeol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for agiven use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be eraployed with liquid carriers to form spreadable pastes. gels. ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of the invention to the skin are known in the art; for example, see 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). Useful dosages of the compounds of the invention can be determined, at least initially, by comparing their in vitro activity and in vive activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U.S. Pat. No. 4,938,949 (incorporated herein by reference). The amount of the compound, or pharmaceutically acceptable salt thereof, required for use in treatment 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 be ultimately at the discretion of the attendant physician or clinician In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg / kg body weight of the recipient per day, e.g., from about 3 to about 90 mg / kg of body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, from about of 10 to about 60 mg / kg of body weight per day, or from about 15 to about 50 mg / kg of body weight per day. Compounds of the 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 invention provides a composition comprising a compound of the invention, or phamaceutically acceptable salts thereof, formulated in such a unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses to be administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided. e.g.. into a number of discrete loosely spaced administrations. Compounds of the invention, or pharmaceutically acceptable salts thereof, can also be administered in combination with other therapeutic agents, for example, other agents that are useful for treating or preventing ischemia, blood loss, or reperfusion injury. In certain embodiments, compounds of the invention, and pharmaceutically acceptable salts thereof. can also be administered in combination with one or more other therapeutic agents that are useful for treating or preventing an ocular disorder or eve disorder. Other delivery systems can include time-release, delayed release. or sustained release delivery systems such as are well-known in the art. Such systems can avoid repeated administrations of the active compound, increasing convenience to the subject and the physician, Many types of release delivery systems are available and known to those of ordinary skill in the art. Use of a long-term sustained release implant may be desirable. Long-term release, as used herein, means that the delivery system or is implant constructed and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days. In certain embodiments, a compound of the invention is formulated for intraocular administration, for example direct injection or insertion within or in association with an intraocular medical device. In certain embodiments, a compound of the invention is formulated as an ophthalmic solution. In certain embodiments, a compound of the invention can be administered via ocular delivery, for example, by local ocular administration, including topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral. suprachoroidal, or sub-tenon administration. A compound of the invention can be administered via ocular delivery either alone or in combination with one or more additional therapeutic agents. The compounds of the invention may be formulated for depositing into a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other device that can be deployed or permanently implanted within a body lumen. As a particular example, it would be desirable to have devices and methods which can deliver compounds of the invention to the region of a body which has been treated by interventional technique. In exemplary embodiment, a compound of the invention may be deposited within a medical device, such as a stent, and delivered to the treatment site for treatment of a portion ofthe body. Stents have been used as delivery vehicles for therapeutic agents (i.¢., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral vessels. Stent designs include those of 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 metal and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents may also be used to deliver a drug at the site of contact with the vasculature, as disclosed 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 in International Patent Application Nos. WO 91 / 12779 (Medtronic, Tne.) and WO 90 / 13332 (Cedars-Sanai Medical Center), for example. The term “deposited” means that the compound is coated, adsorbed. placed. or otherwise incorporated into the device by methods known in the art. For example. the compound may be embedded and released from within (“matrix type”) or surrounded by and released through (“reservoir type”) polymer materials that coat or span the medical device. Tn the latter example, the compound may be entrapped within the polymer materials or coupled to the polymer roaterials using one or more the techniques for generating such materials known in the art. In other formulations, the compound may be linked to the surface of the medical device without the need for a coating, for example by means of detachable bonds, and release with time or can be removed by active mechanical or chemical processes. In other formulations, the compound may be in a permanently immobilized form that presents the compound at the implantation site. In certain embodiments, the compound may 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 are useful for coating a number of devices designed for implantation. The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but frequently a bioabsorbable polymer is preferred for this embodiment since, unlike a biostable polymer, it will not be present long after implantation to cause any adverse. chronic local response. Bioabsorbable polymers that could be used include, but are not limited to. poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly (lactide-co-glycolide) (PLLA / PGA), poly(hvdroxybutyrate), polv(hydroxybutyrate-co-valerate), polvdioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(p-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), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates. poly(trimethylene carbonate), poly(iminocarbonate), copoly (ether-esters) (e.g.. PEO / PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose. starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters. polyacetals, polydihydropyrans, polycyanoacrylates, cross linked or amphipathic block copolymers of hydrogels, and other suitable bioabsorbable poplymers known in the art. Also. biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used, and other polymers could also be used if they can be dissolved and cured or polymerized on the medical device such as polyolefins, polvisobutylene 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 ketones: polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymer; polvhydroxy-propyl-methacrylamide-~ phenol; polvhydroxyethyl-aspartamide-phenol: polyethylencoxide-polylysine substituted with palmitoyl residues; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes: rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose. Polymers and semipermeable polymer matrices may be formed into shaped articles. such as valves, stents, tubing, prostheses and the like. In certain embodiments of the invention, the compound of the invention is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device. Typically, polymers are applied to the surface of an implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose. Methods of spraying include traditional methods as well as microdeposition techniques with an inkjet type of dispenser. Additionally, a polymer can be deposited on an implantable device using photo-patterning to place the polymer on only specific portions of the device. This coating of the device provides a uniform layer around the device which allows for improved diffusion of various analytes through the device coating. In certain embodiments of the invention, the compound is formulated for release 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... months) using at least one of several well-known techniques involving polymer carriers or layers to control elution. Some of these techniques are described in U.S. Patent Application 2004 / 0243225A1, the entire disclosure of which is incorporated herein in its entirety. Moreover. as described for example in U.S. Pat. No. 6,770,729, which is incorporated herein in its entirety, the reagents and reaction conditions of the polymer compositions can be manipulated so that the release of the compound from the polymer coating can be controlled. For example, the diffusion coefficient of the one or more polymer coatings can be modulated to control the release of the compound from the polymer coating. In a variation on this theme, the diffusion coefficient of the one or more polymer coatings can be controlled to modulate the ability of an analyte that is present in the environment in which the medical device is placed (e.g, an analyte that facilitates the breakdown or hydrolysis of some portion of the polymer) to access one or more components within the polymer composition (and for example, thereby modulate the release of the compound from the polymer coating). Yet another embodiment of the invention includes a device having a plurality of polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the jnvention, the release of the compound from the polymer coating can be modulated by the plurality of polymer coatings. In yet another embodiment of the invention, the release of the compound from the polymer coating is controlled by modulating one or more of the properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds, or altematively, the pH of the polymer composition. For example, certain polymer compositions can be designed to release a compound in response to a decrease in the pH of the polymer composition Kits The invention also provides a kit, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat or prevent a disease or condition characterized by aberrant complement activity. In one embodiment, the mammal is a human. It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. EXAMPLES Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. Scheme 1 Br Co, By ii vay NT Sen TFA. Cs,C04 I Be Soe NH, COBu CoH NH Ny { Nay { oS a coga I TFA Tr { Boog, A J Ta, NA 7 C5003 NH, NH; NH; 1a 1b 1e AY Ms vy H Br ~S N 7 14 H © HAT. DIPEA I 7 N. ~ NH, 1e Preparation of (1R.3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-bJindol-9-yl)acetyl)-N-(6-bromo- 3-methylpyridin-2-yl)-2-azabicvclo[3.1.0}hexane-3-carboxamide (1e) Step-1: Preparation of tert-butyl 2-(4-amino-9H-pyrimido[4,3-bJindol-9-y1)acetate (1b) A mixture of 9H-pyrimido[4,5-blindol-4-amine (1a) (0.50 g, 2.71 mmol; CAS# 400754-64- 5), tert-butyl 2-bromoacetate (0.582 g, 2.99 mmol) and Cs2COs (1.061 g, 3.26 mmol) in DMF (20 mL) was stirred at RT for 3 h, diluted with H20 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with H20 (30 mL x 4), brine (30 mL), dried. filtered and concentrated under vacuum and purified by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] to provide rerr-butyl 2~(4-amino-9H- pyrimido[4.5-blindol-9-yl)acetate (1b) (0.64 g, 79 % vield) as a yellow solid; 'H NMR (300 MHz. DMSO-ds) 6 8.35 (d, J = 7.8 Hz, 1H), 829 (s, 1H), 755 (d,.J = 8.1 Hz. 1H), 7.41 (dd, J = 83, 7.1 Hz, 1H), 7.35 — 7.18 (m, 3H), 5.12 (s, 2H), 1.41 (s, 9H). Step-2: Preparation of 2-(4-amino-9H-pyrimido[4,5-blindol-9-yl)acetic acid (1c) A mixture of 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) was stirred at RT for 16 h and concentrated in vacuum to dryness to afford 2-(4-amino-9H-pyrimido[4,5- blindol-9-ylacetic acid (Ic) (0.74 g, 99%) TFA salt as an orange slid; 'H NMR (300 MHz, DMSO-ds) 58.55 (5. 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 (1,.J = 7.6 Hz, 1H). 5.26 (s, 2H); °F NMR (282 MHz, DMSO- de) 3-74.71. Step-3: Preparation of (1R,38,5R)-2-(2-(4-amino-9H-pyrimido[4,5-bJindol-9-y1)acetyl)-N-(6- bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (1e) To a solution of 2-(4-amino-9H-pyrimido[4,5-b}indol-9-yl)acetic acid (1¢) (50.7 mg, 0.142 mmol) TFA salt, (1R.3S,5R)-N~(6-bromo-3-methylpyridin-2-vl)-2-azabicyclo[3.1.0|hexane- 3-carboxamide (1d) HCI salt [(43 mg, 0.129 mmol): prepared according to the procedure reported by Wiles, Jason A_ et al, PCT Int. Appl. (2017), WO 2017035353 Al 20170302; incorporated by reference] and HATU (59.0 mg, 0.155 mmol) in DMF (5 mL) was added dropwise DIPEA (84 mg, 0.646 mmol) and stirred at RT for 16 b. The reaction mixture was diluted with H20 (30 ml) and extracted with EtOAc (20 mL x 2). The combined organics were washed with 0.5 M NaOH (25 mL), H20 (23 mL x 3), brine (25 mL), dried, filtered and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography [silica gel (12 g), eluting with MeOH mn DCM from 0-3%] to provide 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 in water (containing 0.1% HC) from 0-60%] to provide (1R,38.5R)-2-(2~(4-amino-9H-pyrimido[4.5-b]indol-9- yhacety)-N-(6-bromo-3-methylpyridin-2-y1)-2-azabicyclo[3. |. 0]hexane-3-carboxamide (le) (48 mg, 71 % vield) HCI salt as a white solid. "H NMR (300 MHz, DMSO-dq) 10.28 (s, 1H, D:0 exchangeable), 8.83 - 8.59 (m, 3H, 2H D:0 exchangeable), 8.54 (d, J = 7.9 Hz, 1H), 7.70 (d.T=8.2Hz, 1H), 7.62 (d. J = 7.9 Hz, 1H), 7.56 (t. ] = 7.8 Hz, 1H), 7.45 (m. 2H), 5.75 (d,T=175Hz 1H), 547(d, J=17.3 Hz, 1H), 439 (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): Analysis calculated for C2sH22BiN+02.1.1HCL.2.5H20: C, 47.60; H, 4.68; Cl, 6.44; N, 16.19; Found: C. 47.57; H, 4.60; C1. 6.33: N. 16.19. Scheme 2 Br 2 NY TFA Br” C0, / Bu r my Zn, TMSCI, CoB No ZN ; Nas or i”. Pdy(dbals, XPhos NH; 2 Na A NH, 2a 2b 1d H 2a 1d 0 ar ACOH % RNs N. N \ 7 NTN H 0 Nes reesei Y HATU, DIPEA NH, 20 2d Preparation of (1R,38 5R)-2-(2-(4-aminopyrrolo|2,1-f]{1,2,4]triazin-7-y1)acetyl)-N-(6- bromo-3-methylpyridin-2-y1)-2-azabicyclo[3.1.0thexane-3-carboxamide (2d) Step-1: Preparation of fert-butyl 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-y1)acetate (2b) To a suspension of zinc (1.842 g, 28.2 mmol) (Note: Zine dust was activated using aqueous 0.1 M HCI, followed by washing thoroughly with H20, EtOH and Et>0, and drving at 100 °C under vacuum before use) and TMSCI (0.179 mL. 1.408 mmol) in THF (5 mL) at 50 °C was added dropwise rert-butyl 2-bromoacetate (2.75 g. 14.08 mmol) in THF (5 mL) under an argon atmosphere. The mixture was heated at 50 °C for 30 min cooled to RT and was 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), Pdz(dba)s (0.215 g, 0.235 mmol) and XPhos (0.224 g, 0.469 mmol) in THF (10 mL) at RT under an argon atmosphere and heated at 60 °C under argon for 16 h. The reaction mixture was cooled to RT diluted with EtOAc (30 mL), added solid NH«Cl (2 g) stirred at RT 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 NHaCl (30 mL). 20 (30 mL), brine (30 mL), dried, filtered and concentrated in vacuum. The obtained residue was purified by flash column chromatography [SiOz gel (24 g), eluting with EtOAc in hexane from 0-50%] to provide fert-butyl 2-(4-aminopyrrolo[2.1-f][ 1,2.4|triazin-7-v])acetate (2b) (0.65 g, 56 % yield) as a yellow solid; ’H NMR (300 MHz, DMSO-d) & 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). Step-2: Preparation of 2-(4-aminopyrrolo[2,1-f]| 1,2 4Jtriazin~7-yl)acetic acid (2c) Compound 2¢ was prepared according to the procedure reported in step-4 of scheme-1, 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 mamol) in DCM (20 mL) and stirring at RT for 16 b. The reaction mixture was concentrated in vacuum to afford 2-(4-aminopyrrolo[2,1-f][1,2 4]triazin-7-y])acetic acid (2¢) (1.05 g) TFA salt as an orange solid; 'H NMR (300 MHz, DMSO-dr) § 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). '9F NMR (282 MHz, DMSO-de) 5-74.71; MS (ES+): 193 (M+1), (ES-): 191 (M-1). Step-3: Preparation of (1R.38.5R)-2-(2-(4-aminopyrrolo[2.1-f]{ 1,2 4]triazin-7-v])acetyl)-N- (6-bromo-3-methylpyridin-2-y1)-2~azabicyclo[3.1.0]bexane-3-carboxamide (2d) Compound 2d was prepared according to the procedure reported in step-3 of scheme-1 from TFA salt of 2-(4~aminopyrrolo[2, 1-f}[1,2.4]triazin~7-yl)acetic acid (2¢) (54.7 mg, 0.179 mmol) in DMF (5 mL) using HCI salt of (1R,38,5R)-N-(6-bromo-3-methylpyridin-2-y1)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g) eluting with MeOH in DCM from 0 - 53%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-60%] (1R,38,5R)-2~(2-(4~aminopyrrolo[2, 1-f][1,2 4Jtnazin-7-v1)acetyl)-N-(6-bromo-3- methylpyridin-2-v1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (2d) (20 mg, 26 % vield) as a white solid: "H NMR (300 MHz, DMSO-ds) § 10.25 (s, 1H, D:0 exchangeable), 10.01 (s, 1H, D20 exchangeable), 9.21 (s. 1H. D20 exchangeable), 8.20 (s, 1H), 7.64 (d. J = 8.0 Hz. 1H), 7.52 (d, J = 4.6 Hz, 1H), 7.45 (d, T= 7.9 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 438 (dd, T= 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). Scheme 3 / —COH FE, EF Noon 1 y 3 HN \w / I NCO SN N HN 1~ H 1c HATU, DIPEA 7 H; H Np 0 =z | 3a NH, 3h Preparation of (28,4R)- 1-(2~(4-amino-9H-pyrimido[4.5-bJindol-9-yl)acetyl)-N-(6-bromo-3- methylpyridin-2-y1)-4-fluoropyrrolidine-2-carboxamide (3b) Compound 3b was prepared according to the procedure reported in step~3 of scheme-1, from TFA salt of 2-(4-amino-9H-pyrimido(4,5-b]indol-9-vI)acetic acid (1¢) (150 mg, 0.421 mmol) in DMF (5 mL) using HCI salt of (28.4R)-N-(6-bromo-3-methylpyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide (3a) [(143 mg, 0.421 mmol); prepared according to the procedure reported by Wiles, Jason A. et al, PCT Int. Appl. (2017), WO 2017035355 A] 20170302; incorporated by reference], HATU (192 mg, 0.505 mmol) DIPEA (272 mg, 2.105 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse-phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-60%] (28.4R)-1-(2-(4-amino-9H-pyrimido[4,5-blindol-9-ylacety])-N-(6- bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (3b) (123 mg, 36 % yield) HCl salt as a white solid; 'H NMR (300 MHz. DMSO-ds) § (a mixture of two rotamers) 10.92 (s) and 10.48 (s) (2s, 1}, D20 exchangeable), 8.73 (s, 3H, D20 exchangeable), 8.62 (s, 1H), 8.53(d,J=78 He, 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), $37 (d,J = 17.3 Hz. 1H), 4.57 (t, J = 9.4, 7.6 Hz, 1H), 4.48 — 4.23 (m, [H), 4.20 — 3.95 (m, IH). 2.79 — 2.49 (m, 4H), 2.32 - 2.05 (m, 1H); °F NMR (282 MHz, DMSO-d) 3 -176.05, -176.37: MS (ES+): 526.0 (M+1), 524.0 (M- 1); Analysis calculated for C23H21BrFN-02 HC12.75H20: C, 45.11; H, 4.53, CL, .79; N, 16.01; Found: C, 45.12; H, 4.29; CL. 5.71. N, 15.84. Scheme 4 ) oo ny * H + Oy N fH Br Oo Z an 4a A HATU. DIPEA Ne N 0 NH; =, “eo 4b Ng N Eo NH, = Preparation of (1R,38,5R)-2-(2-(4-amino-9H-pyrimido[4,3-b]indol-9-yl)acety1)-N-(6- bromopyridin-2-y1)-2-azabicyclo|3.1.0]hexane-3-carboxamide (4b) Compound 4b was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4~-amino-9H-pyrimido[4.5-b]indol-9-yDacetic acid (1c) (150 mg. 0.421 mmol) in DMF (5 mL) using HCI salt of (1R.38,5R)-N-(6-bromopyridin-2-y1)-2- azabicyclo[3.1.0Jhexane-3-carboxamide (4a) [(134 mg, 0.421 mmol); prepared according to the procedure reported by Altmann, Eva et al., PCT Int. Appl. (2012), WO 2012093101 Al 20120712; incorporated by reference]. HATU (192 mg, 0.505 mmol), DIPEA (272 mg, 2.105 mrool) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-60%)] (I1R,38.5R)-2~(2~(4-amino-9H- pyrimidof4,5-blindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0}hexane-3- carboxamide (4b) (110 mg, 52 % yield) HC! salt as a white solid. '"H NMR (300 MHz, DMSO-ds) & 10.77 (s, 1H. D20 exchangeable), 8.63 (ru, 3H, 2H D:20 exchangeable), 8.53 (d. T=7.9Hz, 1H), 8.01 (d, J=8.1 Hz. 1H), 7.76 - 7.66 (m, 2H). 7.58 (t, T= 7.5 Hz, 1H), 7.44 (¢, Y=175 Hz, 1H), 732 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 17.3 Hz, 1H), 443 (dd, 7 =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): Analysis calculated for: C2:HzoBN-02. HCI. 2.25H20: C, 47.36; H, 4.41; C1. 6.08; N, 16.81; Found: C, 47.25: H, 4.18; Cl, 6.02: N, 16.70. Scheme 5 IZ] [COzBu NaN 7 Bou NSN TFA be NZ NH» N. H SN Br cosBu (Jo Cs;C0y NH, 5a E N By B r 0 Rs Sn \ J H a 0 750M Ad ~~ HATU, DIPEA . i Ny-Br ATTY N, be NAT NH» ae NZ J 5c NH; Be Preparation of (28,4R)~1-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(6- bromopyridin-2-vl)-4-fluoropyrrolidine-2-carboxamide (Se) Step-3: Preparation of tert-butyl 2-(4-amino~TH-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (Sb) Compound Sb was prepared according to the procedure reported in step-1 of scheme-1, from TH-pyrrolo[2,3-d]pyrimidin-4-amine (Sa) (1.0 g, 7.45 mmol; CAS # 1500-85-2) in DMF (20 ral.) using fert-butyl 2-bromoacetate (1.600 g, 8.20 mmol), Cs2C03 (2.91 g, 8.95 mmol) and stirring at RT for 3 h. This gave after workup and purification by flash column chromatography. [silica (24 g), eluting with 0-3% MeOH in DCM] fers-butyl 2~(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-ylacetate (5b) (0.62 g, 34 % yield) as a yellow solid; "HNMR (300 MHz, DMSO-dy) 6 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). Step-4: Preparation of 2-(4-amino-7H-pyrrolo[2,3-d|pyrimidin-7-yl)acetic acid (5¢) Compound Sc was prepared according to the procedure reported in step-2 of scheme-1. 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 RT for 16 h. This gave after workup 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5¢) (1.42 g) TFA salt as an orange solid: "HNMR (300 MHz, DMSO-d) 5 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). Step-5: Preparation of (28,4R)-1-(2-(4-amino-7H-pyrrolo|2,3-d]pyrimidin-7-yl)acetyl)-N-(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (Se) Compound Se was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4~amino-7H-pyrrolo| 2,3~d]pyrimidin-7-yl)acetic acid (5c) (137 mg, 0.448 rmamol) in DMF (5 mL) using TFA salt of (2S.4R)-N-(6-bromopyridin-2-yi)-4~ fluoropyrrolidine-2-carboxamide (5d) [(150 mg. 0.373 mmol); prepared according to the procedure reported by Wiles, Jason A. et al, PCT Int. Appl. (2017), WO 2017035348 Al 20170302; incorporated by reference], HATU (170 mg, 0.448 mmol), DIPEA (241 mg, 1.863 mrool) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with 0 - 3% MeOH in DCM] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-60%] (2S.4R)-1~(2-(4-amino-7H-pyrrolo[2,3~ d]pyrimidin-7-y])acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (Se) (84 mg, 49% yield) as a white solid: 'H NMR (300 MHz, DMSO-ds) & (a mixture of two rotamers) 11.36 (5) and 11.03 (s) (2s, 1H, D20 exchangeable). 9.22 (s, 2H, D0 exchangeable), 8.36 (s, 1H), 8.01 (d,J=8.2 Hz, IH), 7.71 (t,. / = 8.0 Hz, 1H), 7.40 (d,J=3.5 Hz, 1H), 733 (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 (mn, 1H), 2.25 — 1.95 (m, 1H): IF NMR (282 MHz, DMSO-de) 8 -175.70, -175 96; MS (ES+): 462.0 (M+1), 460.0 (M-1); Analysis calculated for CsHi7BrFN7O2. HCL2H:0: C, 40.43; H, 4.15; C1, 6.63; N, 18.33; Found: C, 40.19: H, 3.86: Cl. 6.98: N, 17.96. Scheme 6 e ji “co, / 8 Hoey, NHoae LL = Br cogey AcOH Meal Cs,C03 HN H HN HK A N Xr \ HC(OBt);, NH(OAC So, 1 NC 2 AcOH Rey = Aes 3 - Me Me Ba Bc H TFA SPA oN HATU, DIPEA HN la ory B i Ho Nse™ 4 N, / O0H Sy \ I ¥j—N H © J CN - HATU, DIPEA HN Me: \ ‘Me Me NH, a ad Preparation of (1R.38,5R)-2-(2-(4-amino-6-methy1-9H-pyrimido|[4,5-b]indol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0thexane-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) was added 2-amino-3-methyl-1H-indole-3-carbonitrile (6a) (3.85 g. 22.49 mmol) and NHsOAc (8.67 g. 112 mmol) in a 350-mL. pressure vessel and heated at 100 °C under pressure for 16 h. The reaction mixture was diluted with HzO (20 mL) and stirred for 15 min. The mixture was then filtered and the solid was washed H>0 and air dried to provide 6- methyl-9H-pyrimido[4.5-b]indol-4-amine (6b) (3.60 g, 81%) as a pale-vellow solid: ‘H NMR (300 MHz, DMSO-d) 11.67 (s, 1H). 8.22 (s, 1H), 8.12 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.07 (dd, J= $8.3, 1.5 Hz, 1H), 7.07 (s, 2H), 2.45 (5, 3H); MS (ES+): 1.99 (M1), (ES-): 197 (M-1). Step-2: Preparation of rert-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (6¢) Compound 6¢ was prepared according to the procedure reported in step-1 of scheme-1, from 6-methyl-9H-pyrimido[4,5-blindol-4-amine (6b) (2.00 g. 10.09 mmol; CAS # 1242140-67-5) in DMF (20 mL) using rert-butyl 2-bromoacetate (2.362 g. 12.11 mmol), Cs2C03 (6.57 g. 20.18 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (20 g), eluting with MeOH in DCM from 0-3%)] ferr-butyl 2-(4-amino-6-methyl-9H-pyvrimido[4,5-b]indol-9-v])acetate (6¢) (2.57 g, 82% vield) as a pale yellow solid; 'H NMR (300 MHz, DMSO-ds) 8 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). Step-3: Preparation of 2-(4-amino-6-methyl-9H-pyrimido[4,5-bJindol-9-yhacetic acid (6d) Compound 6d was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2~(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (6¢) (0.220 g, 0.704 mmol) using TFA (8.03 mg. 7.04) in DCM (10 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-methyl-9H-pyrimido[4,5-bJindol-9-yDacetic acid (6d) (300 mg) TFA salt as a purple solid; ‘H NMR (300 MHz, DMSO-ds) 5 8.54 (d, / = 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. IH), 5.24 (s, 2H); F NMR (282 MHz. DMSO-ds) § -74.24: MS (ES+): 257 (M+1), (ES-): 255 (M-1). Step-4: Preparation of (1R,3S,5R)-2~(2-(4~amino-6-ructhyl-9H-pyrimido[4.5-bJindol-9- vhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3. 1.0Thexane-3-carbosamide (6e) Compound 6e was prepared according to the procedure reported in step-3 of scheme-1. from TFA salt of 2-(4-amino-6-methy]-9H-pyrimido[4,5-blindol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using HCI 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 ramol). DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with 0 - 5% MeOH in DCM] followed by purification using reverse phase column chromatography [C18 column (100 g). eluting with ACN in water (containing 0.1% HCI) from 0-60%] (IR,3S.5R)-2-(2-(4~ anino-6-methyl-9H-pyrimido[4,5-b]indol-9-yDacety])-N-(6-bromopyridin-2-y1)-2- azabicyclo[3.1.0]hexane-3-carboxamide (6¢) (48 mg, 68 % yield) HCI salt as a white solid; IH NMR (300 MHz, DMSO-d) 8 10.76 (s. 1H. D20 exchangeable), 8.88 (s. 2H, D:0 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), 742 (dd..J= 8.3, 1.6 Hz. IH), 7.32 (d,J= 7.7 Hz, 1H), 5.76 (d,. / = 17.3 Hz, 1H), 5.41 (d, J = 17.1 Hz, 1H), 4.42 (dd, J = 9.0, 5.5 Hz, 1H), 3.92 (m, 1H), 2.34 (m, 1H), 2.21 (mn, 1H), 1.92 (m, 1H), 1.07 (m, 1H), 0.77 (m, 1H): MS (ES+): 520.0 (M+1); (ES-): 518.0 (M-1); Analysis calculated for C2aHzzBtN-02.1.25HC1.2.75H20: 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. Scheme 7 Fe H f HOC. a LL Me NH, 6d N < 0 A Ta HATU, DIPEA CC Na CaN \ < » 0 . 0 NH, Me 0 3 WN cl mm —— N HATU, DIPEA QQ ALS Me 7b NH, Preparation of (28.4R)-1-(2-(4-amino-6-methyl-9H-pynmido[4,5-blindol-9-yDacetyl)-N-~(3- chloro-2-fluorobenzyvl)-4-fluaoropyvrrolidine-2-carboxamide (7h) Compound 7h was prepared according to the procedure reported in step~3 of scheme-1, from 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 TFA salt of (28,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (7a) [(52.5 mg, 0.135 mmol); prepared according to the procedure reported in Wiles, Jason A. et al, PCT Int. Appl. (2017), WO 2017035349 A] 20170302; incorporated by reference], HATU (61.6 mg, 0.162 mmol) DIPEA (0.118 mL, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash coluron chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-60%)] (2S,4R)-1-(2-(4-amino-6- methyl-OH-pyrimido[4,5-bJindol-9~yl)acety)-N~(3~chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (7b) (30 mg, 43 % vield) HCl salt as a white solid; *H NMR (300 MHz, DMSO-ds) 6 (a mixture of two rotamers) 9.12 (s) and 8.73 - 8.47 (m)(s and m, 4H, 2H exchangeable). 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. / = 7.9 Hz. 1H), 5.65 — 5.49 (m. IH), 5.46 — 5.37 (rm, 1H). 5.32 (d, J = 17.3 Hz, TH), 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); '%F NMR (282 MHz, DMSO-de) -121.26, - 121.77. -176.26, -176.48: MS (ES+): 513.0 (M+1), 511.0 (M-1); Analysis calculated for CosHasCIF2NeQ: HCL2H20: 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, Scheme & COM H NCO NN N = HN 1 6d Me - FZ HATU, DIPEA 8a % H A ™ Br o & 8a NH; } 2 ap Preparation of (1R,3S.5R)-2-(2-(4-amino~6-methyl-9H-pyrimido[4.5-bJindol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8b) Compound 8b was prepared according to the procedure reported in step-3 of scheme- |, from TFA salt of 2-(4-amino-6-methy]-9H-pyrimido[4,5-blindol-9-vl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using HCI salt of (1R,3S,5R)-N-(6-bromopyridin-2-y1)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) [(44.9 mg, 0.135 mmol); prepared according to the procedure reported by Wiles, Jason A. etal, PCT Int. Appl. (2017). WO 2017035353 A1 20170302], HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with 0 ~ 5% MeOH in DCM] followed by purification using reverse phase column chromatography [C18 coluron (100 g). eluting with ACN in water (containing 0.1% HCI) from 0-60%] (1R,38,5R)-2-(2-(4-amino-6-methyl-9H- pyvrimido[4,5-b]indol-9-vl)acety])-N-(6-bromopyridin-2-v1)-5-methyl-2- azabicyclo[3.1.0]bexane-3-carboxamide (8b) (40 mg, 55 % yield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 3 10.76 (s, 1H. D20 exchangeable), 8.57 (s. 1H), 8.47 (s, 2H. D0 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. IH), 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). Scheme 9 / —COH Lod <y" ay / L NS N N = HN 1c vy An NH 0 Hy tn Nat HATU, DIPEA NAN oq, & Ae oe) NH, Preparation of (1R,3S,5R)-2-(2-(4-amino-9H-pyrimido[4.5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-S-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (9a) Compound 9a was prepared according to the procedure reported in step-3 of scheme-1. from TFA salt of 2-(4-amino-9H-pyrimido[4.5-blindol-9-vl)acetic acid (1c) (50 mg, 0.14 mmol) in DMF (1.3 mL) using HCl salt of (1R,38,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclof3.1.0]hexane-3~carboxamide (8a) (46.7 mg, 0.14 mmol), HATU (80 mg, 0.211 mmol), DIPEA (0.122 nL, 0.702 mmol) and stirnng at RT for 16 h. This gave after workup and purification by flash coluron chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-100%] followed by purification using reverse phase column chromatography [C18 column (50 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2-(2-(4-amino-9H-pyrimido[4,3-blindol-9-yl)acetyl)-N-(6-bromopyridin-2~y1)~3- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (9a) (49 mg, 67% vield) HCl saltas a white solid; 'H NMR (300 MHz, DMSO-d) 3 10.78 (s, 1H, D20 exchangeable), 8.77 (s, 2H. D:20 exchangeable). 8.66 (s, 1H), 8.54 (d.J=7.9 Hz, 1H), 8.01 (d,J=8.2 Hz, IH). 7.75 - 7.67 (ro. 2H), 7.61 — 7.55 (ra, 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, TH); MS (ESH): 520.0 (M#1), 542.0 (M+Na); (ES): 518.0 (M-1); Analysis calculated for C24H22BrN-02.1.75(H20).1.25(HCl): C, 48.25: H. 4.51; Cl. 7.42: N. 16.41; Found: C, 48.06: H, 4.27; C1. 7.28: N. 16.27. Scheme 10 / —COH 10a HATU, DIPEA = TN 100 6d nN. / —COMH NN Ni HaN - 6d CH NH, Preparation of (1R,38,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-blindol-9-y)acetyl)-N- (6-bromo-3-methylpyridin-2-yl)-3-methyl-2-azabicyclo|3.1.0]hexane-3-carboxamide (10b) Compound 10b was prepared according to the procedure reported in step-3 of scheme-1. from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido(4,5-b]indol-9-vl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (2 mL) using HCl salt of (1R,38.5R)-N~(6-bromo-3- methylpyridin-2-y1)-5-methyl-2-azabicyclo[3.1.0}hexane-3-carboxamide (10a) [(46.7 mg, 0.14 mmol): prepared according to the procedure reported by Wiles, Jason A. et al., PCT Int. Appl. (2018), WO 2018160889 A1 20180907; incorporated by reference], HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38.5R)-2-(2~(4-amino-6-methyl-9H-pyrimido[4,3-bindol-9~v]acetyl)-N~(6- bromo-3-methylpyridin-2-y1)-5-methyl-2-azabicyclo[3. 1 0Jhexane-3-carboxamide (10b) (49 mg, 67% vield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-ds) § 10.29 (s, 1H, D:0 exchangeable), 8.72 — 8.51 (m, 3H, 2H D>0 exchangeable), 8.37 (s, 1H). 7.71 ~ 7.53 (m, 2H), 745 (d, J=79 Hz, 1H), 7.38 (d.J=8.5 Hz, 1H), 5.67 (d, J= 17.4 Hz, 1H), 538 (d, J = 17.3 Hz, 1H), 4.36 (dd, J = 9.2, 5.2 Hz, 1H), 3.66 (dd, J = 5.6, 2.4 Hz, 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): Analysis calculated for CasH26BrN-02.3H20.1.1SHCI: 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. Scheme 11 CFy NH Ny CoH HNN [NH J No. ¥ Hone™en TN hciomen None Nel do Br cogBu {cos H [RN 2) N! aii Ba HC(OMe)s NH,0Ac Ny Br CO Bu NE i" AcOH HN Cs2C03 CF CF; ah 1Mc CFa CF3 CFy 1a 1b 1c COM a el Np N, 10a TEA Eh ed HN HATU, DIPEA HN Hd fle NH, CFs Preparation of (1R,3S,5R)-2-(2~(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-bindol-9- yhacety1)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0lhexane-3- carboxamide (11) Step-1: Preparation of 2-amino-3-(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). Cul (0.199 g. 1.044 mmol), and K2COs (2.89 g, 20.89 mmol) were suspended in a 1:1 mixture of DMSO (20 mL) and H20 (20 mL) and stirred at 60 °C for 16 h under an argon atmosphere. The reaction mixture was diluted with saturated NHCl (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with HzO (30 mL x 4), brine (30 mL), dried, filtered and concentrated in vacuums, The residue obtained was purified by flash column chromatography [SiOz gel (40 g), eluting with EtOAc in hexane from 0-30%] to provide 2-amino-3-(trifluoromethyl)- 1H-indole-3~carbonitrile (11b) (1.24 g. 53 % yield) as an orange solid: "HNMR (300 MHz, DMSO-do) § 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). °F NMR (282 MHz, DMSO-d) 6-58.93; MS (ES+): 226 (M+1); (ES-): 224 (M-1). Step-2: Preparation of 6-(trifluoromethyl)-9H-pyrimido[4.5-b]indol-4-amine (11c) Compound 11¢ was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-3-(triftuoromethyl)- 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 NHiOAc (2.122 g, 27.5 mmol). This gave after workup and purification [SiOz gel (24 g), eluting with MeOH in DCM from 0-5%] 6-(triflaoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (11c) (1.13 g, 4.48 mmol) as a pale vellow solid; ‘H NMR (300 MHz, DMSO-d) § 12.25 (s. 1H), 8.78 (s. 1H), 8.31 (5. 1H), 7.66 (dd, J = 8.4. 1.7 Hz. IH), 7.60 (d. J = 8.5 Hz, 1H). 7.46 (s, 2H). F NMR (282 MHz, DMSO-ds) & -58.13; MS (ES+): 253 (M+1): (ES-): 251 (M-1). Step-3: Preparation of ferr-batyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido(4,5-bjindol-9- vl)acetate (11d) Compound 11d was prepared according to the procedure reported in step-1 of scheme-1, from 6-(trifluoromethyl)-9H-pyrimido[4.5-blindol-4-amine (1c) (0.75 g, 2.97 mmol) in DMEF (20 mL) using tert-butyl 2-bromoacetate (0.580 g, 2.97 mmol), Cs2COs (1.163 g, 3.57 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] rerr-butyl 2-(4- amino-6-(trifluoromethyl)-9H-pyrimido[4.5-blindol-9-ylacetate (11d) (0.89 g, 82% yield) as a pale orange solid; 'H NMR (300 MHz, DMSO-ds) 5 8.83 (s, 1H), 8.36 (s. 1H), 7.84 - 7.70 (m, 2H), 7.60 (s. 2H), 5.21 (s. 2H), 1.41 (5, 9H). Step-4: Preparation of 2~(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-blindol-9-yl)acetic acid (11) Compound 11e was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-anmino-6-(trifluoromethyl)~-9H-pyrimido[4,3-blindol-9-vDacetate (11d) (0.89 2, 2.429 mmol) using TFA (4.43 g, 38.9 mmol) in DCM (7 mL) and stirring at RT for 16 h. This gave after workup 2~(4-amino-6-(trifluoromethy1)-9H-pyrimido(4,5-bindol-9-ylacetic acid (L1e) (1.26 g) TFA salt as an orange solid: 'H NMR (300 MHz, DMSO-d) 5 8.96 (s, 1H), 8.57 (s, 1H), 8.43 (5, 2H), 7.96 (d, JT = 8.6 Hz, 1H), 7.84 (dd, J = 8.6, 1.7 Hz. 1H), 5.31 (s. 2H). °F NMR (282 MHz, DMSO-de) -58.51, 74.65; MS (ES+): 311 (M+1); (ES-): 309 (M-1). Step-3: Preparation of (1R.38,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- blindol-9-y1)acetyl)-N-(6-bromo-3-methylpyridin-2-v1)-5-methyl-2-azabicyclo[3.1.0]hexane- 3-carboxamide (11f) Compound 11f was prepared according to the procedure reported in step-3 of scheme-1, from 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 HCI salt of (1R,38,5R)-N-(6-bromo-3- methylpyridin-2-y1)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g). eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R.38,5R)-2-(2-(4-amino-6-(trifluoromethy!)-9H-pyrimido[4,5- blindol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0|hexane- 3-carboxamide (11f) (55 mg, 77% vield) HCl salt as a white solid: 'H NMR (300 MHz. DMSO-d) 5 10.29 (s, TH, D20 exchangeable), 8.99 (s, 1H), 8.59 (m, 3H, 2H D20 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 = 173 Hz, 1H), 436 (dd, J = 9.2, 5.2 Hz, 1H), 3.67 (dd, J=54,25 Hz, LH), 2.60 — 2.54 (ma, 1H), 2.09 — 2.02 (m, 1H). 2.00 (s, 3H), 1.34 (5, 3H), 1.06 (t.J= 5.3 Hz, 1H), 0.99 (dd, J = 5.4, 2.4 Hz, IH). ""F NMR (282 MHz, DMSO-ds) & - 58.51; MS (ES+): 602.0 (M-+1), 623.9 (M+Na); (ES-): 600.0 (M-1); Analysis calculated for CasHpBrFaN:02.2.5H:0 IHC: C, 45.66; H, 4.27; C1, 5.18: N, 14.34; Found: C. 45.66; H, 4.02: ClLA20:N, 14.26. Scheme 12 H HN / —COH Ia Ny N, Ce HN 1c HATU, DIPEA > \ 10a Nl N=! 12a hy J Nee 10 Yl ( 12a NH; Preparation of (1R,38,5R)-2-(2-(4-amino-9H-pyrimido[4.5-b]indol-9-ylacetyl)-N-(6-bromo- 3-methylpyridin-2-y1)-5-methyl-2-azabicyclo[3.1.0)hexane-3-carboxamide (12a) Compound 12a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-9H-pyrimido[(4,53-b]indol-9-yl)acetic acid (1c) (50 mg, 0.14 mmol) in DMF (2 mL) using HCl salt of (1R,38.5R)-N-(6-bromo-3-methylpyridin-2-y1)-3-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 ~ 100%] followed by purification using reverse phase column chromatography [C18 column (50 g). eluting with ACN in water (containing 0.1% HCl) from 0-60%] (1R.38,5R)-2-(2-(4-amino-9H-pyrimido[4,3-b]indol-9-yl)acety)-N-(6-bromo-3- methylpyridin-2-y1)-5-methyl-2-azabicyclo[3.1.0}hexane-3-carboxamide (12a) (47 mg, 63 % yield) as a white solid; 'H NMR (300 MHz, DMSO-d) 3 10.31 (s, 1H, D20 exchangeable). 8.77 (s, 2H, D:0 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 (1. 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), 437 (dd, J = 9.2, 5.3 Hz, 1H). 3.68 (dd, J= 5.6, 24 Hz, [H), 2.61 — 2.52 (m, 1H), 2.00 — 2.01 (m, LH). 2.00 (s, 3H), 1.34 5, 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); Analysis calculated for C2sH2BrN+0:.2.5H20.1.1HCL: C, 48.47; H, 4.90; C1, 6.29; N, 15.83: Found: C, 48.70; H, 4.84; Cl, 6.26; N, 15.63. Scheme 13 / —CO:H NN NN oS I HN NCO TN N N= HN 2 ge 1c HATLU, DIPEA i N- H —~ NON 0 0 r . Oy 138 Nes HN a / 3p N, # $ 7 Xy=N Res HN HN: NH 0 N 13a mm Preparation of (8)-1-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-y1)acety])-N-(6-bromopyridin- 2-vl)pyrrolidine-2-carboxamide (13b) Compound 13b was prepared according to the procedure reported in step-3 of scheme-1. from TFA salt of 2-(4-amino-9H-pyrimido[4,5-bjindol-9-yl)acetic acid (1c) (50 mg, 0.14 wmol) in DMF (2 mL) using TFA salt of (S)-N~(6-bromopyridin-2-yl)pyrrolidine-2~ carboxamide (13a) [(53.9 mg, 0.140 romol): Wiles, Jason A. et al., PCT Int. Appl. (2017), ‘WO 2017035353 Al 20170302), HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-60%] (S)-1-(2-(4-amino-9H-pyrimido[4,5- blindol-9-y1)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (13b) (42 mg, 61% yield) HCI salt as a white solid: "TH NMR (300 MHz. DMSO-ds) 5 11.23 and 10.80 (2s, 1H D:0 exchangeable), 8.63 — 8.50 (mn, 3H, 2H D:0 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, 4.3 Hz, 1H), 3.80 (it, J=9.7.53 Hz, 2H), 2.23 ~ 1.76 (m, 4H); MS (ES+): 494.0 (M+1); (ES-): 492.0 (M-1); Analysis calculated for C22H20BiN702.2.75H20.1HCE: C, 45.53: H. 4.60: C1, 6.11: N, 16.89; Found: C, 45.78: H, 4.22: C1. 637: N, 16.65. Scheme 14 FE, COH ~~ F Ne of a, ¥ NN ~~ HH Fe HN '%, — i IY Br SO J Q 0 11e 1 > I \ Nh HN HN = 0 NH o cI 11¢ CF Ns N Sopp —— 2a i ’ HATU. DIPEA NAC \ NH, = CF, Preparation of (28,4R)- 1~(2~(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9~ vhacety])-N-(6-bromo-3-methylpyridin-2-y1)-4-fluoropyrrolidine-2-carboxamide (14a) Compound 14a was prepared according to the procedure reported mn step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-blindol-9-ylacetic acid (11e) (50 mg, 0.118 mmol) in DMF (2 mL) using HCl salt of (28,4R)-N-(6-bromo-3- methylpyridin-2-y1)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g). eluting with ACN in water (containing 0.1% HCI) from 0-60%] (28.4R)-1-(2-(4-amino-6-(trifluoromethy])-9H-pyrimido[4,5-b]indol-9-yDacetyl)-N- (6-bromo-3-methylpyridin-2-v1)-4-fluoropyrrolidine-2-carboxamide (14a) (40mg, 57% yield) HCl salt as a white solid; 'H NMR (300 MHz. DMSO-d) § (a mixture of two rotamers)10.89 and 10.46 (2s, 1H. D20 exchangeable), 8.96 (s. 1H), 8.55 (s, LH), 8.44 (5, 2H. D20 exchangeable), 7.90 7.69 (m, 2H), 7.59 (d. J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.76 - 533 (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); YF NMR (282 MHz, DMSOQ-db) § -58.47. ~ 58.75,-176.20: MS (ES+): 594.0 (M+1); (ES-): 592.0 (M-1); Analysis calculated for C24H20BrFaN-02.1.75H20.1HCL: C, 43.52: H, 3.73; C1, 5.35; N, 14.80; Found: C, 43.54; H, 3.24; Cl, 4.96: N. 14.54. Scheme 15 NCH N—N N= HaN 11e CF3 HATU, DIPEA © 2d YY 45s 4g NT y J N S—8r - NH, Preparation of (1R,38,5R)-2-(2~(4-amino-6-(trifluoromethyl)-9H-pyrinmdo[4,5-bindol-9~ yhacety])-N-(6-bromo-3-methylpyridin-2-y1)-2-azabicyclo[ 3. 1.0Thexane-3-carboxamide (1523) Compound 15a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-bJindol-9-yl)acetic acid (11e) (50 mg, 0.118 mmol) in DMF (2 mL) using HCI salt of (1R,38.5R)-N~(6-bromo-3- methylpyridin-2-y1)-2-azabicyelo[3.1 OJhexane-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 RT for 16 h. This gave after workap and purification by flash column chromatography [silica gel (24 g). eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%)] (IR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,3-b]indol- 9-ylacetyl)-N-(6-bromo-3-methylpyridin-2-v1)-2-azabicyclo[3.1.0)hexane-3-carboxamide (15a) (47 mg, 68% vield) HCI salt as a white solid; H NMR (300 MHz, DMSO-d) § 10.27 (s, 1H, D.O exchangeable), 9.00 (s, 1H), 8.70 — 8.54 (m, 3H, 2H D.O 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. 2.3 Hz. 1H), 2462.18 (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): F NMR (282 MHz, DMSO-ds) § -58.52: MS (ES+): 587.9 (M+1): (ES-): 586.0 (M-1); Analysis calculated for C2sHa BrFsN+02.HCL1.75H:0: C, 45.75; H, 3.92; C1, 5.40; N, 14.94: Found: C, 45.96; H, 3.65; Cl, 4.95: N, 14.71. Scheme 16 HC(OMe}s. NH{OAC _HC{OMe}s NHsQAc Ce,C0; AcOH ot ) NH S- I SLA N o. oN H PZ 5—NH x er NN HNN Ne ° ¢ Ter ( HO(OMe)y NHAC} ———— = ~CFs Tod HN cry CaCO NN NC ? NH. el BN B - - NH 16a on 16b 16c 4a TFA id 1.3 HATU, DIPEA HaN Yon N COM SN N= HN “CF, 16d 188 Preparation of (1R,38,5R)-2-(2~(4-amino-7-(trifluoromethyl)-9H-pyrinmdo[4,5-bindol-9~ yhacety!)-N-(6-bromopyridin-2-v1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (16¢) Step-1: Preparation of 7-(trifluoromethy!)-9H-pyrimido[4,3-b]indol-4~amine (16b) Compound 16b was prepared according to the procedure reported in step-1 of scheme-6, 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 NH:OAc (3.34 g, 43.3 mmol). This gave after workup 7-(triflusromethyl)-9H- pyrimido[4,5-b]indol-4-amine (16b) (2.08 g, 77% yield) acetic acid salt as a pale yellow solid: 'H NMR (300 MHz, DMSO-d) 3 12.20 (s, 1H), 11.98 (s, 1H), 8.52 (d. / =8.3 Hz. TH), 8.31 (s. IH), 7.76 — 7.65 (m, 1H), 7.58 — 7.47 (m, 1H). 7.43 (s, 2H), 1.91 (5, 3H); MS (ES+): 253.10 (M+1). Step-2: Preparation of tert-butyl 2-(4-amino-7-(trifluororethyl)-9H-pyrimido[4,5-blindol-9- yl)acetate (16¢) Compound 16¢ was prepared according to the procedure reported in step-1 of scheme-1, from 7-(trifluoromethyl)-9H-pyrimido[4,5-bindol-4-amine (16b) (2 g, 7.93 mmol) in DMF (50 mL) using Cs2C03 (3.10 g, 9.52 mmol). This gave after workup and parification by flash column chromatography [silica gel (40 g), eluting with EtOAc in Hexane from 0-100%] rerz- butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4.5-b]indol-9-yl)acetate (16¢) (0.93 g, 32% vield) as a pale vellow solid: 'H NMR (300 MHz, DMSO-ds) 8 8.57 (d, J = 8.2 Hz, 1H), 8.36 (s, 1H), 8.06 (d, / = 1.5 Hz, 1H), 7.65 ~ 7.51 (m, 3H), 5.25 (s, 2H), 1.40 (s, 9H): MS (ES+): 367.10 (M+1). Step-3: Preparation of 2-(4-amino-7~(trifluoromethyl)-9H-pyrimido(4.5-blindol-9-vljacetic acid (16d) Compound 16d was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-y acetate (16¢) (0.92 g, 2.51 mmol) using TFA (14.41 mL, 37.7 mmol; 20% TFA in DCM) and stirring at RT for 16 h. This gave after workup 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-blindol-9- vhacetic acid (16d) (0.9 g, 84% yield) TFA salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 5 8.64 (d,J = 8.3 Hz, 1H). 8.47 (s, 1H). 8.21 (s, 1H), 8.02 (s, 2H), 7.67 (d,. / = 8.3 Hz, 1H), 5.31 (s, 2H); MS (ES+): 311.00 (M+1). Step-4: Preparation of (1R.38,5R)-2-(2-(4-amino-7-(trifluoromethyv1)-9H-pyvrimido[4,5- blindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0}hexane-3-carboxamide (16e) Compound 16e was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4.5-bjindol-9-yl)acetic acid (16d) (75 rag. 0.177 munol) in DMF (2 mul.) using HCI salt of (1R,38,5R)-N-(6-bromopyridin-2-yf)- 2-azabicyelo(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 RT for £6 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%) followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%)] (1R,38,5R)-2-(2~(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,3-blindol-9~ vhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0Thexane-3-carboxamide (16€) (62 mg, 61% yield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-ds) & 10.76 (s, 1H, D20 exchangeable), 8.73 (d, J = 8.1 Hz. 3H. 2H D0 exchangeable), 8.65 (s. 1H), 8.17 (s, 1H). 8.00(d, / J=8.1 Hz, IH). 7.77-7.61 (m, 2H). 7.30 (d.J=7.7Hz, 1H), 5.87 (d,J= 174 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,. / =8.7, 5.5 Hz, 1H). 0.77 (td, J = 5.2.2.3 Hz, [H), °F NMR (282 MHz, DMSO-d) § -39.33; MS (ES+): 574.0 (M+1); (ES-): 572.0 (M-1); Analysis calculated for C24Hi19BrFsN-02.1.5H0.1HCI: C, 45.19; H, 3.63; CL, 5.56: N, 15.37; Found: C, 45.06; H, 3.61; CI, 5.38: N, 15.36. Scheme 17 o. oN O20 x TT Nee x Le AcOH oT ~~ No Cs,C0s Na N==d Pdy{dna)s XPhos la Ne Yu HN Sy €5,C03 o oA on Xe TY NH F ) NH & ACT Ne Ha i N, HG(OMe),, NH.0AC by > 1 ¢ i TT eon C00; = == TY AcOH HN Br 2 " Nia 17a 17h 17¢ H H 6 J yer LT ~~ HATU, DIPFEA ) po NH, TIS NaH .X J _ © {0 NH; 17d 178 2 a n= oy " a N= —_— i EA on ¢ TON HATU, DIP Nex J = NH, 178 Preparation of ferr-butyl (4-amino-9-(2-((1R,3S.5R)-3~((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4.5-blindol-7-yl)carbamate (17f) Step-1: Preparation of 7-bromo~9H~pyrimido[4,5-b]indol-4-amine (17b) Compound 17b was prepared according to the procedure reported in step-1 of scheme-6. from 2-amino-6-bromo-~1H-indole~3-carbonitrile (17a) (2 g, 8.47 mmol: CAS # [427028-36- 1) using trimethyl orthoformate (18.34 mL, 169 mmol), AcOH (2.423 mL, 42.4 mmol) and NHsOAc (3.27 g, 42.4 mmol). This gave after workup 7-bromo-9H-pyrimido[4.3-blindol-4- amine (17b) (2.29 g. 84% yield) as a pale vellow solid: "TH NMR (300 MHz, DMSO-ds) 11.97 (5, 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). Step-2: Preparation of tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-bJindol-9-yl)acetate (17¢) Compound 17¢ was prepared according to the procedure reported in step-2 of scheme-16, from 7-bromo-9H-pyrimido[4.5-bJindol-4-amine (17h) (2.2 g. 6.81 mmol) in DMF (75 mL) using tert-butyl 2-bromoacetate (1.056 mL, 7.15 mmol), Cs2CO3 (4.88 g. 14.98 mmol) and stirring at RT for 15 h. Additional fert-butyl 2-bromoacetate (1.006 mL, 6.81 mmol) and KaCO: (0.941 g. 6.81 mmol) were needed for completion of reaction. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in hexane from 0-100%)] rert-butyl 2-(4-amino-7-bromo-9H-pvrimido[4,5-b]indol-9-yl)acetate (17¢) (1.25 g. 49% vield) as a pale vellow solid: '"H NMR (300 MHz, DMSO-ds) 5 8.31 (1, J =42 Hz, 2H), 791 (d.J= 1.7 Hz, 1H), 7.46 - 7.36 (mn, 3H), 5.14 (s. 2H), 1.41 (s, 9H). 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 degassed solution of tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9- vhacetate (17¢) (200 mg. 0.530 mmol) in toluene (10 mL) was added XPhos (50.5 mg. 0.106 ramol). t-butyl carbamate (93 mg, 0.795 mmol), Pda(dba)s (48.5 mg. 0.053 nmol) and cesium carbonate (173 mg, 0.530 mmol), filled with nitrogen and heated at 90 “°C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), brine (50 ml), dried and concentrated in vacuum. The obtained residue was purified by flash colurnn chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-50%] to give tert-butyl 2-(4-amino-7-(tert-butoxycarbonylamino)-9H-pyrimido[4.3-b)indol-9- vlhacetate (17d) (92mg. 42% vield) as a vellow solid: MS (ES+): 414.20 (M+1). Step-4: Preparation of 2-(4-amino-7-((7ert-butoxvearbonyl)amino)-9H-pyrimido[4.5-b]indol- 9-ylacetic acid (17e) To a stirred solution of ferr-butyl 2-(4-amino-7-(rert-butoxycarbonylamino)-9H- pyrimido[4.5-b]indol-9-yl)acetate (17d) (90 mg, 0.218 mmol) in THE / MeOH (4 mL: ratio 1:1) was added lithium hydroxide hydrate (1.088 mL, 1.088 momol) and stirred at RT for 15 h. The reaction mixture was concentrated in vacuo, diluted with water (1 mL), acidified to pH 5-7 using 1M HCl and concentrated to dryness to afford 2-(4-amino-7-((ter- butoxycarbonyl)amino)-9H-pyrimido[4,5-blindol-9-v])acetic acid (17e) (67 mg, 86 % vield): 'H NMR (300 MHz, DMSO-d) 3 9.71 (s, 1H), 8.63 ~ 8.45 (m, 4H), 8.38 (d..J = 8.6 Hz. IH), 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). Step-3: Preparation of fert-butyl (4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2- yhcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-y1)-2-oxocthyl)-9H-pyrimido[4,5-bindol-7- vl)carbamate (17f) Compound 17f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-((te#t-butoxycarbonyl)amino)-9H-pyrimido[4,5-blindol-9-yacetic acid (17e) (60mg, 0.168 mmol) in DMF (1 mL) using TFA salt of (1R,38,5R)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), cluting with DMA-80 in DCM from 0 - 100%] tert-butyl 4-amino-9-(2-((1R.38,5R)-3-(6~ bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3. 1. OThexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5- blindol-7-ylcarbamate (17f) (48mg, 46% vield). 10 mg of this compound was purified by reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC) from 0-100%] to yield terr-butyl 4-amino-9~(2-((1R.3S,5R)-3-(6~ bromopyridin-2-ylearbarmoyl)-2-azabicyclo[3.1.0Thexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5- blindol-7-vlcarbamate (17f) (6 mg) HCI salt as a white solid; 'H NMR (300 MHz, MeOD-ds) 58.46 (s. TH), 8.19 (d.J=8.7 Hz, 1H), 8.05 (d,.J= 8.2 Hz. IH), 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, TH). MS (ES+): 621.2 (M+1): (ES-): 619.1 (M- 1. Scheme 18 YW) TEA, ay \ A & Neg NM a NH. NH, 18a 17f Preparation of (1R,38,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,7-diamino-9H-pyrimido[4,5- blindol-9-yacetyl)-2-azabicyclo[3. 1.0Jhexane-3-carboxamide (18a) Compound 18a was prepared according to the procedure reported in step-3 of scheme-1, from tert-butyl (4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0Jhexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-bJindol-7-vl)carbamate (17f) (35mg, 0.056 mmol) in DCM (1 mL) using 2.2. 2-trifluoroacetic acid (0.087 mL, 1.126 mmol) and stirring at RT for 16 h. This gave after workup and purification twice by reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-N-(6-bromopyridin-2-y1)-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) HCI salt as a white solid. 'H NMR (300 MHz. DMSO-ds) 5 10.74 (s. 1H, D:0 exchangeable), 8.45 (s, 1H), 8.29 (s, 2H, D:z0 exchangeable), 8.18 (d, J = 8.6 Hz, 1H), 7.95 (d, = 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 (mn, 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). Scheme 19 ~COH £ £ H HN NCO a= ’ N = HN 1c ie HATU, QO H Ye py UH NSE H [ I DIPEA HoN N- ) rr Ny a — N, i 5d 19a Preparation of (28,4R)-1-(2-(4-amino-9H-pyrimido[4.5-b]indol-9-yl)acetyl)-N-(6~ bromopyridin-2-y1)-4-fluoropyrrolidine-2-carboxamide (19a) Compound 19a was prepared according to the procedure reported m step-3 of scheme-1, from TFA salt of 2-(4-amino-9H-pyrimido[4.5-bJindol-9-yDacetic acid (1c) (150 mg. 0.421 mmol) in DMF (§ mL) using TFA salt of (28,4R)-N-(6-bromopyridin-2-yl)-4-flaoropyrrolidine-2- carboxamide (5d) (169 mg, 0.421 mmol). HATU (192 mg, 0.505 mmol), DIPEA (272 mg. 2.105 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%) followed by purification using reverse phase column chromatography (C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%)] (2S.4R)-1-(2-(4~amino-9H- pyrimido[4,5-bJindol-9-yl)acety])-N-(6-bromopyridin-2-y1)-4-fluoropyrrolidine-2- carboxamide (19a) (62 mg, 61% yield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-ds) & (a mixture of two rotamers) 11.37 (s) and 10.98 (s) (2s, 1H, D20 exchangeable), 8.80 — 8.56 (ma. 3H. 2H D20 exchangeable), 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=7.7Hz, 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); *F NMR (282 MHz, DMSQ-ds) § -175.73, -176.14: MS (ES+): 512.0 (M+1), (ES-): 510.0 (M-1): Analysis calculated for C2zHisBrFN-02. HCI.2.5H:0: 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. Scheme 20 EF, F, Ta ) po E fH Z N at F H 0 7a Ci I NM SN F A 0 0 RN cl HATU. DIPEA Ng -N, Lo Ney NN, Eo NH, = 1c 20a Preparation of (28,4R)-1-(2-(4-arino-9H-pyrimido[4,5-blindol-9-y)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (20a) Compound 20a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-9H-pyrimido(4,5-b]indol-9-v)acetic acid (1c) (200 mg, 0.561 mmol) in DMF (10 mL) using TFA salt of (28,4R)-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 RT for 16 b. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%) followed by purification using reverse-phase column chromatography [C-18 column, 100 g, eluting with 0.1% aqueous HCl in H20 and MeCN from 0-100%] (28,4R)-1-(2-(4-amino-9H- pyrimido[4,5-blindol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide (20a) (121 mg. 43% yield) HCl salt as a white solid; 'H NMR (300 MHz. DMSO-ds) (a mixture of two rotamers) § 9.15 (t,.J= 5.8 Hz) and 8.79 — 8.64 (m, 3H, D20 exchangeable), 8.61 (d,. / = 3.0 Hz. 1H), 8.59 - 8.50 (rm, 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); °F NMR (282 MHz, DMSO-d) § 121.24, -121.76, -176.25. ~176.47; MS (ES+): 499 / 501 (M+1). Scheme 21 fy £ r 1 N NN Br N ( 0 1 @ EA 5d HATU, HN 1 N Ne f DIPEA HN Me INT a NN 0 Ne HN 6d Me 21a Preparation of (28,4R)-1-(2-(4-amino-6-methyl-9H-pyrimido[4,5-blindol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (21a) Compound 21a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2~(4-amino-6-methyl-9H-pyrimido[4,5-blindol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using TFA salt of (2S.4R)-N-(6-bromopyridin-2-v1)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with MeOH in DCM from 0-3%] followed by purification using reverse phase column chromatography [C18 coluron (100 g). eluting with ACN in water (containing 0.1% HCl) from 0-100%] (28.4R)-1- (2-(4-amino-6-methyl-9H-pyrimido[4,5-blindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide (21a) (35 mg, 49% yield) HCI salt as a white solid: ‘H NMR (300 MHz, DMSO-d) & (a mixture of rotamers) 11.35 (s) and 10.97 (s, 1H, D20 exchangeable), 8.76 ~ 8.52 (m, 3H, 2H D>0 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, [H), 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); "°F NMR (282 MHz, DMSO-ds) 5 - 175.73, -176.15; MS (ES+): 526.0 (M+1), (ES-): 524.0 (M-1); Analysis calculated for CosH21BrfN7Q2.1.1HCL2 25H:0: C, 45.51: H. 4.42; Cl, 6.42; N, 16.15; Found: C. 45.21; H, 4.47, Cl, 640; N, 15.88. Scheme 22 ” | nN )—COjBu N )COH _~ = NN 8° >co,'Bu a Tr \ TFA Cs;CO5 HoN aw / HN NK 7 LI NH, XC A J Ne ) Me Me Me 6b 22b 4a 2 H NB N \ Va {I~ 3 0 N = 0 0 WNL mS ex Ao Oo 4a ON N HATU. DIPEA rR 0 ves Ao N N. ¢ \ Ne . Me Me. L 0 0 0 % vo Me NH, Whe NH, 22¢ (-}-isomer 22d (+)-isomer Preparation of (1R,38,5R)-2-((-)-2-(4-amino-6-methyl-9H-pyrimido[4.5-bjindol-9- yhpropanoyh)-N-(6-bromopyridin-2~yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22¢) and (IR.38,5R)-2~((+)-2-(4-amino-6-muethyl-9H-pyrimido[4.5-blindol-9-y)propanoyl)-N-(6- bromopyridin-2-v1)-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- vl)propanoate (22a) Compound 22a was prepared according to the procedure reported in step-1 of scheme-1, from 6-methyl-9H-pyrimido(4,5-blindol-4-amine (6b) (200 mg, 1.009 mmol) in DMF (10 mL) using (R)-ferr-butyl 2-bromopropanoate (253 mg, 1.211 mmol; CAS # 54631-38-8), Cs2CO3 (657 mg, 2.018 ramol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-3%] a mixture of two enantiomers of fert-butyl 2-(4-amino-6-methyl-9H-pyrimido(4,5-b]indol-9- yl)propanoate (22a) (250 mg. 76% vield) as a pale vellow solid: 'H NMR (300 MHz, DMSO- ds) 38.26 (d, T= 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). Step-2: Preparation of 2-(4-amino-6-methyl-9H-pyrimido[4,5-bJindol-9-y1)propanoic acid (22b) Compound 22b was prepared according to the procedure reported in step-2 of scheme-1, from rert-butyl 2-(4-amino-6-methyl-9H-py rimido[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 RT for 16h. This gave after workup a mixture of two enantiomers of 2-(4-amino-6-methyl-9H- pyrimido[4,5-blindol-9-yl)propanoic acid (22b) (304 mg) TFA salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 5 8.55 (5. TH), 8.49 — 8.36 (m, 2H), 8.36 (5, 1H), 7.62 (d. J = 8.5 Hz, 1H), 737 (dd. J = 8.6, 1.6 Hz, 1H), 5.86 (q, J= 7.1 Hz, 1H), 1.75 (d,J = 7.2 Hz, 3H); °F NMR (282 MHz, DMSO-d) 8 -74.15; MS (ES+): 271 (M+1), (ES): 269 (M-1). Step-3: Preparation of (1R,38,5R)-2~((-)-2~(4-amino-6-methyl-9H-pyrimido[4,5-blindol-9- yhpropanoyh)-N-(6-bromopyridin-2~yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22¢) and (IR.38,5R)-2~((+)-2-(4-amino-6-methyl-9H-pyrimido[4.5-blindol-9-y)propanoyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo|3.1.0]hexane-3-carboxamide (22d) Compounds 22¢ and 22d were prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-y1)propanoic acid (22b) (50 mg. 0.130 mmol) in DMF (5 mL) using HCI salt of (1R.3S,5R)-N~(6- bromopyridin-2~-y])-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.5 mg. 0.130 mmol), HATU (59.4 mg, 0.156 mmol). DTPEA (84 mg, 0.651 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%]. 1. (1R,38.5R)-2~((=)-2-(4-amino~6~-methyl-9H-pyrimido[4.5-blindol-2-vl)propanoyl)-N~ (6-bromopyridin-2-y1)-2-azabicyelo[3.1.0]hexane-3-carboxamide (22¢) (17 mgs. 25%) HCI salt as a white solid; !H NMR (300 MHz, DMSO-ds) 6 10.80 (s, 1H, D:0 exchangeable), 8.64 (s, 1H). 8.62 - 8.50 (m. 2H, D»0 exchangeable), 8.40 (s, 1H), 8.08(d, J=81Hz 1H), 7.76 (1, J=79Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.37 (dd, J =79, 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, 30 mins run time (Temp 40 °C). Ry= 10.54 (peak-1 (22¢), 98.0742 %); Re = 19.473 (peak-2; (22d) 1.388%) 97.4084% ee; Optical rotation [ap =-224 (c= 0.1, MeOH) (1R,38.5R)-2~((+)-2-(4-amino-6-methyl-9H-pyrimido[4.5-b]indol-9-y])propanoyl)-N- (6-bromopyridin-2-vl)-2-azabicyclof3.1.0]hexane-3-carboxamide (22d) (22 mgs. 32%) HCl salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 3 10.64 (s, 1H, D20 exchangeable), 8.62 (s, 1H), 8.59 - 8.46 (m. 2H, D20 exchangeable), 8.36 (s, 1H), 7.92(d, J =8.2 Hz 1H), 7.72 (d. J = 7.9 Hz, 1H). 7.66 (d. T= 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, T= 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 nyu, 30 mins run time (Temp 40 °C); Ri= 10.54 (peak-1 (22¢) 0 %); Ru = 19.427 (peak-2: (22d) 100%) >99.99% ce: Optical rotation [ajo = +92.632 (c = 0.095, MeOH). Scheme 23 { Neon \ NCH 7 H HNN we TY HOE), NHR [ol Cul, K,CO4 NC Me AcOH LL g Sent Gul, K,CO3 ne” Nos ME AcOH CFz 23g NCTNCN oo 23b / —COy8u HN “Me TTR H,N te _N _N_ / —COsu ny Rs Br” co Bu ao TN Tihs HN Me CsC0s HN Me te nN. / —COsBu 7 %—N Ne } HN Me 23¢ 934 any “ H N N Ps Br ae 4a 7) IN. IN, or oO - NCO NY > A 7 y—N Fg 2 Ne Te NN —————————— ¢ A Me HN oo HATU, DIPEA fon Ni NH, 23a Sf of Preparation of (1R.38,5R)-2-(2-(4-amino-7-methy]-9H-pyrimido[4,5-bindol-9-yl)acetyl)-N- (6-bromopvridin-2-yl)-2-azabicvelo[3.1.0thexane-3-carboxamide (23f) Step-1: Preparation of 2-amino-6-methyl-1H-indole-3-carbonitrile (23b) Compound 23b was prepared according to the procedure reported in step-1 of scheme-11, 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), Cul (0.407 g, 2.136 mmot), K2COs (5.91 g. 42.7 mmol) and heating at 60 °C for (6 h under an argon atmosphere. This gave after workup and purification [S102 gel (40 g). eluting with EtOAc in hexane from 0-40%] 2-amino-6-methyl-1H-indole-3-carbonitrile (23b) (2.65 g, 73% vield) as an brown solid; ‘H NMR (300 MHz, DMSO-¢k) § 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 (ESH): 172 (M+1); (ES-): 170 (M-1), Step-2: Preparation of 7-methyl-9H-pyrimido[4,5-bJindol-4-amine (23¢)} Compound 23¢ was prepared according to the procedure reported in step-1 of scheme-6, 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 NHiOA¢ (5.97 g, 77 mmol). This gave after workup and purification [SiOzgel (24 g), eluting with MeOH in DCM from 0-3%)] 7-methyl-9H-pyrimido[4,3-b]indol-4-amine (23c) (1.45 g) as a brown vellow solid; 'H NMR (300 MHz, DMSO-de) 5 11.70 (s. 1H), 8.21 (s. 1H), 8.16 (d. J = 7.9 Hz, 1H), 7.23 (s. 1H), 7.15 - 6.96 (rm, 3H), 2.45 (s, 3H); MS (ES+): 199 (M+1); (ES-): 197 (M-1). Step-3: Preparation of tert-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-y acetate (23d) Compound 23d was prepared according to the procedure reported in step-1 of scheme-1, from 7-methyl-9H-pyrimido[4.5-blindol-4-amine (23c) (1.45 g, 7.31 ramol) in DMF (25 mL) using tert-butyl 2-bromoacetate (1.427 g, 7.31 mmol) Cs2€03 (2.86 g, 8.78 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] rert-butyl 2-(4- amino-7-methyl-9H-pytimido[4.5-b]indol-9-yl)acetate (23d) (0.84 g, 37% vield) as a pale vellow solid: 'H NMR (300 MHz, DMSO-de) 3 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, OH): MS (ES+): 313 (M+1). Step-4: Preparation of 2-(d-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yvl)acetic acid (23e) Compound 23e was prepared according to the procedure reported in step-2 of scheme-1. from tert-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-blindol-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 RT for 16 h. This gave after workup 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) (1.01 ©) TFA salt as a vellow solid; '"H NMR (300 MHz, DMSO-d) 3 8.51 (s, IH), 8.36 (d, / = 8.0 Hz, 1H), 8.24 (s, 210), 7.59 (s, 1H), 7.26 (d, 1H), 5.21 (5, 2H), 2.49 (s, 3H); °F NMR (282 MHz, DMSO-d) § -74.09; MS (ES+): 257 (M+1), (ES-): 255 (M-1). Step-5: Preparation of (1R 38,5R)-2-(2~(4-amino-7-methyl-9H-pyrinmdo[4,5-bindol-9- yhacety!)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (23f) Compound 23f was prepared according to the procedare reported in step-3 of scheme-1, from TFA salt of 2-(4~-amino-7-methyl-9H-pyrimido[4.5-blindol-9-vl)acetic acid (23e) (50 mg, 0.135 mmol) in DMF (5 mL) using HC! salt of (1R 38,5R)-N-(6-bromopyndin-2-yl)-2- azabicyclof3.1.0]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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2~(2-(4-amino-7-methyl-9H-pyrimido[4.5-b]indol-9-yDacetyl)-N-(6- bromopyridin-2~yl)-2~azabicyclo[3.1.0]hexane-3-carboxamide (23f) (44 mg, 63% yield) HCL salt as a white solid; "H NMR (300 MHz, DMSOQ-ds) § 10.76 (s, 1TH, D:0 exchangeable), 8.57 (s, 1H), 8.44 (s, 2H, D20 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), 442 (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); Analysis calculated for C2aH2:BiN702,1.2HCL2 5H20: C, 47.32; H, 4.67; C1. 6.98: N. 16.10; Found: C, 47.10: H. 4.59: Cl, 6.75: N, 15.97 Scheme 24 Br J HN, x] N = WY J H OQ o. 8a oo a” Ho Ne a HATU, DIPEA NaN Ly M NH, © a i Jn Me OH 23e 24a Preparation of (1R,38,5R)-2-(2-(4-amino-~7-methyl-9H-pyrimido[4,5-b]indol-9-y])acetyl)-N- (6~bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (24a) Compound 24a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4~amino-7-methyl-9H-pyrimido[4.5-blindol-9-v1)acetic acid (23e) (50 mg, 0.135 mmol) in DMF (5 mL) using HCI salt of (1R.3S,5R)-N-(6-bromopyridin-2-y1)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (44.9 my, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and punfication by flash column chromatography [sihca gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] (1R,3S.5R)~2-(2+(4-amino~7-methyl-9H-pyrimido[4.5-bindol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0Thexane-3-carboxamide (24a) (36 mg, 50% yield) HCI salt as a white solid: '"H NMR (300 MHz, DMSO-ds) 6 10.77 (s, 1H, DO exchangeable), 8.61 (s, 3H, 2H D20 exchangeable), 8.39 (d, J = 8.1 Hz. 1H), 8.01 (d.J=8.2 Hz. 1H), 7.70 (t,J=8.0 Hz, IH). 7.52 (s, IH), 7.31 (d. J="7.7Hz, 1H), 7.26 (d, / =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), 131 (s, 3H), 1.08 0.97 (m, 1H). 0.97 - 0.89 (m, 1H); MS (ES+) 534.0 (M+1), 532.0 (M-1); Analysis calculated for C2sH24BrN202 HCL 2.25H:20: 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. Scheme 25 7 FE, H HH YS / —COH 7a eo F ACL oC HN | HATU, DIPEA N. N ; = Ny Youd CF NH. 11e 25a Preparation of (28,4R)-1-(2-(4-amino-6-(trifluoromethy!)-9H-pyrimido[4,5-blindol-9- yhacetyt)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (25a) Compound 25a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(trifluoromethy])-9H-pyrimido[4.5-blindol-9-yljacetic acid (11e) (30 mg, 0.118 mmol) in DMF (10 mL) using TFA salt of (28,4R)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (45.8 mg. 0.118 mmol), HATU (33.8 mg. 0.141 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirnng at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%)] (2S.4R)-1-(2~(4-amino-~6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9~ yhacety1)-N-(3-chloro-2-fluorobenzyl)-4-fluoropy rrolidine-2-carboxamide (25a) (28 mg, 42% yield) HCI salt as a white solid; "H NMR (300 MHz, DMSO-d) § (a mixture of two rotarers) 8.98 (d,J= 3.6 Hz. IH), 8.71 — 8.52 (m. 4H. 2H D:0 exchangeable), 7.88 (d.J= 8.6 Hz. IH). 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). 223-191 (m, TH); ¥F NMR (282 MHz. DMSO) 3-58.53, -121.26, -121.72, -176.26. ~ 176.42: MS (ES+): 567.0 (M+1), (ES-): 565.0 (M-1) Scheme 26 EF 5 F Ly Hp i NB" < ~ aD N \ H 0 Ze HoN FE, 1 a pe i N, Br N / ~COH ~ - SN SY yA o HO sd No N _ y~N © 0 i ul HATU, DIPEA N= = ps HN 11e CPx 28a Preparation of (28,4R)-1-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-blindol-9- yhacetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (26a) Compound 26a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[(4,3-b]indol-9-vl)acetic acid (11e) (50 mg. 0.118 mmol) in DMF (5 mL) using TFA salt of (2S.4R)-N~(6-bromopyridin-2-y1)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (28.4R)-1- (2-(4-amino-6-(trifluoromethyl)-9H-pyrimido(4,5-blindol-9-ylacetyl)-N-(6-bromopyridin-2- vl)-4-fluoropyrrolidine-2-carboxamide (26a) (33 mg. 48% vield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-d) § 10.97 (5. 1H, D20 exchangeable), 8.95 (s, 1H), 8.64 — 8.38 (m, 3H, 2H D:0 exchangeable), 7.98 (d, J = 8.2 Hz, 1H), 7.84 (dd, J = 8.4, 5.0 Hz, 2H), 7.68 (t.. / = 8.0 Hz, 1H), 7.31 (d, / = 7.7 Hz, 1H), 5.71 ~ 5.57 (m. 1H), 5.51 - 5.39 (m, 1H), 4.62 (dd. J=97,75 Hz, 1H), 4.32 (dd, / =22.1, 12.6 Hz, 1H), 4.18 — 4.08 (mn, 1H), 4.01 (dd, J = 12.8,3.0 Hz, 1H), 2.68 ~ 2.33 (m, 1H), 2.30 - 1.97 (m, 1H); 'F NMR (282 MHz, DMSO-de) 8-58.51, -175.70; MS (ES+): 580.0 (M+1), (ES-): $78.0 (M-1); Analysis calculated for C23HisBrFaN-02.HCL.2.5H:0: C, 41.74; H, 3.66; C1, 5.36; N, 14.81; Found: C. 41.66; H. 3.49: C1510: N, 14.74 Scheme 27 AP 4a Ply N H 0 / 4a oH NY WY Yo o N H 0 4a NeN NA HATU, DIPEA Nz NH; NH; 2 n CF CFs 11e 27a Preparation of (1R.3S8,5R)-2-(2-(4-amino-~6-~(trifluoromethyl)-9H-pyrimido[4.5-b)indol-9- yhacety!)-N-(6-bromopyridin-2-v1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (27a) Compound 27a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-blindol-9-ylacetic acid (11e) (50 mg, 0.118 mmol) in DMF (10 mL) using HFICI salt of (1R,38,5R)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1.0Jhexane-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 RT for 16 bh. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] (I1R.38,5R)-2-(2-(4-amino-6-(trifluorornethyl)-9H-pyrimido[4,5-blindol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (27a) (42 mg, 62% yield) HCl salt as a white solid; H NMR (300 MHz, DMSO-ds) 3 10.75 (s, 1H, D20 exchangeable), 8.96 (s, 1H), 8.59 (s. 1H), 8.52 (s. 2H, 1:20 exchangeable), 8.00 (d, / =8.2 Hz, 1H), 7.85 (s. 2H). 7.70 (t, J = 8.0 Hz, 1F). 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 (mn. 1H), 0.81 ~ 0.74 (m. 1H); °F NMR (282 MHz, DMSO-de) § -38.47; MS (ES+): 574.0 (M+1); (ES-): 572.0 (M-1); Analysis calculated for C2sHioBrFsN-0: HCL2H,O: C, 44.56; H, 3.74; Br, 12.35; C1, 5.48: N, 15.16; Found: C, 44.27; H, 3.69; Cl. 5.59: N, 14.75. Scheme 28 H / —COH 8a % H N__N._Br Ny o ZF 8a Tf <5" Ao ° HN HATU, DIPEA 11e J NV N Nd CFy He NH “73 28a Preparation of (1R,38,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-blindol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-5-methyl-2-azabicyclo[3.1.0lhexane-3-carboxamide (28a) Compound 28a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4.5-b]indol-9-yDacetic acid (11e) (50 mg. 0.118 vumol) in DMF (5 mL.) using HCI salt of (1R.38,5R)-N-(6-bromopyridin-2-yt)~ 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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)~2-(2-(4-amino~-6~(trifluororethyl)-9H-pyrimido[4.5-b]indol-9~ vhacetyl)-N-(6-bromopyridin-2-y1)-5-methyl-2-azabicyclo[3.1.0Jhexane-3-carboxamide (28a) (50 mg, 72% yield) HCI salt as a white solid: 'H NMR (300 MHz, DMSO-ds) 5 10.76 (s, 1H, D0 exchangeable), 8.96 (s. 1H), 8.71 - 8.43 (m. 3H. 2H D20 exchangeable), 8.01 (d. J=8.2Hz, LH), 7.91 — 7.80 (m, 2H), 7.69 (t,J = 8.0 Hz, 1H), 7.31 (d, / = 7.7 Hz, IH), 5.76 (d.J=174 Hz, 1H), 541 (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); ‘°F NMR (282 MHz, DMSO-d) -38 53; MS (ES+): 588.0 (M+1). (ES-): 586.0 (M-1); Analysis calculated for C2sH21BrF:N-02.1.1HCL.1.75H:0: C,4549,;H,391; CL 591; N, 14.86; Found: C, 45.32: H. 3.90; C1. 5.87: N. 14.62. Scheme 29 TFA ——rr iy * H N N. rs Br I da 2 “ A J -CO;'Bu py COM NA Ny Br A o & il -N H 0 oy TFA, WBS fd 0 10 WN N | a mY, HN lay HN WN ee a MT nN COM ~ y—N Ne 7 HN = N A 29d 2% NH; 29f CO, 4 H NT A Co A GOH SAH Ng Br A 3S = rN H 0 Ny TFA, No o ov 7 Ae NSAP - N HNN HN N Ee ¢ 7 2 =, HATU, DIPEA rad eh 29d 29¢ NH, Preparation of (1R,38,5R)-2-(2-(4-amino-9H-pyrido[4',3"4,5 |pyrrolo[2,3-d|pyrimidin-9- vhacetyl)-N~(6-bromopyridin-2-y1)-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 portion-wise a solution of malononitrile (4.21 g. 63.7 mmol) in THF (40 mL). The resulting cloudy mixture was stirred at 0 °C for 1 h. followed by slow addition of 4-chloro-~3-nitropyridine (29a) (5.00 g, 31.5 yamol) in THF (10 mL). The roixture was then heated at 60 °C under argon for 3 h. The cooled mixture was quenched with HoO (30 mL) and extracted with EtOAc (50 mL x S). The combined organic extract was washed with H20 (50 mL x 2), brine (50 mL), dried over anhydrous Na:SQs, filtered and concentrated to provide 2-(3-mtropyridin~4~yl)malouonitrile (8.77 g) as an orange-red solid. which was used as such in the next reaction; MS (ES+) 189 (M1), (ES-) 187 (M-1). To 2-(3-nitropyridin-4-yl)malononitrile (4.40 g, 23.39 mmol) suspended in DMF (20 mL) at it was added a solution NaHCO: (9.82 g. 117 mmol) in H2O (20 mL) followed by solid Na2$204 (12.22 g, 70.2 mmol). The resulting mixture was stirred at rt for 16 h and filtered. The filtrate was extracted with EtOAc (50 mL x 4). The combined organic extract was washed with H20 (30 mL x 4) brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (Si02. 40 g, eluting with 0-20% DMA-80 in DCM) to provide 2-amino-1H-pyrrolo[2.3- ¢[pyridine-3-carbonitrile (29b) (0.673 g, 18 % yield) as a beige solid. '"H NMR (300 MHz, DMSO-d) 5 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). Step-2: Preparation of 9H-pyrido|4',3":4,5]pvrrolo[2,3-d|pvrimidin-4-amine (29¢) 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 was added formamidine acetate (2.422 g, 23.27 mmol). The cloudy pale-yellow mixture was heated at 80 °C for £6 h, during which the cloudy mixture tumed to a clear solution, and then a precipitate formed. The resulting cloudy pale-yellow mixture was hot-filtered. The filtered cake was washed thoroughly with boiling EtOH to provide the product 9H-pyrido[4'.3"4.5]pyrrolo[2,3-d]pyrimidin-4-amine (29¢) (0.35 8, 65.0 % yield) as a pale-yellow solid. "H NMR (300 MHz, DMSQ-ds) § 12.15 (s. 1H), 8.78 (s, TH), 8.38 (d, J = 5.3 Hz. 1H), 8.34 (s, 1H), 8.31 (d. T= 5.4 Hz, 1H), 7.49 (5, 21); MS (ES+): 186 (M+1), (ES-): 184 (M-1). 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 according to the procedure reported in step-~1 of scheme-1. from 9H-pyrido[4',3"4,5]pyrrolo[2,3-d]pytimidin-4-amine (29¢) (0.35 g, 1.890 mmol) in DMF (25 mL) using tert-butyl 2-bromoacetate (0.369 g, 1.890 mmol), Cs2COs (1.232 g, 3.78 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g). eluting with MeOH in DCM from 0-7%)] tert-butyl 2-(4~ amino-9H-pyrido[4'.3":4,5]pyrrolo[2,3-d[pyrimidin-9-yDacetate (29d) (0.27 g, 48% yield) as a pale vellow solid; 'H NMR (300 MHz, DMSO-ds) & 8.94 (s, 1H). 8.45 (d. J = 5.3 Hz, 1H), 8.30 (s, 1H), 8.38 — 8.34 (m, 1H), 7.66 (s, 2H), 5.22 (5, 2H), 1.41 (5. 9H); MS (ES+); 300 (M1), (ES-1): 298 (M-1). Step-4: Preparation of 2~(4-amino~-9H-pyrido[4',3"4.5]pyrrolo[2.3-d]pyrimidin-9-yl)acetic acid (29¢) Compound 29e was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2~(4-amino-9H-pyrido[4'.3":4,5]pyrrolo|2,3-d]pyrimidin-9-vl)acetate (29d) (270 rag. 0.902 muuol) in DCM (10 mL) using TEA (1029 mg, 9.02 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-9H-pyrido[4',3"4.5]pyrrolo[2,3-d]pyrimidin-9- yhacetic acid (29¢) (0.53 g) TFA salt as a white solid; 'H NMR (300 MHz, DMSO-ds) § 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); “F NMR (282 MHz, DMSO-d) 5 -74.66.: MS (ES+): 244 (M+1), (ES-): 242 (M-1). Step-5: Preparation of (1R,38,5R)-2-(2-(4-amino-9H-pyrido[4',3".4,5|pyrrolo[2,3- d]pyrimidin-9-vl)acetyl)-N~(6-bromopyridin-2-y1)-2-azabicyclo|3.1.0]hexane-3-carboxamide (29) Compound 29f was prepared according to the procedure reported in step-3 of scheme-1, from 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 HCl salt of (1R,3S.5R)-N-(6-bromopyridin-2-v})- 2-azabicyclo[3.1.0Jhexane-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 RT for 16 h. This gave after workap and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 ~ 3%) followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (IR,38,5R)-2-(2-(4-amino-9H-pyrido[4'.3":4,5]pyrrolo[ 2, 3~d]pyrimidin-9-yacetyl)-N-(6- bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (29f) (57 mg. 80 % yield) HCI salt as a white solid: "H NMR (300 MHz. DMSO-ds) 8 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 (tJ = 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 (m, 1H), 2.40 — 2.29 (mm. 1H), 2.29 — 2.13 (m. 1H), 2.00 - 1.85 (m, 1H). 1.16 — 1.00 (m, 1H), 0.98 — 0.80 (m, 1H); MS (ES+): 507 / 509 (M+1), (ES-): 505 / 507 (M-1). Scheme 30 Me { Duos H - IN, Me HC{OMe)a. NHAC [7 T NCO: (OMe)s. NH r TT Br” ~CO.Bu JT \ Cs2C0; NC N\_. / AcCH Y Ta? 52003 Cul. K,COs HE H HN. , W Ma NC JF NL. A © Br CF; Se RX NTTCOH oy TNS, fi Ty we Neen i M2 HC(OMe)s, NH.OAC N, Me dS Cul, KpCOz Me LL ™ NH 40a 300 30¢ ) po EO TO 0" N H 0 Zz, TFA 1h Br HATU. DIPEA mes \ 7 i Nt ma 4 N Me Ne Ad —_— 7 NH, NHp 1 TFA il i ja aad No Nm — AST ——. N, A ~Y nl A HATU. DIPEA r TF ; % % NH; NH; 20d a0 ap Preparation of (1R,38,5R)-2-(2-(4-amino-8-methy]-9H-pyrimido[4,5-blindol-9-yl)acetyl)-N- (6-bromopyridin-2-y1)-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 according to the procedure reported in step-1 of scheme-11, 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 malononitrile (2.094 g, 31.7 mmol). L-proline (0.608 g, 5.28 mmol), Cul (0.503 g, 2.64 mmol), a solution of K2COs (7.30 g, 52.80 mmol) in water (20 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [S102 gel (40 g), eluting with EtOAc in hexane from 0-40%)] 2- amino-7-methyl-1H-indole-3-carbonitrile (30b) (2.35 g, 52% vield) as a brown solid; 'H NMR (300 MHz, DMSO-ds) § 10.73 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.58 (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). Step-2: Preparation of §-methyl-9H-pyrimido[4,3-bJindol-4-amine (30c¢) Compound 30c was prepared according to the procedure reported in step- 1 of scheme-6, from 2-amino-7-methyl- 1H-indole-3-carbonitrile (30b) (4.28 g, 25 mmol) using trimethyl orthoformate (26.3 g, 250 mmol), AcOH (4.50 g, 75 mmol) and NH:OAc (5.78 g, 75 mmol). 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: 'H NMR (300 MHz, DMSO-ds) 3 11.81 (s, 1H), 8.26 (s, 1H), 8.10 (dd, T=74, 1.8 Hz, IF). 7.21 - 7.02 (m, 45D), 2.54 (5, 3H). MS (ES+): 199 (M1). Step-3: Preparation of tert-butyl 2-(4-amino-8-methyl-9H-pyrimido([4,5-b]indol-9-yDacetate (30d) Compound 30d was prepared according to the procedure reported in step-1 of scheme-1, from 8-methyl-9H-pyrimido[4.5-blindol-4-amine (30c) (3.07 g, 15.49 mmol) in DMF (20 mL) using ters-butyl 2-bromoacetate (3.02 g, 15.49 mmol) Cs2CO3 (6.06 g, 18.59 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] rers-butyl 2-(4- amino-8-methyl-9H-pytimido[4.5-b]indol-9-yl)acetate (30d) (3.52 g, 73% yield) as a pale vellow solid: 'H NMR (300 MHz, DMSO-d) 3 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). Step-4: Preparation of 2-(4~amino-8-methy]-9H-pyrimido[4.5-b]indol-9-vl)acetic acid (30e) Compound 30e was prepared according to the procedure reported in step-2 of scherue-1, from tert-butyl 2-(4-amino-8-methyl-9H-pyrimido[4,5-blindol-9-yl)acetate (30d) (0.12 g, 0.384 mmol) using TFA (438 mg , 3.84 mmol) in DCM (5 mL) and stirring at RT for 16 h. 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; 'H NMR (300 MHz, DMSO-d) § 8.87 — 8.66 (m. 2H). 8.64 (s, 1H), 8.36 (dd, J= 5.8. 3.4 Hz, IH), 7.40 - 7.25 (m, 2H). 5.47 (s, 2H), 2.70 (s, 3H); 198 NMR (282 MHz, DMSO-d) 6-74.60; MS (ES+): 257 (M1), (ES-): 255 (M-1). Step-5: Preparation of (1R,3$,5R)-2-(2-(4~-amino-8-methyl-9H-pyrimido[4.5-b]indol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3. 1.0]hexane-3-carboxande (30f) Compound 30f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-8-methy]-9H-pyrimido[4,5-bJindol-9-yl)acetic acid (30e) (50 mg. 0.135 mmol) in DMF (5 mL) using HCI 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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with MeOH in DCM from 0 - 4%) followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2-(2~(4-amino-8-methyl-9H-pyrimido[4,5-blindol-9-yl)acety])-N~(6- bromopyridin-2-yl)-2-azabicyclo[3.].0Thexane-3-carboxamide (30f) (44 mg. 63% vield) HCI salt as a white solid; ‘H NMR (300 MHz, DMSO-ds) 3 10.82 (s, 1H, D20 exchangeable), 8.82 — 8.54 (in, 3H, 2H D:0 exchangeable), 8.42 — 8.28 (m. 1H), 8.00 (d, J=8.2 Hz, IH), 7.70 (t. J=8.0Hz, 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); Analysis calculated for C2aH2BrN-02.1.IHCL2.5H.0: 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. Scheme 31 H Ak TFA, da N_ N- N = CID NH, Ney WE HATU. DIPEA NH; SARE a NH, 2d 31g 31f Preparation of (1R,38,5R)-2-(2-(4-amino-9H-pyrido[2',3"4,5 |pyrrolo(2,3-d]pyrimidin-9- vhacetyl)-N~(6-bromopyridin-2-y1)-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 portion-wise to a cold solution of malononitrile (3.29 g, 49.8 mmol) in THF (40 mL) at 0 °C. The resulting cloudy mixture was stirred at 0 °C for 1 h, followed by slow addition of 2-bromo-3-nitropyridine (31a) (3.00 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 H20 (30 mL) and extracted with EtOAc (50 mL x 5). The combined organic extract was washed with H20 (50 mL x 2), brine (50 mL), dried, filtered and concentrated to provide 2-(3-nitropyridin-2-yl)malononitrile (8.62 g) as an orange-red solid, which was used as such in the next reaction; MS (ES+): 189 (M+]), (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 h and filtered hot. The filtered cake was washed thoroughly with boiling EtOH. The filtrate was concentrated to dryness. The concentrate was suspended in H20 (50 mL), neutralized with 3 M aqueous NaOH until pH 7, and then extracted with EtOAc (50 mL x 3). The combined extract was washed with HO (30 mL x 2), brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash colurun chromatography (SiOz, 40 g. eluting with 0-20% DMA-80 in DCM) to provide 2-amino-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) (320 mg, 9 % yield) as beige solid: lH NMR (300 MHz, DMSQ-gs) 6 10.82 (s, 1H), 8.04 (dd. J = 5.0, 1.4 Hz, 1H), 7.36 (dd. J = 78, 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). Step-2: Preparation of 9H-pyrido[2',3":4.5]pyrrolo|2,3-d]pyrimidin-4-amine (31¢) Compound 31c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) (0.31 g, 1.960 mmol) asing trimethyl orthoformate (4.16 g, 39.2 mmol), AcOH (0.589 g, 9.80 mmol) and NH«OAc (0.755 g, 9.80 mol). This gave after workup and purification [silica gel (12 g), cluting with DMA-80 in DCM from 0-30%)] 9H-pyrido[2',3"4,5]pyrrolo[2.3-d]pyrimidin-4-amine (31c) (100 mg, 28% vield) as a pale-yellow solid; *H NMR (300 MHz, DMSO-ds) 8 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). Step-3: Preparation of tert-butyl 2-(4-amino-9H-pyndo[2',3":4.5]pyrrolo[ 2.3-d]pyrimidin-9- vl)acetate (31d) Compound 31d was prepared according to the procedure reported in step-2 of scheme-16. 9H-pyrido[2',3"4.,5]pyrrolo[2,3-d]pyrimidin-4-amine (31¢) (80 mg, 0.432 mmol) in DMF (2.5 mL) using tert-butyl 2-bromoacetate (0.077 mL, 0.518 mmol), Cs2C0x (282 mg, 0.864 mmol) and stirring at RT for 1.5 h under nitrogen atmosphere and quenching by adding water. The solid separated was filtered and dried to give tert-butyl 2~(4-amino-9H- pytido[2'.3"4.5]pyrrolo[2,3-d]pyrimidin-9-y])acetate (31d) (109 mg, 84 % vield) as a pale vellow solid; H NMR (300 MHz, DMSQ-ds) 6 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 (5, 2H). 1.40 (5, 9H); MS (ES+): 300.1 (M+1). Step-4: Preparation of 2-(4-amino-9H-pyrido(2',3"4,3|pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (31e) Compound 31e was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-9H-pyrido|2'.3":4,5]pyrrolo| 2,3~d]pyrimidin-9-vl)acetate (31d) (80 mg, 0.267 mmol) using 20% TFA in DCM (1534 pL, 4.01 mmol) and stirnng at RT for 16 h. This gave after workup 2-(4-amino-9H-pyrido[2',3":4.5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (31e) (64 mg, 98% vield) TFA salt as a yellow solid; 'H NMR (300 MHz, DMSO-ds) 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 Haz, TH), 5.28 (s, 2H): MS (ES+): 244.10 (M+1). Step-5: Preparation of (1R,38,3R)-2~(2-(4-amino-9H-pyrido[2',3"4,5|pyrrolo[2,3- d]pyrimidin-9-ylacetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 31f) Compound 31f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-9H-pyrido[2',3":4,5]pyrrolo[2,3-d]pyrimidin-9-y1)acetic acid (31e) (60 mg. 0.247 mmol) in DMF (2 ul) using 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. {.233 mmol) and stirring at RT for | h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%) followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%) (IR 38,5R)-2-(2-(4-arino-9H-pyrido[2'.3"4, 5]pyrrolo[2,3-d]pyrimidin-9-yhacetyl)~ N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 OJhexane-3-carboxamide (31f) (79 mg, 63% yield) HCl salt as a white solid; 'H NMR (300 MHz, DMSO-d) § 10.77 (s, IH, D:0 exchangeable), 8.97 (s, 1H, D20) exchangeable), 8.75 ~ 8.64 (m, 2H), 8.31 (d, J = 8.4 Hz. 1H), 8.00 (d, J = $2 Hz, 1H), 7.75 7.61 (m, 2H), 7.31 (d,.J= 7.7 Hz, IH). 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, IF). 2.40 ~ 2.13 (m, 2H), 1.99 ~ 1.82 (m. 1H), 1.07 (dt, J = 8.7. 5.4 Hz, 1H), 0.80 (td, J = 5.2, 2.3 Hz, 1H): MS (ES+): 507.1 (M+1); (ES-): 505.0 (M-1): Analysis calculated for C22Hi9BrNsO:z 1.75H0.1.2HCL: C, 45.35; H, 4.10; CI, 7.30: N, 19.23; Found: C, 45.38: H. 4.02: C1, 7.16; N, 18.95. Scheme 32 oO ‘NH, NET CN SP coH H TNC”) FIOM T Sof Cs,CO; Cul, K,C05 Nt EO I “Se 5 NH; A Se 4 H NH NHN a“ JO EtOH 0 NT Fs ? < Te ¥ F PF Bh F 32a 32b 32¢ Sl, 9 0 CA “0 N. N, Br AN oN A N S N 7 OH YY TY ° “ H y N. 7S Br TU HATU. DIPEA (0 N N. N, TEA, a =N F ON Br f 7 CH Ng BI “ NCS r oN on N i N 1} 7 N N 0 Z 4a oN N TFA 7 N © J = HATU, DIPEA N by PN ¢ O NH, F F HN Ns = NH, r 32d 3% 2 af Preparation of (1R,38,5R)-2-(2-(4-amino-6-fluoro-9H-pyrimido[4,5-blindol-9-yhacety])-N- (6-bromopy ridin-2-v1)-2-azabicyclo[3.1.0thexane-3-carboxamide (32f) Step-1: Preparation of 2-amino-3-flaoro-1H-indole-3-carbonitrile (32b) Compound 32b was prepared according to the procedure reported in step-1 of scheme-11, 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 8, 4.22 mmol), Cul (0.402 g. 2.110 mmol), K2COs (5.83 g. 42.2 vunol) and heating at 60 °C for 15 h under an argon atmosphere. This gave after workup and purification [SiOz gel (80 g), eluting with EtOAc in hexane from 0-50%] 2-amino-3-fluoro-1H-indole-3-carbonitrile (32b) (2.657 g, 72% vield) as a brown solid; MS (ES+): 176.05 (M+1) Step-2: Preparation of 6-fluoro-9H-pyrimido[4,3-b]indol-4-amine (32¢) Compound 32¢ was prepared according to the procedure reported in step-2 of scherne-29, from 2-amino-5-fluoro-1H-indole-3-carbonitrile (32b) (1.2 g, 6.85 mmol) in ethanol (30 mL) using formaridine acetate (5.76 g, 54.8 mmol) and refluxing for 40 h. This gave after workup 6-fluoro-9H-pyrimido[4,5-bJindol-4-amine (32¢) as a brown solid (2.706 g) which was used as such in the next step; MS (ES+): 203.00 (M+1). Step-3: Preparation of tert-butyl 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-vD)acetate (32d) Compound 32d was prepared according to the procedure reported in step-1 of scheme-1, from 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32¢) (346 mg, 1.71 mmol) in DMF (10 mL) using rers-butyl 2-bromoacetate (0.252 mL, 1.71 mmol), cesium carbonate (1.337 g) and stirring at RT for 47 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with hexanes / 10% methanol in ethyl acetate (1:0 to 1:1)] tert-butyl 2-(4-amino-6-fluoro-9H-pyrimido[4.5-bJindol-9-vDacetate (32d) (160 mg, 30% yield) as a light yellow solid; TH NMR (300 MHz, DMSO-de) § 8.32 — 8.22 (mm, 2H). 7.57 (dd, J=8.9, 4.5 Hz, 1H), 7.38 (s, 2M), 7.26 (td. J = 9.2, 2.5 Hz, 1H), 5.12 (5, 2H), 1.39 (s, 9H); F NMR (282 MHz, DMSO-ds) 5 -122.42; MS (ES+): 317.10 (M-+1). Step-4: Preparation of 2-(4-amino-~6-fluoro-9H-pyrimido[4.5-blindol-9-yl)acetic acid (32¢) Compound 32e was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2~(4-amino-6-fluoro-9H-pyrimido[4,5-blindol-9-yl)acetate (32d) (140 mg, 0.443 ramol) in DCM (10 mL) using TFA. The reaction mixture was concentrated to dryness to afford 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-vl)acetic acid (32e) which used as such for the next step; MS (ES+): 261.10 (M+1); (ES-): 259.00 (M-1). Step-5: Preparation of (1R,38,5R)-2+(2-(4-amino-6-fluoro-9H-pyrimido(4,3-b]indol-9- vhacetyl)-N~(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (32f) Compound 32f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-fluoro-9H-pyrimido[4,5-blindol-9-ylacetic acid (32¢) (0.443 mmol, from above step-4) in DMF (15 mL) using HCl salt of (1R.38,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-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 RT for 16 h. This gave after workup and purification by flash coluran chromatography [silica gel (12 g). eluting with MeOH in DCM from 0 - 5%] followed by treating of product obtained with acetonitrile (2 mL) and 50 mM aq. HCI (8 mL) and lyophilization (1R,38,5R)-2-(2-(4- amino-6-fluoro-9H-pyrimido[4.5-b]indol-9-yl)acety])-N-(6-bromopyridin-2-y1)-2- azabicyclo[3.1.0]hexane-3-carboxamide (32f) (53 mg. 23% vield) HCI salt as a light brown solid; "HNMR (300 MHz, DMSO-ds) 10.76 (s, 1H, D20 exchangeable), 8.73 (s, 2H, D:0 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), 732 (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); °F NMR (282 MHz, DMSO-ds) §-119.89; MS (ES+): 524.10 & 526.10 (M+1); MS (ES-): 522.00 & 524.00 (M-1): Analysis calculated for C2:HisBrFN-02.1 2HCL.2.75H20: C, 44.73; H. 4.19: N_ 15.87; Cl, 6.89; Found: C. 44.84: H. 4.13: N. 15.51: CL. 681. Scheme 33 NH; SA a LK & & NH HN. 8 | eoH NSC = Cs,CO; N N A v ~F (Or i NH. (Or NH, NH, 33a 230 33 H li Ho Ne Br © ~C my 2 H N N Ny, Br H | o ZF 4a TFA HATU, DIPEA NH, 23d NH; 33 Preparation of (1R.38,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyelo[3.1.0}hexane-3-carboxamide (33¢) Step-1: Preparation of 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b) Compound 33b was prepared according to the procedure reported in step-2 of scheme-29. from 2-amino-6-fluoro- IH-indole-3-carbonitrile (33a) (1.2 g, 6.85 mmol; CAS # 378236-80- 7) in ethanol (30 mL) using formamidine acetate (5.76 g, 34.8 mmol) and refluxing for 20 h. This gave after workup 7-fluoro-9H-pyrimido[4.5-b]indol-4-anune (33h) as a brown solid (2.62 g) which was used as such in the next step; 'H NMR (300 MHz, DMSO-ds) & 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); **F NMR (282 MHz, DMSO-d) § -116.72; MS (ES+): 203.10 (M+1). Step-2: Preparation of terr-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yacctate (33¢) Compound 33¢ was prepared according to the procedure reported in step-1 of scheme-1. from 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b) (346 mg, 1.71 mmol) in DMF (10 mL) using fert-butyl 2-bromoacetate (0.252 mL, 1.71 mmol), cesium carbonate (1.337 g) and stirring at RT for 46 h. This gave after workup and purification by flash column chromatography [silica gel (40 g). eluting with hexanes / 10% methanol in ethyl acetate (1:0 to 1:1] tert-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-blindol-9-yhacetate (33¢) (151 mg, 28% yield) as a light yellow solid: 1H NMR (300 MHz, DMSO- / 6) & 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): "°F NMR (282 MHz, DMSO-de) 5 116.10; MS (ES+): 317.20 (M+1). Step-3: Preparation of 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-vDacetic acid (33d) Compound 33d was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-bJindol-9-yl)acetate (33¢c) (145 mg, 0.458 mmol) in DCM (10 mL) using TFA. This gave after workup 2-(4-amino-7-fluoro-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (33d) which was used as such in next step; MS (ES+): 261.10 (M+1): (ES-): 259.00 (M-1). Step-4: Preparation of (1R,38,5R)-2+(2-(4-amino-7-fluoro-9H-pyrimido[4,3-bindol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (33e) Compound 33e was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-fluoro-9H-pyrimido[4,5-blindol-9-yDacetic acid (33d) (119 mg. 0.458 mmol) in DMF (15 mL) using HCI salt of (1R,38.5R)-N-(6-bromopyridin-2~y1)-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 RT for 16 h. This gave after workup and purification by reverse phase column chromatography [C18 cotumn (100 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%] followed by purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%], dissolving the product in acetonitrile (3 mL) and 0.1% aq. HCI (20 mL) followed by lyophilization (IR,38.5R)-2~(2~(4-amino-7-fluoro-9H-pynimido[4,5-b]indol-9-yhacetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]bexane-3-carboxamide (33e) (31 mg, 13% vield) HCl salt as a white solid; '"H NMR (300 MHz, DMSO-de) § 10.77 (s, 1H, D20 exchangeable), 8.76 ~ 8.66 (m, 3H, D20 exchangeable), 8.63 (s, 1H), 8.36 (dd. J = 8.8, 5.2 Hz, 1H), 8.00 (d, J=82Hz, IH). 7.75 -7.63 (m, 2H), 737 - 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); *F NMR (282 MHz, DMSO- ds) & -113.65; MS (ES+): 524.10 & 526.10 (M+1); MS (ES-): 522.10 & 524.00 (M-1); Analysis calculated for C23HisBrFN702.1.1HCL.2.0H: 0: C, 46.00; H, 4.03; C1, 6.49: N, 16.33; Found: C, 46.28; H, 4.10; CL, 6.44; N, 15.96. Scheme 34 TEA Br" NC0O,By ACOH T \o / Cs,COy a fl ~~ A Ne J 7 Br cosy f I > _ C2003 Y ) wy NH, CO; / Bu HN H NR N J i N = \ a 7 HC(OE)s., NH,OAC C | 7 Br” CO, By L | LIN TY 3 fil SN 7 \ NC’ ACOH hn 5,003 I mm a 2 Br Cie Br Br Br 34a 4b 4c ) oo Br i Ho Ns N \ / H 8 iy je Br HATU. DIPEA oF: NN Cl Nay NH Br dE NN C7 Ng NH; Br 34a 346 Preparation of (1R,38,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4.5-b]indol-9-yl)acety])-N- (6-bromopyndin-2-vl)-2-azabicyclo[3.1.0}hexane-3~carboxamide (3de) Step-1: Preparation of 6-bromo-9H-pyrimido[4.5-b]indol-4-amine (34b) Compound 34b was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-3-bromo-1H-indole-3-carbonitrile (34a) (2.20 g. 9.32 mmol: CAS # 1242140- 64-2) using triethyl orthoformate (31.0 mL, 186 nunol), AcOH (2.66 mL. 46.6 vunol) and NH:OAc (3.59 g, 46.6 mmol). This gave after work up 6-bromo-9H-pyrimido[4,5-b]indol-4- amine (34b) (1.58 g, 64% yield) as a pale yellow solid; 'H NMR (300 MHz, DMSO-d) & 11.99 (s. IH), 8.58 (d. J= 1.9 Hz, 1H), 8.26 (s. 1H). 7.48 (dd, J = 8.6. | 8 Hz, 1H). 7.39 (d. J = 8.6 Hz, 1H), 7.30 (s, 2H); MS (ES+): 263 / 265 (M+1). Step-2: Preparation of tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-bJindol-9-yl)acetate (34¢) Compound 34¢ was prepared according to the procedure reported in step-1 of scheme-1, 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), Cs2C0s (2.348 g, 7.21 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert-butyl 2-(4-amino-6-bromo-9H- pyrimido[4.5-b]indol-9-yl)acetate (34¢) (2.265 g, 72% yield) as a pale orange solid; ‘H NMR (300 MHz, DMSO-ds) 5 8.64 (s, 1H), 8.31 (s, 1H), 7.56 (s, 2H), 7.44 (s, 2H), 5.13 (5, 2H), 1.40 (s, 9H): MS (ES+): 377 / 379 (M+1), (ES-): 375 / 377 (M-1). Step-3: Preparation of 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) Compound 34d was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-blindol-9-yl)acetate (34¢) (0.300 g, 0.795 mmol) in DCM (10 mL} using TFA (0.907 g, 7.95 mmol) and stirring at RT for 16 h This gave after workap 2-(4-amino-6-bromo-9H-pyrimido[4,3-bJindol-9-vl)acetic acid (34d) (0.387 g) TFA salt as a yellow solid; ‘H NMR (300 MHz, DMSQ-ds) 3 8.79 (s, 1H), 8.70 ~ 8.44 (m, 3H), 7.77 (d, J = 8.8 Hz. [H), 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). Step-4: Preparation of (1R,38,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-bJindol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (34e) Compound 34e was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-bromo-9H-pyrimido[4.5-blindol-9-yl)acetic acid (34d) (50 mg, 0.115 mmol) in DMF (5 mL) using HC! salt of (1R,38,5R)-N-(6-bromopyridin-2-y1)-2- azabicyclof3.1.0]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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2~(2-(4-amino-6-bromo-9H-pyrimido[4.5-b]indol-9-yI)acety])-N~(6- bromopyridin-2-y])-2-azabicyclo[3.1.0]hexane-3-carboxamide (34e) (26 mg. 39% yield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-d) § 10.75 (s, 1H, D:0 exchangeable), 8.76 (d,J= 3.1 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.38 (s, 2H, D:0 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=174 Hz, 1H), 4.40 (dd, J=9.2. 5.5 Hz, TH), 3.94 - 3.86 (m, IH), 2.38 — 2.26 (m, IH). 2.26 - 2.15 (m, 1H), 1.96 ~ 1.84 (m, 1H), 1.13 - 0.97 (m, 1H), 0.81 ~ 0.72 (m, 1H); MS (ES+) 584.0 (M+1); (ES-): 582.0 (M-1); Analysis calculated for C2:HisBuN-02HCL.2.25H:0: C, 41.71: H, 3.73: C1, 5.35; N, 14.81; Found: C, 41.55; H, 3.58; Cl, 5.49; N, 14.65 Scheme 35 CFa Gms NET en AcOH Cul, KzCO5 HN, NH ge | NC SNH Brg 7 NC” CN | N / P" HC(OMe)s, NH, 0AC o em errr Br Cul, K;CO; ACOH 35a . fi Ho N / COyBu ) “- yN Br” >co,’B8u Ne nr \_ Br TFA Br” "COBU Ng \ _TFA_ CO NCR og oN [TCO r | ’ ar” co,'Bu ) y Br Ny, J ———22 Ny - Cs,C0;3 NH, HoN 35¢ 254 coH Hg CO oo, J LT 0 Atty CGH B Br N : 1. ————— 1 Br YU NCOs [= Ng J Br HN 4 “Br N 0 Na NU nes 35e 3 NH, 35F Preparation of (1R,38,5R)~2-(2-(4~-amino-8-bromo-9H-pyrimido[4,5-bJindol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (35f) Step-1: Preparation of 2-amino~7~bromo-1H-indole-3~carbonitrile (35b) Compound 35h was prepared according to the procedure reported in step-1 of scheme-11, from N-(2.6-dibromophenyl)-2.2.2-trifluoroacetamide (35a) (7.79 g. 22.45 nunol; CAS # 340034-49-3) in DMSO (20 mL) using roalononitrile (1.780 g, 26.9 mmol), L-proline (0.517 g, 4.49 mmol), Cal (0.428 g, 2.245 mmol), K:COs (6.21 g, 44.9 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOz gel (40 8). eluting with EtOAc in hexane from 0-40%] 2-amino-7-bromo-1H-indole-3-carbonitrile (35b) (4.18 g, 18% vield) as a pale orange solid; 'H NMR (300 MHz, DMSO-ds) 5 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.) = 7.8 Hz. 1H), 6.69 (s, 2H): MS (ES+): 236 ; (ES-): 234 (M-1). Step-2: Preparation of 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35¢) Compound 35¢ was prepared according to the procedure reported in step-1 of scheme-6. 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 NHsOAc (6.82 g, 89 mmol). This gave after workup 8-bromo-9H-pyrimido[4.5-b]indol-4-amine (35¢) as a pale- vellow solid residue was used as such for the next step: ‘H NMR (300 MHz, DMSO-ds) § 1197 (s, 1H), 8.32 (d, J = 7.9 Hz, 2H), 7.56 (d. J= 7.8 Hz, 1H), 7.30 (s, 2H), 7.17 (1, J=7.8 Hz, 1H). Step-3: Preparation of rert-butyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-blindol-9-yl)acetate (35d) Compound 35d was prepared according to the procedure reported in step-1 of scheme-1, from 8-bromo-9H-pyrimido[4,5-blindol-4-amine (35¢) (4.11 g, 15.62 mmol) in DMF (20 mL) using rerr-butyl 2-bromoacetate (3.05 g, 15.62 mmol) Cs2C0: (6.62 g, 20.31mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH mn DCM from 0-3%] tert-butyl 2~(4- amino-8-bromo-9H-pyrimido[4,S-blindol-9-ylacetate (35d) (4.11 g, 88% yield) as a pale orange solid; 'H NMR (300 MHz, DMSO-s) 6 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). Step-4: Preparation of 2-(4-amino-~8-bromo-9H-pyrimido[4.5-bJindol-9-yl)acetic acid (35e) Compound 35e was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-anino-8-bromo-9H-pyrmdo[4,5-b]indol-9-yl)acetate (35d) (0.230 g, 0.663 ramol) using TFA (1.511 g, 13.25 mmol) in DCM (20 mL) and stirring at RT for 16 bh. 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; "H NMR (300 MHz, DMSO-ds) & 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). Step-5: Preparation of (1R,38,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4.5-b]indol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyelo[3. 1. 0]hexane-3-carboxanide (35f) Compound 35f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-8-bromo-9H-pyrimido[4.5-blindol-9-y acetic acid (35) (50 mg. 0.115 mmol) in DMF (5 mL) using HCI 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 ramol), DIPEA (74.3 mg, 0.575 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%) followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%) (IR,38,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-ylacetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (35f) (38 mg. 57% yield) HCI salt as a white solid; "H NMR (300 MHz, DMSO-d) 5 10.76 (s. 1H, D20 exchangeable), 8.59 (s. 1H), 8.55 - 8.32 (m, 3H, 2H D0 exchangeable), 8.00 (d, J = 8.2 Hz, 1H), 7.70 (1, 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, / =9.0,5.7 Hz, IH). 3.91 - 3.87 (mm, 1H), 2.40 - 2.25 (m, 1H), 2.25 - 2.15 (m, 1H), 2.00 — 1.84 (m, 1H), 1.12- 0.99 (m, 1H), 0.81 — 0.69 (m, 1H); MS (ES+): 584.0 (M+1), (ES-): 582.0 (M-1); Analysis calculated for C23H190BraN-02. HCL.2H:20: C, 42.00: H, 3.68: CI, 5.39; N, 14.91; Found: C, 41.98; H, 3.61; Cl, 5.08; N, 14.77. Scheme 36 AcOH oN ML Cs.COy N / —COBu HN For ~~ MK hy i HC(OEY; NHOA: Ng Br” COBu Ng | > He Ze Cs:C0; ) NC OMe AcOH HoN ome UL Lu Mane AN NH Ne ] HN OMe COs Bu A CN HaN OMe 36c Ne= / TT HN le OMe 7 HIN Ay 26a 360 36c ) poo TFA po Ho NBT LN YY sa S HATU, DIPEA ¥ e Tr -OMe NEL. NH, 2 Hoon (30 Nes NH 36d 288 Preparation of (IR, 38,5R)-2~(2~(4-amino-7-methoxy-9H-pyrimido[4,5-blindol-9-yl)acety1)- N-(6-bromopyridin-2-v1)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (36e) Step-1: Preparation of 7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (36b) Compound 36b was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-6-methoxy-1H-indole-3-carbonitrile (36a) (2.50 g. 13.35 mmol; CAS # 1016680-93-5) using triethyl orthoformate (44.4 mL, 267 mmol), AcOH (3.82 mL, 66.8 mmol) and NHsOAc (5.15 g, 66.8 mmol). This gave after work up 7-methoxy-9H- pyrimido[4,5-bJindol-4-amine (36b) (0.89 g, 31% yield) as a brown yellow solid; 'H NMR (300 MHz, DMSO-ds) 8 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). Step-2: Preparation of fert-butyl 2-(4-amino-7-methoxy-9H-pyrimido[4.5-b]indol-9- yl)acetate (36¢) Compound 36¢ was prepared according to the procedure reported in step-1 of scheme-1, 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 Cs2C03 (1.624 g, 4.99 mmol) and stirring at RT for 16 b. This gave after workup and purification by flash column chromatography [silica gel (24 g). eluting with MeOH in DCM from 0-3%) tert-butyl 2-(4- amino-7-methoxy-9H-pyrimido[4,5-blindol-9-yl)acetate (36¢) (0.83 g, 61% yield) as a pale yellow solid; 'H NMR (300 MHz, DMSO-ds) 8 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). Step-3: Preparation of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) Compound 36d was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-7-methoxy-9H-pyrimido[4,5-blindol-9-y acetate (36¢) (0.83 g, 2.53 mmol) in DMF (20 mL) using TFA (5.76 g, 50.6 mmol) and stirring at RT for 16 h. The reaction mixture was concentrated in vacuuru to afford 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; 'H NMR (300 MHz, DMSO-ds) 8 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 (5. 2H), 3.89 (5. 3H). Step-4: Preparation of (1R.38,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-blindol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36e) Compound 36e was prepared according to the procedure reported in step-3 of scheme-1, from 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 HCI salt of (1R,3S,5R)-N-(6-bromopyndin-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2~(2-(4-amino-7-methoxy-9H-pyrimido[4.5-bJindol-9-y])acetyl)-N-~(6- bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36) (52 mg, 75% yield) HCL salt as a white solid; 'H NMR (300 MHz. DMSO-de) 8 10.67 (s. 1H, D20 exchangeable), 8.48 (s, 1H), 8.35 (dd, J = 12.4, 6.2 Hz, 3H, 2H D:0 exchangeable), 7.94 (d, J = 8.2 Hz, 1H), 7.64 (1, J = 8.0 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.19 (d, } = 2.2 Hz, 1H). 6.97 (dd, J = 8.7. 2.2 Hz, 1H), 5.64 (d, J = 173 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 (rm, 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); Analysis calculated for CasH2BrN-03, 1. 2HCL2 25H:0: C, 46.44; H, 4.50; C1, 6.85; N, 15.80; Found: C, 46 47; H. 4.50: Cl, 6.46: N, 15.867. Scheme 37 H / —COH N H oO \ Z 8a \ HN ome HATU, DIPEA / —COM PN Ng | HN OMe oa 0 i N N ¢ 3 Lop N=, AL 17a 36d NH, 37a Preparation of (1R,38,5R)-2-(2-(4~amino-7-methoxy-9H-pyrimido[4.5-blindol-9-yDacetyl)- N-(6-bromopyridin-2-y1)-5-methy]-2-azabicyclo[3.1.0thexane-3-carboxamide (37a) Compound 37a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-y]acetic acid (36d) (100 mg. 0.259 mmol) in DMF (5 mL) using HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-y1)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] (1R,38,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-blindol-9-yDacetyl)- N=(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0}hexane-3-carboxamide (37a) (85 mg, 60% vield) HCl salt as a white solid; ‘H NMR (300 MHz, DMSO-ds) 8 10.73 (s, 1H, D20 exchangeable), 8.55 (s. 1H). 8.46 (s, 2H. D20 exchangeable), 8.39 (d, / =8.8 Hz, 1H). 8.01 (d,J=8.2Hz, IH). 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, = 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, IH). 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). Scheme 38 —COyBu i gry HC(OMe)s, NHsOAc Ne I Me Br CO,Bu be oN _N_ / —COostBu HR more hs Ir 0 HC(OMe)s, NH OAc Ng Br” CO, Bu 8 men en 2 NC OD AcOH HN Cs,C03 HN OMe OMe OMe 38a 38b 38¢c TFA 4 H y hos 0 PR tL boo HN Yt HATU. DIPEA N / —COH A SN Ne HN OMe e N. N 30 ( 0 \ OMe NH, 38d ag 38e Preparation of (1R,38,5R)-2-(2-(4~amino-6-methoxy-9H-pyrimido[4.5-blindol-9-yDacetyl)- N-(6-bromopyridin-2-y1)-2-azabicvclo[3. 1 O]hexane-3-catboxamide (38¢) Step-1: Preparation of 6-methoxy~-9H-pyrimido[4,5-blindol-4-amine (38b) Compound 38b was prepared according to the procedure reported in step-1 of scheme-6. from 2-amino-5-methoxy~H-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 NH4OAc (6.38 g, 83 mmol). This gave after work up 6-methoxy-9H-pyrimido[4,5- blindol-4-amine (38b) (2.78 g. 78% vield) as a pale yellow solid: 'H NMR (300 MHz, DMSO-ds) 3 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). Step-2: Preparation of terr-butyl 2-(4-amino-6-methoxy-9H-pyrimido[4,5-blindol-9- vl)acetate (38¢) Compound 38¢ was prepared according to the procedure reported in step-1 of scheme-1. 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) Cs2C03 (1.077 g, 3.30 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert-butyl 2-(4~ amino-6-methoxy-9H-pyrimido[4,5-bJindol-9-yl)acetate (38c¢) (0.56 g, 62% yield) as a pale yellow solid; "H NMR (300 MHz, DMSO-ds) 5 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). Step-3: Preparation of 2-(4~anino-6-methoxy-9H-pyrinudo[4,5-bindol-9-yl)acetic acid (38d) Compound 38d was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-6-methoxy-9H-pyrimido[4,5-bJindol-9-yl)acetate (38¢) (0.56 g, 1.705 mmol) in DCM (20 mL) using TFA (1.945 g, 17.05 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-methoxy-9H-pyrimido[4.5-bJindol-9-v)acetic acid (38d) (0.68 g.) TFA salt as a yellow solid; 'H NMR (300 MHz, DMSOQ-ds) &§ 8.69 — 8 44 (m, 3H), 8.05(d, J=24 Hz, 1H), 7.70 (d, / =9.0Hz, 1H), 7.17 (dd, J= 89, 2.4 Hz, 1H), 5.23 (s, 2H), 3.89 (s, 3H). YF NMR (282 MHz, DMSO-ds) & -74.16; MS (ES+): 273 (M+1), (ES-): 271 (M-1). Step-4: Preparation of (1R,38,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,3-b]indol-0- yhacety!)-N-(6-bromopyridin-2-v1)-2-azabicyclo[3. 1.0Jhexane-3-carboxamide (38¢) Compound 38e was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-methoxy-9H-pyrimido[4.5-blindol-9-yl)acetic acid (38d) (50 mg, 0.129 mmol) in DMF (5 mL) using HCl salt of (1R,3S,5R)-N-(6-bromopyridin-2-y1)-2- azabicyelo[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 RT for 16 b. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (I1R.38,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4.5-b]indol-9-yDacetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0}hexane-3-carboxamide (38¢) (41 mg, 59% yield) HCl salt as a white solid: ‘H NMR (300 MHz, DMSO-d) § 10.75 (s, LH). 8.81 (s, 2H). 8.60 (s, TH), 8.07 (s. TH), 7.99 (d, J = 8.1 Hz, 1H), 7.69 (t.J = 8.0 Hz, 1H), 7.61 (d, J= 9.0 Hz, 1H), 731 (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), 3.90 ~ 3.86 (m. 4H), 2.40 ~ 2.27 (m, 1H), 227-213 (m, 1H), 1.98 — 1.83 (m, 1H), 1.12 - 1.00 (m, 1H), 0.84 — 0.70 (m, 1H); MS (ES+): 536 / 538 (M+1), (ES-): 534 / 536 (M-1); Analysis calculated for C2sH22BrN-03 HC1.2. 75H0: 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. Scheme 39 CF, NET CN HC(OMe)s, NH,0Ac Sy eos y—NH 22 8 ne Ls FEIN N Ft N 2 Neen Lr HC(OMe)s, NH a iii He 0 Cul, K,CO3 NC 2 AcOH COMe COMe 30a 390 H CN / —CO, / Bu ra I Bt Br” "CO;Bu CO-Bu nN i" TFA Cs,CO4 pa SCY HN NH, X 12 H N. as ~ N J J Br’ x 3 , C NH, CO;Me 39¢ 39d 20 pt / ~COyBu ZINN . Na / i" HN COMe 39d HH Ld svi N H 04g 7 i i HN J HATU, DIPEA NCO FN—N Ne HN \ CO;Me ry HN Br YO 0. N N 0 C NH. CO Me 3% NH, 36f Preparation of methyl 4-amino-9-(2-((1R,38.5R)-3~((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3. 1 0]hexan-2-y1)-2-0x0ethyl)-9H-pyrimido[4,5-bJindole-6-carboxylate (39f) Step-1: Preparation of methyl 2~-amino-3-cyano-1H-indole-5-carboxylate (39b) Compound 39b was prepared according to the procedure reported in step-1 of scheme-11, 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), Cul (0.337 g, 1.772 mmol), K:COs (4.90 g, 35.4 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiO2 gel (40 g), eluting with EtOAc in hexane from 0-40%)] methyl 2-amino-3-cyano-~1H-indole-3~ carboxylate (39b) (2.94 g, 77% yield) as a brown solid; ‘H NMR (300 MHz, DMSO-ds) 8 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). Step-2: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylate (39¢) Compound 39¢ was prepared according to the procedure reported in step-1 of scheme-6, from methyl 2-amino-3-cyano-1H-indole-3-carboxylate (39b) (2.94 g, 13.66 mmol) using trimethyl orthoformate (29.0 g, 273 mmol), AcOH (3.91 mL, 68.3 mmol) and NH«OAc (5.27 2, 68.3 mmol). The pale~yellow solid residue obtained after workup was used as such for the next step; 'H NMR (300 MHz, DMSO-d) 8 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 (5, 3H). Step-3: Preparation of methyl 4-amino-9-(2-(ferr-butoxy)-2-oxoethyl)-9H-pyrimido[4,5~ blindole-6-carboxylate (39d) Compound 39d was prepared according to the procedure reported in step-1 of scheme-1, from methyl 4-amino-9H-pyrimido[4.5-b]indole-6-carboxylate (39¢) (2.68 g, 11.06 mmol) in DMF (20 ml.) using tert-butyl 2-bromoacetate (2.158 g, 11.06 mmol), Cs2COx (433 g, 13.28 ramol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g). eluting with MeOH in DCM from 0-3%) methyl 4-amino- 9-(2~(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4.5-bJindole-6-carboxvlate (39d) (2.50 g, 63% yield) as a pale orange solid; "H NMR (300 MHz, DMSO-ds) 3 9.00 (d..J = 1.6 Hz, 1H), 8.34 (s. IHD), 8.04 (dd. J = 8.6, 1.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H). 7.54 (5, 2H), 5.18 (5, 21D), 3.91 (s, 3H). 1.40 (s, 9H). Step~4: Preparation of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-blindol-9-yhacetic acid (39e) Compound 39e was prepared according to the procedure reported in step-2 of scheme-1. from methyl] 4-amino-9-(2-(fert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-blindole-6-carboxylate (39d) (2.50 g, 7.02 mmol) using TFA (16 g, 140 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol- 9-ylacetic acid (39) (3.70 g) TFA salt as a yellow solid; 'H NMR (300 MHz, DMSO-ds) 8 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): °F NMR (282 MHz, DMSO-ds) & -74.65. Step-5: Preparation of methyl 4-amino-9-(2~((1R,38,5R)~3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3. L. 0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-blindole-6~ carboxylate (390) Compound 39f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(d-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b}indol-9-yl)acetic acid (39e) (50 mg, 0.121 mmol) in DMF (§ mL) using HCl salt of (1R,38,5R)-N-(6-bromopyridin-2-y1)- 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 RT for 16 bh. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%)] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] methyl 4-amino-9~(2~((1R.38,5R)-3-((6-bromopyridin-2-vl)carbamoyl)-2~ azabicyclof3.1.0]hexan-2-v1)-2-oxoethyl)-9H-pyrimido[4.5-blindole-6-carboxylate (39f) (53 mg, 78% yield) HCI salt as a white solid; '"H NMR (300 MHz, DMSO-ds) § 10.76 (s, 1H, D20 exchangeable). 9.13 (s, 1H). 8.59 (s, 1H), 8.54 (s, 2H, D:z0 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), 731(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 (mu, 1H), 0.84 — 0.74 (m, 1H); MS (ES+): 564.0 (M+1). (ES-): 562.0 (M-1): Analysis calculated for C2sHzzBiN-04 HCL2.75H20: C, 46.17, H, 4.42; CLL 5.45; N, 15.08; Found: C, 46.19: H, 4.27: C1, 5.68: N, 14.87. Scheme 40 H Nn Br p— OH ) oo x H Nes Br 2 r HATU, DIPEA roo N ey i Na NH, COMe 3%e NH» oo NN C] Na NH, COMe 40a 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-y1)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxylate (40a) Compound 40a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-blindol-9-yl)acetic acid (39) (100 mg, 0.241 mmol) in DMF (5 mL) using HCI salt of (IR.38,5R)-N-(6-bromopyridin-2- vl)-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%)] methyl 4-amino-9-(2-((1R.3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-3- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-blindole-6-carboxylate (40a) (53 mg. 78% yield) HCI salt as a white solid: 'H NMR (300 MHz, DMSO-ds) § 10.77 (s, 1H, D20 exchangeable), 9.14 (s, TF), 8.79 - 8.52 (m, 3H, 2H D:20 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, / = 17.3 Hz, IH). 437 (dd, J=9.0, 5.9 Hz, 1D), 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+): 378.0 (M+1), (ES-): 576.0 (M-1): Analysis calculated for C26H2aBN-04 HC1.2.25H:0: C, 47.65: H, 4.54; CL, 5.41; N, 14.96; Found: C, 47.54; H, 4.50; Cl, 529: N, 14.92. Scheme 41 CFs Zu NC“ eN Sy eos 7 > 4 COMe H.R [ NC COMe Cul. KzCQ4 41a 41b ° CO,B! u 2 H N cr Ny CO,Me NH AcOH | \a / f 2 be = Cs,C04 NH, ZN No. N HC(OMe)s, NHOAC i acoms TFA —_———— CoMe mbm Ny AcOH NH; Cs,C04 CO;Me NH, 41c 41d ) FH wy Br N 7 H © Aa n= H 0 ~~. (ON Cot xy HATU, DIPEA I N et Nay COMe NH. NH, No nN Cl Nn Ny COMe NH 41e 41f Preparation of methyl 4-amino-9-(2-((1R.38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicvclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-carboxvlate (41f) Step-1: Preparation of methyl 2-amino-3-cyano- 1H-indole-6-carboxylate (41b) Compound 41b was prepared according to the procedure reported in step-1 of scheme-11, 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) and using malononitrile (1.430 g, 21.65 mmol), L-proline (0.415 g, 3.61 nmumol), Cul (0.344 g, 1.804 mmol), K2COs (4.99 g. 36.1 mmol) and heating at 60 °C for 16 b under an argon atmosphere. This gave after workup and purification [SiOz gel (40 g), eluting with EtOAc in hexane from 0-50%] methyl 2-amino-3-cyano-1H-indole-6- carboxylate (41b) (1.32 g, 34% yield) as a brown solid; 'H NMR (300 MHz, DMSO-d) 10.96 (s, TH), 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 (5, 3H); MS (ES+): 216 (M+1), (ES-): 214 (M-1). Step-2: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-7-carboxylate (41c) Compound 41¢ was prepared according to the procedure reported in step-1 of scheme-6, 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 mumol) and NH:OAc (2.364 g. 30.7 mmol). This gave after workup methyl 4-amino-9H-pyrimido[4.5-blindole-7- carboxylate (41¢) (0.83 g, 56 % yield) as a pale-yellow solid. 'H NMR (300 MHz, DMSO-ds) $12.14 (s, 1H). 8.43 (d, T= 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, [H), 7.41 (s, 2H). 3.90 (s, 3H): MS (ES+); 243 (M+1), (ES-): 241 (M-1). Step-3: Preparation of methyl 4-amino-~9-(2-(ferr-butoxy)-2-oxoethyl)-9H-pyrimido[4,5~ blindole-7-carboxylate (41d) Compound 41d was prepared according to the procedure reported in step-~1 of scheme-1. from methyl 4-amino-9H-pytimido[4,5-blindole-7-carboxylate (41¢) (0.83 g, 3.43 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.668 g, 3.43 mmol), Cs:COs (1.340 g, 4.11 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] methyl 4-amino- 9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-bJindole-7-carboxylate (41d) (0.67 g, 55% vield) as a pale orange solid; 'H NMR (300 MHz, DMSO-de) 8 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). Step-4: Preparation of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-bJindol-9-y1acetic acid (41e) Compound 41e was prepared according to the procedure reported in step-2 of scheme-1, from methyl 4-amino-9-(2-(rert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-blindole-7-carboxylate (41d) (0.67 g, 1.880 mmol) using TFA (4.29 g, 37.6 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5- blindol-9-yl)acetic acid (41e) (3.70 g) TFA salt as a yellow solid; ‘H NMR (300 MHz, DMSO-de) 58.71 ~ 8.47 (m, 4H), 8.36 (d,.J = 1.4 Hz, 1H), 7.99 (dd. J= 8.3, 1.4 Hz, 1H), 35.36 (s, 2H). 3.93 (s, 3H); MS (ES+): 301 (M+1), (ES-): 299 (M-1). Step-5: Preparation of methyl 4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2- yl)earbamoyl)-2-azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-bjindole-7- carboxylate (41f) Compound 41f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4.5-blindol-9-vl)acetic acid (41e) (50 mg. 0.121 mmol) in DMF (5 mul.) using HCI salt of (1R,38,5R)-N-(6-bromopyridin-2-yf)- 2-azabicvelo[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 RT for 16 h. This gave after workup and punfication by flash column chromatography [sihea gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0~100%] methyl 4~-amino-9~(2~((1R.38,5R)-3-((6~-bromopyridin-2-vl)carbamoyl)-2~ azabicyclo[3. 1.0Jhexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-blindole-7-carboxylate (41f) (48 mg, 71% yield) HCI salt as a white solid: 'H NMR (300 MHz, DMSO-ds) § 10.77 (s. 1H, D0 exchangeable). 8.59 (d. J= 8.5 Hz, 1H), 8.57 (s, 1H), 8.45 (s, 2H, D0 exchangeable), 8.28 (s, TH), 8.05 — 7.92 (m. 2H), 7.70 (t,.J=8.0 Hz, IH). 7.31 (d. J=7.7 Hz, 1H), 5.86 (d,.J = 17.4 Hz. 1H), 549 (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); Analysis calculated for C2sHz:BrN704. 1.1. HCL2. 75 HzO: C, 4591: H. 4.41: C1, 5.96; N, 14.99; Found: C, 45.90; H, 421; Cl, 598: N, 14.69. Scheme 42 / —COH 2 H < Br T H I< Br LS Ty HATU, DIPEA HN ZN / CoH ZN Ne HN COMe ; So N. a CoMe " Nd 41e NH oo Preparation of methyl 4-amino-9-(2-((1R.38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5- ruethyl-2-azabicyclo[3. 1. 0Thexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-bJindole-7-carboxylate (42a) Compound 42a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido(4,5-b]indol-9-vl)acetic acid (41e) (100 mg, 0.241 mmol) in DMF (5 mL) using HC! salt of (IR.38,5R)-N-(6-bromopyridin-2- yh-5-methyl-2-azabicyclo[3.1.0Jhexane-3-carboxande (8a) (R0 mg, 0.241 wunol), HATU (110 mg, 0.290 mmol), DIPEA (156 mg, 1.207 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] methy] 4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-S- methyl-2-azabicyclo[3.1.0]hexan-2-y1)-2-ox0ethyl)-9H-pyrimido[4,5-bJindole-7-carboxylate (42a) (82 mg. 59% vield) HCI salt as a white solid: 'H NMR (300 MHz, DMSO-d) 5 10.77 (s, 1H, D20 exchangeable), 8.70 — 8.41 (m, 4H, 2H D0 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, / = 7.7 Hz, 1H), 3.83 (d, J= 17.4 Hz, 1H), 5.43 (d,. / = 17.3 Hz, 1H). 4.38 (dd, J= 9.0, 5.9 Hz, 1H), 3.92 (s, 3H). 3.73 - 3.70 (tm, 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); Analysis calculated for CasHasBrN-Q4 HCL2.5. H20: C, 47.32, H, 4.58, C1, 5.37; N, 14.86; Found: C, 47.48; H, 4.28, ClL523:;N. 1468 Scheme 43 LIOH i ~Ny Ao ® 2 ~COH Ni NH (vo N é | COMe Nes Y.. NH, 41f 43a Preparation of 4-amino-9-(2-((1R,38.5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-v1)-2-oxoethyl)-9H-pyrimido[4.5-blindole-7-carboxylic acid (43a) Compound 43a was prepared according to the procedure reported in step-4 of scheme-17. from methyl 4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0Jhexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-blindole-7-carboxylate (41f) (78 rag. 0.138 mmol) in THF ({ mL) and water (2 mL) using 2M aqueous lithium hydroxide hydrate (0.138 mL, 0.276 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography (C18 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] 4-amino-9-(2-((1R,3S,5R)-3-((6~ bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3. | 0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4.5- blindole-7-carboxylic acid (43a) (34 mg, 45% yield) HCI salt as a white solid: "HNMR (300 MHz, DMSQ-ds) 6 (a mixture of two rotamers) 10.85 (s) and 10.77 (s) (2s, 1H, D:0 exchangeable), 8.93 (s. 2H. D0 exchangeable), 8.69 (d, J=4.9 Hz, IH). 8.63 (d.J=83 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), 128-117 (m) and 1.16 — 1.04 (m) (2m, 1H), 1.02 — 0.83 (m) and 0.79 — 0.67 (m) (2m, IH): MS (ES+): 550 / 552 (M+1), (ES-): 548 / 550 (M-1):; Analysis calculated for CaaH20BrN-04. 1. 1HCL3H:0: C, 44.72; H, 4.24; C1, 6.05: N, 15.21; Found: C, 44.67: H, 4.12; CL 607:N. 1523 Scheme 44 Ao LIOH Ao [ QL N ey Ng 7 \ NH, CoH I 0 eh Na NH; COMe 30f 44a Preparation of 4-amino-9-(2-((1R,38.5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0Jhexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-b}indole-6-carboxylic acid (44a) Compound 44a was prepared according to the procedure reported in step-4 of scheme-17. from TFA salt of methyl 4-amino-9-(2-((1R,38,5R)-3-({6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0Jhexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-blindole-6-carboxylate (39f) (156mg, 0.276 mmol) in in THF (2 mL) and water (4 mL) using 2M aqueous lithium hydroxide hydrate (0.553 mL, 0.553 nmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%) 4-amino-9-(2-((1R.38.5R)- 3-((6-bromopyridin-2-yl)carbamoy])-2-azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-6-carboxylic acid (44a) (31 mg, 20% yield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-d) (a mixture of two rotamers) 3 12.98 (s, IH, D:0 exchangeable), 10.86 and 10.77 (2s. TH, D:0 exchangeable). 9.11 (s, 1H), 8.60 and 8.58 (2s, 1H), 8.48 (s, 2H, D20 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 Hz, 1H), 4.42 (dd. J= 9.1, 5.5 Hz, IH), 3.91 (m, 1H). 2.40 ~ 2.12 (m, 2H). 1.93 (m, 1H), 130-0.53 (nm, ZH). MS (ES+): 550.1 (M+1): (ES-): 548.0 (M-1); Analysis calculated for CaaH20BrN-04 2.25H20.0.95HCI: C. 46.08; FH, 4.10; C1, 5.38; N, 15.67: Found: C, 46.42; H, 4.03: Cl, 4.94: N, 15.29. Scheme 45 4 ol Pa . 08 2 Bu EE N Nd Novy Zeal Ha 7 TN Ha COE Pd(OH), Pd(PPh3),Cly KoCO, NH, I: NN C7 Ny NH, Br ro N er - NA NH, — COLE AE CO;'Bu w ert ls "Ng 7 \ Pd(C NH, = CO,Et 45a Arlo fet ae 45a 45b oo Ao 2 Mn VY U, TFA 45¢ ela 45d ro -, N er "No? NH, a CO,Et Sa pl TRI LL 8B a Ao 7 4a N N — 0] Ny 2 NH, 45d COE Preparation of ethyl 3-(4-amino-9-(2-((1R.38.5R)-3-((6-bromopy ridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-y1)-2-0x0ethyl)-9H-pyrimido[4.5-b}iudol-6-y])propanoate (45d) Step-1: Preparation of (E)-ethyl 3-(4-amino-9-(2-(fers-butoxy)-2-oxocthyl)-9H-pyrimido(4,5- blindol-6~vl)acrylate (45a) A mixture of tert-butyl 2-(4-amino-6-bromo-9H-pyrimido[4.5-b]indol-9-yl)acetate (34¢) (200 mg, 0.53 mmol). ethyl acrylate (80 mg, 0.795 mmol). Pd(PPha).Cl: (37.2 mg, 0.053 mmol), and KaCOs (220 mg, 1.591 mmol) were suspended in DMF (4 mL) in a sealed scintillation vial. The vial was flushed with nitrogen and the yellow mixture then heated at 100 °C for 16 h. The resulting black mixture was filtered. The filtrate was diluted with H20 (25 mL) and extracted with EtOAc (25 mL x 3). The combined extract was washed with FO (25 mL x 4), brine (25 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel, 24 g, eluting with 0-60% EtOAc in hexane) to provide (E)-cthyl 3-(4-amino-9~(2-(rert-butoxy)-2~oxoethyl)-9H-pyrimido[4.5-b)indol-6- vhacrylate (45a) (102 mg, 49 % yield) as a pale-yellow solid. ‘H NMR (300 MHz, DMSO- ds) 58.78 (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), 748 (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, T= 7.1 Hz, 3H); MS (ES+): 397 (M1), (ES-): 395 (M-1). 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-(fert-butoxy)-2-oxoethyl)-9H-pyrimido[4.5- blindol-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 under a hydrogen atmosphere for 16 h at 100 °C. The reaction mixture was cooled to room temperature filtered through Celite, washed with ethyl acetate and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM 0-3%] to afford ethyl 3-(4-amino-9-(2-(fert-butoxy)-2-oxoethyl)-OH-pyrimido[4,5-blindol-6- vh)propanoate (45b) (80 mg, 80 % yield) as a white semisolid; 'H NMR (300 MHz, DMSO- de) 88.25 (d, J = 9.1 Hz, 2H), 744 (d, J = 8.3 Hz. 1H), 7.36 - 7.14 (m, 3H), 5.08 (5, 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). Step-~3: Preparation of 2-(4-amino-6-(3~cthoxy-3-oxopropyl)-9H-pyrimido[4,5-bjindol-9- vl)acetic acid (45¢) Compound 45¢ was prepared according to the procedure reported in step-2 of scheme-1. from ethyl 3-(4-amino-9-(2-(fert-butoxy)-2-oxoethy])-9H-pyrimido[4,5-blindol-6-yl)propanoate (45b) (78 mg, 0.196 mmol) in DCM (5 mL) using TFA (223 mg, 1.96 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H- pynmido[4,5-b]indol-9~yDacetic acid (45¢) TFA salt as a pale yellow solid: 'H NMR (300 MHz, DMSO-ds) & 8 55 (s, 1H), 8.41 (d,.J = 10.5 Hz, 2H), 7.68 (d, J= 8.4 Hz, 1H), 743 (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, / = 7.8 Hz. 2H), 1.17 (t,.J = 7.1 Hz, 3H). °F NMR (282 MHz, DMSO-de) 5 ~74.25: MS (ES): 343 (M+1), (ES-): 341 (M-1). Step~4: Preparation of ethyl 3-(4~amino-9-(2-((1R.3S,5R)-3-((6-bromopyridin-2~ vlcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4,5-blindol-6- vl)propanoate (45d) Compound 45d was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (45¢) (96 mg, 0.21 mmol) in DMF (5 mL) using HCI salt of (1R,38.5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexanc-3-carboxamide (4a) (67.0 mg. 0.210 mmol), HATU (96 mg, 0.252 mmol), DIPEA (136 mg, 1.05 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl 3-(4-amino~9-(2-((1R,38.5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4.5-b}iudol-6-y])propanoate (45d) (44 mg, 35% yield) HCl salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 8 10.75 (s, 1H, D:0 exchangeable), 8.58 (s, 1H), 8.533 (s, 2H, D:0 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). 732(d.J=77Hz 1H),5.73(d, / = 173 Hz, IH). 539 (d. J=173 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, 1H), 2.26 ~ 2.13 (mn, 1H), 1.98 - 1.84 (m, 1H), 1.16 (¢t, J = 7.1 Hz, 3H), 1.10 — 1.01 (m, 1H), 0.81 — 0.72 (m, TH); MS (ES+): 606 / 608 (M+1), (ES-): 604 / 606 (M-1); Analysis calculated for CasHasBrN-04.1.25 HCL. 17S H20: 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. Scheme 46 CF4 NCTTNeN {coun H (cFcop0 aNd E 500)! & Ys EtsN sr Cul, K,CO3 HNN | NC’ COOCH; COOCH; HaN (CF5G0)0 Br eieisosesmemseseeserhe EN COOCH; 46a 6b 46c ‘NHy 2 N CO,Bu ZS NH NL] ¥ il alii] wes fy TFA Br” CO,'Bu mod ous UY EtOH HN de) Cs,C04 HN N. [Z S—NH Ne HN ROOC NS ui ~) H - Ny HN HaCH,COOC 46d (R= Me, Et mixture) 460 H ‘ HO 1 >» Sa oO 2 “ H y ho 0 43 "2 HATU, DIPEA HN r=N OF N wa HN H,CH,C00C A Vii i Ng / / HN H3CH,COOC 46f 46g Preparation of ethyl 4-amino-9-(2-((1R,3S.5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-OH-pyrimido[4.5-b]indole-3-carboxylate (46g) 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 # 106896- 48-4) and triethylamine (6.82 mL, 48.9 mmol) in DCM (30 mL) was added trifluoracetic anhydride (4.08 mL, 29.3 mmol) dropwise and stirred at RT for 15 h. The reaction mixture was diluted with dichloromethane (75 mL), washed with water (50 mL), dried, filtered and concentrated in vacuum to afford methyl 2-bromo-3-(2,2,2-trifluoroacetarnido)benzoate (46b) as a vellow gum (8.17 g) and was used as such for next step; MS (ES+): 325.90 (M+1), (ES-): 323.90 (M-1). Step-2: Preparation of methyl 2-amino-3-cyano-1H-indole-4-carboxylate (46¢) Compound 46¢ was prepared according to the procedure reported in step-1 of scherne-11, from methyl 2-bromo-3-(2.2,2-triflucroacetamido)benzoate (46b) (1594 g, 4.89 mmol) in DMSO (8 mL) using malononitrile (388 mg. 5.87 wumol), L-proline (0.113 g, 0.978 mmol), Cul (93 mg, 0.489 mumol). K2COs (1.352 g. 9.78 mmol) in water (8 mL) and heating at 60 °C for 13 h under an argon atmosphere. This gave after workup and purification [Si02 gel (24 g), eluting with EtOAc in hexane from 0-66%] methyl 2-amino-3-cyano-1H-indole-4~ carboxylate (46¢) (115 mg, 11% vield) as a brown solid; (ES-): 214.00 (M-{). Step-3: Preparation of methyl / ethyl 4-amino-9H-pyrimido[4.3-b]indole-5-carboxylate (46d) Compound 46d was prepared according to the procedure reported in step-2 of scheme-29, from methyl 2-amino-3-cyano-1H-indole-4-carboxylate (46¢) (105 mg, 0.488 mmol) in ethanol (10 mL) using formamidine acetate (513 mg, 4.88 mmol) and heating at 100°C in a microwave The reaction mixture was filtered, washed with ethanol. and dried under vacuum. The residue was purified by flash column chromatography [SiO2 gel (24 g), elating with EtOAc in hexane from 0-100% and then using hexanes / 10% methanol in ethyl acetate (1:1)] a mixture of methyl / ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) (66 mg) as a brown solid, which was used as such for the next step; MS (ES+): 243.10, 257.10 (M+1). Step-4: Preparation of methyl / ethyl 4-amino-9-(2-(rert-butoxy)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-5-carboxylate (46¢) Compound 46e was prepared according to the procedure reported in step-1 of scheme-1, from a mixture of methyl / ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) (65 mg) in DMEF (5 mL) using fert-butyl 2-bromoacetate (0.048 mL. 0.322 mmol), Cs2C0z (219 mg, 0.671 mmol) and stirring at RT for 14 h. This gave after workup and purification by flash column chromatography [SiO2 gel (24 g), eluting with 10% methanol in ethyl acetate in hexanes from 0-100%6] methyl 4-amino-9-(2-(ferr-butoxy)-2-oxoethyl)-9H-pyrimido[4,5~ blindole-S-carboxylate (7 mg, 7%): MS (ES+): 357.10 (M+1); ethyl 4-amino-9-(2-(tert- butoxy)-2-oxoethyl)-9H-pyrimido[4,5-blindole-3-carboxylate (46¢) (16 mg, 9% yield) as a white solid: MS (ES+): 371.20 (M+1): (ES-): 369.00 (M-1). Step-5: Preparation of 2-(4-amino-3-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-vl)acetic acid (46f) Compound 46f was prepared according to the procedure reported in step-2 of scheme-1, from ethyl 4-amino-9-(2-(fers-butoxy)-2-oxoethyl)-9H-pyvrimido|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 RT for 17 h. This gave after workup 2-(4-amino-3-(ethoxycarbonyl)-9H-pyrimido[4,5-b)indol-9- ylacetic acid (46f) which was used as such in next step-6 without further purification; MS (ES+): 315.10 M+1). Step-6: Preparation of ethyl 4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2-azabicyclo[3. 1.0fhexan-2-y1)-2-oxoethy])-OH-pyrimido[4.5-b]indole-3-carboxylate (46g) Compound 46g was prepared according to the procedure reported in step-3 of scheme-1. from 2+(4-amino-~3-~(ethoxycarbonyl)-9H-pynmdo[4,5-bJindol-9-yhacetic acid (46f) (13.51mg, 0.043 mmol) in DMF (7 mL) using HCl salt of (1R.38.5R)-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 ramol) DIPEA (0.045 ml, 0.258 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with hexanes / 10% MeOH in EtOAc from 0 - 100%] followed by conversion to HCI salt by dissolving product in acetonitrile (1.5 mL) and 0.1% aq. HCI (6 mL) and lyophilization ethyl 4-amino-9-(2- ((1R,38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]bexan~2-~y1)-2~ oxoethyl)-9H-pyrimido[4,5-b]indole-3-carboxylate (46g) (6.5 mg, 26% yield) HC] salt as a white solid; "HNMR (300 MHz, DMSO-d) & 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. IH). 2.43 - 2.12 (m. 2H). 2.01 - 1.85 (m, TH), 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). Scheme 47 CF3 Et;N Ca Cul, KyCO5 yp—NH COOCH; "N= "MU2R ~~, HN, FOOCH: econo d A oe EtsN Ed Br ty — Cul, KyCOs 47a NF 1 —=N / —CO, Bi Hf I i. a oN. Bu NH { NH Br” C0,Bu HN 7=N bY JH HN COOCH; Alc 47d a7e H Q Hoy TFA ee iN. EMS = 4a ary * H N “OU o & : 4a HATU, DIPEA ry COOCH; N: 2 he Nk. NH, i Ho Ne® Lo 0 eS COOCH; N N 2d 3 NH; 47 2 47g Preparation of methyl 4-amino-9-(2-((1R.38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclof3.1.0]hexan-2-v1)-2-oxoethyl)-9H-pyrimido[4.5-blindole-8-carboxylate (47g) Step-1: Preparation of methyl 3-bromo-2-(2,2.2-trifluoroacetamido)benzoate (47b) Compound 47h was prepared according to the procedure reported in step-1 of scheme-46, from methyl 2-amino-3-bromobenzoate (47a) (5 g. 21.73 mmol; CAS # 104670-74-8) in DCM (30 mL) using triethylamine (7.57 mol, 54.3 mmol). trifluoroacetic acid anhydride (4.53 mL, 32.6 mmol) and stirring at RT for 43 h. This gave after workup and purification by flash column chromatography [$102 gel (120 g). EtOAc in hexane from 0-14%] methyl 3- bromo-2~(2,2,2-trifluoroacetamido)benzoate (47b) as a yellow solid (5.27 g. 74% viceld) and was used as such for next step; 'H NMR (300 MHz, DMSO-d) § 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); \F NMR (282 MHz, DMSO-ds) 8 -74 44; MS (ES-): 323.90 & 325.90 (M-1). Step-2: Preparation of methyl 2-amino-3-cyvano-1H-indole-7-carboxylate (47¢) Compound 47¢ was prepared according to the procedure reported in step-1 of scheme-11, from methyl 3-bromo-2-(2.2,2-triflucroacetamido)benzoate (47b) (2 g. 6.13 mmol) in DMSO (12 mL). using malononitrile (0.486 g. 7.36 mmol), L-proline (0.141 g, 1.227 ramol). Cul (0.117 g, 0.613 mmol), a solution of K2COs (1.695 g, 12.27 mmol) in water (12 mL) and heating at 60 °C for 13 h under an argon atmosphere. This gave after workup and purification by flash column chromatography [8i0: gel (24 g), eluting with EtOAc in hexane from 0- 33%] methyl 2-amino-3-cyano-1H-indole-7-carboxylate (47¢) (305 mg, 23% yield) asa brown solid: 'H NMR (300 MHz, DMSO-ds) & 10.75 (s, 1H), 7.51 (dd. J =7.8, 1.1 Hz, 1H), 741(d,J =7.6Hz, 1H), 7.09 (t,J = 7.7 Hz, 1H), 6.93 (s, 2H), 3.91 (s, 3H): MS (ES+): 216 00 Step-3: Preparation of methy] 4-amino-9H-pyrimido[4.5-blindole-8-carboxylate (47d) Compound 47d was prepared according to the procedure reported in step-2 of scheme-29, from methyl 2-amino-3-cyano-1H-indole-7-carboxylate (47¢) (300 mg, 1.394 mmol) in ethanol (10 mL) using formamidine acetate (1466 mg, 13.94 mmol) and heating at reflux for 45 h. This gave after workup a grey solid residue (268 mg) which was used as such for the next step; *H NMR (300 MHz, DMSO-d) § 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. Step-4: Preparation of methyl 4-amino-9-(2-(tert-butoxy)-2-~oxoethyl)-9H-pyrimido[4.5- blindole-8-carboxylate (47¢) Compound 47e was prepared according to the procedure reported in step-1 of scherne-1, from methyl 4-amino-9H-pyrimido[4,3-blindole-8-carboxylate (47d) (240 mg, 0.991 mmol) in DMEF (6 mL) using rerr-butyl 2-bromoacetate (0.176 mL, 1.189 mmol), Cs:COs (807 mg. 2.477 mmol) and stirring overnight at RT. This gave after workup and purification by flash column chromatography [S102 gel (24 g), eluting with 10% methanol in ethyl acetate in hexanes from 0-100%] methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- blindole-8-carboxylate (47e) (353 mg, 25% yield) as an off white solid; ‘H NMR (300 MHz, DMSO-ds) 5 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. Step-5: Preparation of 2~(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-blindol-9-yl)acetic acid (47) Compound 47f was prepared according to the procedure reported in step-2 of scheme-1, from raethyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-blindole-8-carboxylate (47¢) (80 mg, 0.224 mmol) using TFA in DCM (10 mL) and stirring at RT. This gave after workup 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4.5-bJindol-9-y acetic acid (47f) which was used as such in next step-6 without purification; MS (ES+): 301.10 (M+1). Step-6: Preparation of methyl 4-amino-9-(2-((1R,38,5R)-3~((6-bromopyridin-2- vhcarbamoyl)-2-azabicyclo[3.1.0hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4.5-b]indole-8- carboxylate (47g) Compound 47g was prepared according to the procedure reported in step-3 of scheme-1, 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 HCI salt of (IR.38,5R)-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 RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 3 %] followed by conversion to HCI salt by dissolving product in acetonitrile (2 mL) and 0.1% aq. HCl (8 mL) and lyophilization methyl 4-amino-9-(2-((1R,38.5R)-3~((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3. | 0]hexan-2-y1)-2-oxoethyl)-9H-pyrimido[4.5- blindole-8-carboxylate (47g) (38 mg. 30% yield) HCl salt as a white solid; "HNMR (300 MHz, DMSO-de) § 10.72 (s, 1H, D0 exchangeable), 8.65 (d, J = 7.7 Hz, 1H), 8.51 (s, 1H), 8.17 7.91 (m, 3H, 2H D20 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). Scheme 48 o ~~ 0. oO xX o sr IL 0 N Na = \ Br Br NH; 7 NH; 34b 480 o o 0.0 o x ~A XN ig ay ang J NH, ) SE N — er N: Y Cs,C0s, Et:N ¢ Vl Pddoay, Xphos [AWA ok HN Nex == Cs,C0Os N= = ds Br NH; Br NH, NY 34b 480 LL Rr LiOH 2 % H Ney Lo oO da NF ok HATU, DIPEA NH, NH, 480 Br ay Rs a xX N N, Q < NH, FY 48¢c 48d Preparation of fert-butyl (4-amino-9-(2~((1R.38,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 0]hexan-2-y1)-2-oxoethyl)-OH-pyrimido[4.5-blindol-6-y])carbamate (48d) Step-1: Preparation of ethyl 2-(4~amino-6-bromo-~-9H-pyrimido[4,5-blindol-9-vl)acetate (48a) Compound 48a was prepared according to the procedure reported in step-2 of scheme-16, from 6-bromo-9H-pyrimido[4.3-b]indol-4-amine (34b) (540 mg. 2.053 mmol) in DMF (10 mL) using ethyl 2-bromoeacetate (0.228 mL, 2.053 mmol), Cs2CO: (802 mg. 2.463 mmol), triethylamine (1.716 mL, 12.32 mmol) and stirring at RT for 27 h. This gave after workup 2- (4-amino-6-bromo-9H-pyrimido[4,5-blindol-9-yl)acetate (48a) (166 mg) as a light yellow solid: 'H NMR (300 MHz, DMSO-ds) 5 8.63 (d.J= 1.8 Hz, 1H), 8.29 (s. IH), 7.60 (d.J = 8.7 Hz. 1H), 7.54 (dd, J = 8.7, 1.8 Hz, IF), 7.45 (s, 2H), 5.23 (s, 2H), 4.13 (q,. / = 7.1 Hz, 2H), 1.19 (t, J= 7.0 Hz, 3H); MS (ES+): 349.00 & 350.90 (M+1). Step-2: Preparation of ethyl 2-(4-amino-6-((rer+-butoxycarbonyl)amino)-9H-pyrimido[4,5- blindof-9-yl)acetate (48b) Compound 48b was prepared according to the procedure reported in step-3 of scheme-17, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-blindol-9-yl)acetate (48a) (150 mg, 0.430 mmol) in toluene (8 mL) using XPhos, t-butyl carbamate, Pd2(dba)s, Cs2C0s (140 mg, 0.43 mol) and heating at 90 °C for 20 h. This gave after work up and purification ethyl 2-(4- amino-6-((fert-butoxycarbonyl)aminoe)-9H-pyrimido[4,3-bJindol-9-yl)acetate (48b) (10 mg, 6% vield); MS (ES+): 386.20 (M+1). Step-3: Preparation of 2-(4-amino-6-((fert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (48¢) Compound 48c¢ was prepared according to the procedure reported in step-4 of scheme-17, from ethyl 2-(4-amino-6-((zerr-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 RT for 18 h. This gave after work up 2-(4- amino-6-((fert-butoxy carbonyl)amine)-9H-pyrimido(4,5-b]indol-9-vl)acetic acid (48c) which was used as such in next step~4; MS (ES+): 358.20 (M+1); (ES-): 356.10 (M-1). Step-4: Preparation of tert-butyl (4-amino-9-(2-((1R,38,5R)-3-((6-bromopyridin-2- vhcarbamoyl)-2-azabicyclo[3.1.0|hexan-2-y1)-2-oxocthyl)-9H-pyrimido[4,5-b]indol-6- vl)carbamate (48d) Compound 48d was prepared according to the procedure reported in step-3 of scheme-1, from 2-(4-amino-6-((terr-butoxycarbonyl)amino)-9H-pyriraido[4.5-bindol-9-y acetic acid (48¢) (from above step-3, 0.026 mmol) in DMF (6 mL) using HCI salt of (1R,38,5R)-N~(6- bromopyridin-2-y1)-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 RT for [4 h. This gave after workup and purification by flash colurun chromatography [silica gel (4 g). eluting with MeOH in DCM from 0 - § %)] followed by conversion to HCl salt in acetonitrile (1 mL) using 0.1% aq. HCl (5 mL) and lyophilization rert-butyl (4-amino-9-(2~((1R.38,5R)- 3-((6-bromopyridin-2-y1)carbamoy])-2-azabicyclo[3.1.0]hexan-2-y1)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6-yl)carbamate (48d) (6 mg, 37% vield) HCI salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 3 10.76 (s, 1H, D20 exchangeable). 9.26 (s, 1H, D:0 exchangeable), 8.54 (s. 1H). 8.38 (s, 1H). 8.29 (s, 2H, D20 exchangeable), 8.01 (d. J=8.1 Hz, 1H), 7.70 (t, J = 8.0 Fz, 1H), 7.56 (d,.J = 8.8 Hz, 1H), 7.40 (d. 7 = 8.1 Hz, 1H), 7.32 (d, J #77 Hz, 1H), 5.70 (d,J = 17.3 Hz, 1H), 537 (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). Scheme 49 h 4a O Z HATU, DIPEA NHz Br NH. LOW % id 3 rir NH, oN 48a afm 460 a0e 9 al - Neary EN ¢ 0 Pa(PPh Nes = Netz % 48a Preparation of (1R,3S.5R)-2-(2-(4-amino-6~cyano-9H-pyrimido[4.5-b)indol-9-yl)acetyl)-N- (6-bromopyridin-2-y1)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (49¢) Step-1: Preparation of ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-y])acctate (49a) To a mixture of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (300 rag. 0.859 mmol) and dicyanozine (303 mg. 2.58 numol) in DMF (8 mL) was added Pd(PPhs)s (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 x 60 mL). brine (60 mL). dried, filtered, concentrated in vacuum and triturated with ethyl acetate (20 mL). The solid obtained was collected by filtration and dried in vacuum to afford ethyl 2- (4-amino-6-cyano-9H-pyrimido[4,3-b]indol-9-yl)acetate (49a) (160 mg, 63% vield) as a white solid; 1H NMR (300 MHz. DMSO-de) § 8.94 - 8.93 (mm, 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, / = 7.2 Hz, 3H); M§ (ES+): 296.10 (M=+1); (ES-): 294.10 (M-1) Step-2: Preparation of 2-(4-amino-6-cyano-9H-pyrimido[4,5-bjindol-9-yl)acetic acid (49b) Compound 49b was prepared according to the procedure reported in step-4 of scheme-17, 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 rug, 1.625 mmol) in water (3 mL) and stirring at RT for 15 h. This gave after workup 2~(4- amino-6-cyano-9H-pyrimido[4,5-blindol-9-ylacetic acid (49b) (72 mg, 100% yield) which was used as such in next step-3 without further purification; MS (ES+): 268.10 (+1). Step-3: Preparation of (1R,38,5R)-2-(2~(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9~ ylacetyl)-N-(6-bromopyridin-2-v1)-2-azabicyelo[3. 1.0]hexane-3-carboxamide (49¢) Compound 49¢ was prepared according to the procedure reported in step-3 of scheme-1, from 2-(4-amino-6-cyano-9H-pyrimido[4,5-blindol-9-y)acetic acid (49b) (0.072 g, 0.271 mmol) in DMF (10 mL) using HCI salt of (IR 38,5R)-N-(6-bromopyridin-2-y1)-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 RT for 22 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). 10% MeOH in EtOAc in hexane from 0 — 100 %] followed by conversion to HCI salt in acetonitrile (5 mL) using 0.1% aq. HCI (30 mL) and Ivophilization (1R,38,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido(4,5- bJindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (49¢) (54 mg, 38% yield) HC salt as a white solid: 'H NMR (300 MHz, DMSO-d) 3 10.76 (s, 1H, D20 exchangeable), 9.09 (d, J = 1.5 Hz, 1H), 8.74 ~ §.54 (m. 3H, 2H D:0 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, IH). 5.81 (d.J=17.4 Hz, 1H), 545d, / = 17.3 Hz, 1H), 4.42 (dd. J= 9.0, 5.5 Hz, 1H), 3.95 ~ 3.84 (m, 1H), 2.42 ~ 2.08 (mn. 2H), 1.98 ~ 1.83 (m, 1H), 1.16 - 0.98 (m, 1H), 0.90 ~ 0.67 (m, LH); MS (ES+): $31.10 & $33.10 (M+1); MS (ES-): 529.00 & 531.10 (M-1); Analysis calculated for C2sH:9BrNs02.0.85HC1.2.0H>0: C,48.17,H, 4.02; Cl, 5.04; N, 18.73; Found: C. 48.54; H,. 4.17: C1. 5.36: N. 18.40. Scheme 50 { Sun Su FN NCTON ENN He (OMe)s, NHOAS AcOH Jord Nf AcOH HN ni NC her Ment Cul, K,CO, p CFy HN. R | NC ¥ 50a "0b do, 50¢ CO, Bu Wiad ong 7 N. Br" CoB J IN TRA NC OP da HATU. DIPEA NHp F 50e 50n ony H H 4Bu ox 2 Ore N TFA an sa = Sia HATU. DIPEA NH, F 50e | Ia / CCe sr comu of TN dt Bho C8200; ER HoN F (3 oD 50d NHy F 50f Preparation of (1R,3S,5R)~2~(2-(4-amino-5-fluoro~-9H-pyrimido[4.5-b]indol-9-y1)acetyl)-N-~ (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (50f) Step-1: Preparation of 2-amino-4~fluoro-~1H-indole~3~carbonitrile (50b) Compound 50b was prepared according to the procedure reported in step-1 of scheme-11, from N-(2-bromo-3-fluorophenyl)-2,2.2-triflucroacctamide (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), Cul (0.333 g, 1.748 mmol), K2COx (4.83 g, 35.0 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification by flash column chromatography [SiOz gel (40 g), eluting with EtOAc in hexane from 0-50%)] 2- amino-4-fluoro-1H-indole-3-carbonitrile (50b) (0.3 g, 10% yield) as an brown solid: 'H NMR (300 MHz, DMSO-de) 5 10.97 (s, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.91 ~ 6.83 (m, 3H), 6.75 (ddd, J = 10.8, 8.1, 1.0 Hz, 1H); MS (ES+): 176.0 (M+1), (ES): 174.0 (M-1). Step-2: Preparation of 5-fluoro-9H-pyrimido[4.5-b]indol-4-amine (50¢) Compound 50¢ was prepared according to the procedure reported in step-1 of scheme-6. 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 NH:OAc (0.660 g, 8.56 mmol). This gave after workup and purification by reverse phase column chromatography [C18 column (30 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%] 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50¢) (83 rug. 24% vield) as a brown yellow solid; 'H NMR (300 MHz, DMSO-ds) § 13.18 (s, 1H), 8.60 (s, 1H), 7.61 ~ 7.38 (m, 2H). 723 (dd. J= 11.3, 7.8 Hz, 1H); MS (ES+): 203.04 (M+1). Step-3: Preparation of tert-butyl 2-(4-amino-3-fluoro-9H-pyrimido[4.5-b]indol-9-y1)acetate (50d) Compound 50d was prepared according to the procedure reported in step-2 of scheme-16. from HCl salt of 5-fluero-9H-pyrimido[4.5-b]indol-4-amine (50¢) (80 mg, 0.335 mmol) in DMF (2.5 mL) using fert-butyl 2-bromoacetate (63.4 mg, 0.335 mmol) Cs2COs (218 mg, 0.670 mmol) and stirring at RT for 1.5 h. The solid separated was collected by filtration. dried to give tert-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-blindol-9-yDacetate (50d) (83 mg, 78 % yield) as a pale vellow solid; "H NMR (300 MHz, DMSO-ds) & 8.36 (s, 1H), 7.54 7.40 (m, 2H), 7.14 (ddd, J = 11.5, 7.2, 1.7 Hz. 1H), 5.16 (5. 2H), 1.41 (s, 9H): MS (ES+): 317.10 (M+) Step-4: Preparation of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yDacetic acid (50e) Compound 50e was prepared according to the procedure reported in step-2 of scheme-1. from tert-butyl 2-(4-amino-3-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d) (80 mg, 0.253 mmol) using 20% TFA in DCM (1452 pl, 3.79 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yacetic acid (50e) (85 mg, 90% vield) TFA salt as a vellow solid; "TH NMR (300 MHz, DMSO-d) 8 8.46 (s, 1H), 7.58 (d,J= 8.2 Hz, 1H), 749 (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). Step-5: Preparation of (1R,38,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9- yhacety!)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (50f) Compound S0f was prepared according to the procedure reported in step-3 of scheme- |, from TFA salt of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-blindol-9-y]acetic acid (50e) (50 mg, 0.134 mmol) in DMF (1.5 mL) using 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 mol), DIPEA (0.116 mL, 0.668 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%] (I1R.38,5R)-2-(2-(4-amino-5-fluore-9H-pyrimido[4,5-blindol-9-y1)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo]3.1.0Jhexane-3-carboxamide (500) (33 mg, 76% yield) HCl salt as a white solid: ‘H NMR (300 MHz, DMSQ-ds) 3 10.77 (s, 1H, D20 exchangeable), 8.68 (5. TH), 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 (1d, J = 5.2, 2.4 Hz, 1H); °F NMR (282 MHz, DMSO0-ds) -113 23; MS (ES+): 524.0 (M+1); 546.0 (M+Na); (ES-): 522.0 (M-1); Analysis calculated for C2sHisBrFN-02.1.75H:0.1HCL: C, 46.64; H, 4.00; C1, 53.99; N, 16.55: Found: C.4650;H,3.71; CL. 573; N, 16.29. Scheme 51 Br COo,Bu HC(OMe)s, NH4OAC =N HNC GH 7 = ] ~NH ~~ | > HC(OMe),, NHOA: NS Br” CO,Bu MX \ AcOH HN C2C03, K,CO5 Ble Ho 51d OH AN TEA a 3 oN 51d A H YA Ny Br F 2 4 4a yy mses he . HN a” A= HATU, DIPEA _N / COBu SN N__. FTF HoN br Sad IN, N, ~ . & Oy N- N. \ 4a = 13 {2 HATU, DIPEA Nd NH Ae ant TE yi Oe a 51f NHz 51g Preparation of (IR, 38,5R)-2+(2~(4-anino-8-fluoro-9H-pyrimido[4,3-b]indol-9-y1)acetyl)-N- (6-bromopyridin-2-y1)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (51g) Step-1: Preparation of 2,2.2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (51b) Compound 51b was prepared according to the procedure reported in step-1 of scheme-46, 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 acid anhydride (4.40 mL, 6.65 mmol) and stirring at RT for 16 h. This gave after workup 2,2,2-trifluoro-N-(2-fluoro-6- iodophenyl)acetamide (51b) (6.5 g, 93% vicld) as a yellow solid. which was used as such for the next step; HNMR (300 MHz, DMSO-d) & 11.42 (s, 1H), 7.81 (dt. / = 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), Step-2: Preparation of 2-amino-7-fluore-1H-indole-3-carbonitrile (51c¢) Compound S1c was prepared according to the procedure reported in step-1 of scheme-11, from 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (S1b) (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), Cul (0.366 g, 1.922 mmol), K2COs (5.31 g. 38.4 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOz gel (40 g), eluting with EtOAc in hexane from 0-50%)] 2-amino-7-fluoro- 1 H-indole-3-carbonitrile (51¢) (1.535 2, 46% vield) as a yellow solid; 'H NMR (300 MHz, DMSO-ds) 8 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). Step-3: Preparation of §-fluoro-9H-pyrimido[4,3-b]indol-4-amine (51d) Compound 51d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-fluoro- {H-indole-3~carbonitrile (51¢) (1.5 g, 8.56 mmol) using trimethyl orthoformate (18.74 mL, 171 mmol), AcOH (2.449 mL, 42.8 mmol) and NH:0Ac (3.30 g, 42.8 mmol). This gave after workup 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51d) (1.54 8. 69% vield) as a pale yellow solid: TH NMR (300 MHz. DMSO-d) 5 12.33 (s. 1H), 11.98 (s, 1H), 8.29 (s, TH), 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). Step-4: Preparation of fert-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (51e) Compound Sle was prepared according to the procedure reported in step-2 of scheme-16, from AcOH salt of 8-fluoro-9H-pyrimido[4.5-b}indol-4-amine (51d) (1.5 g. 5.72 mmol) in DMEF (35 mL) using tert-butyl 2-bromoacetate (1.171g, 6.01 mmol), Cs2C0: (4.10 g, 12.58 mmol) stirring at RT for 13 h, followed by the addition of KxCO3 (0.791 g, 5.72 mmol), fert- butyl 2-bromoacetate (0.845 mL. 5.72 mmol) and stirring for additional 3 h. This gave after workup tert-butyl 2-(4-amino-8-fluoro-9H-pyrimudo[4,5-blindol-9-yacctate (Sle) (1.15 g. 64% vield) as a pale vellow solid; "H NMR (300 MHz, DMSO-d) § 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). Step-5: Preparation of 2-(4-amino-8-fluero-9H-pyrimido[4,5-blindol-9-yl)acetic acid (51f) Compound 51f was prepared according to the procedure reported in step-2 of scheme- |, from tert-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-blindol-9-yDacetate (51e) (0.9 g, 2.85 mmol) using 20% TFA in DCM (16.33 mL, 42.7 mmol)) and stirring at RT for 16 h. This gave after workup 2-(4-amino-8-fluoro-9H-pyrimido[4.5-b]indol-9-yl)acetic acid (51f) (0.92 2. 86% yield) TFA salt as a white solid; 'H NMR (300 MHz, DMSO-ds) & 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). Step-6: Preparation of (1R.35,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4.5-b]indol-9~ vl)acetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3. 1. 0Jhexane-3-carboxamide (51g) Compound 51g was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2~(4-amino-8-fluoro-9H-pyrimido[4,5-blindol-9-yl)acetic acid (51f) (75 mg, 0.200 mamol) in DMF (2 mL) using TFA salt of (1R,3S.5R)-N-(6-bromopyridin-2-y})-2~ azabicyclof3.1.0Jhexane-3-carboxamide (4a) (79 mg. 0.200 mmol), HATU (114 mg, 0.301 mmol), DIPEA (0.175 mL, 1.002 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 ~ 100%] followed by purification using reverse phase column chromatography [C18 column (50 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%] (IR,38,5R)-2~(2~(4-amino-8-fluoro-9H-pyrimido[4,5-blindol-9-yl)acetyl)-N-(6- bromopyridin-2-y1)-2-azabicyclo[3.1 Olhexane-3-carboxamide (51g) (81 mg. 77% yield) HCI salt as a white solid: 'H NMR (300 MHz, DMSQ-ds) § 10.78 (s, 1H, Dz0 exchangeable), 8.60 (s, 1H), 8.45 (s, 2H, D20 exchangeable), 8.32 (dd, J= 5.8, 3.0 Hz, 1H), 8.02 (d,J=82 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 (wm, 2H), 2.01-1.83 (m. 1H), 1.10 (dt, = 9.3, 5.4 Hz, 1H). 0.64 (q. / = 3.8, 2.9 Hz, 1H). "°F NMR (282 MHz, DMSO0-ds) 8 -134.64. MS (ES+): 524.1 (M+1); (ES-): 522.1 (M-1); Analysis calculated for CasHioBrFN-0:22H0.0.9HCI: 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. Scheme 52 NeTNeN HC(OMa)3, NHOAC Ceo rH N AcOH Han | A NC Br 4 a ’ nH ~N NH nN HN Br ! > - CLA HN NH Cul, KCOy NC" \e / at of, 5Za 528 B2¢ » Ho Ned® <b a H N, TO 4a === A w NH, NH, o BLOC. 2 3 Ho Neer! TFA N . § ar 4 0) Ned Ne NH, NH, N FA CaN 4a = ” N Br" C0,Bu Nowe! or Ti & o rm BEA i. or C;C03, K;CO3 { J i» §_ / NH; NH; NH, " Bh 52d Ee CE Preparation of (IR,38,5R)-2-(2-(4-amino-~7-bromo-9H-pyrimido[4,5-blindol-9-yl)acetyl)-N-~ (6-bromopyridin-2-yl1)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (52f) Step-1: Preparation of 2-amino-6-bromo-1H-indole-3-carbonitrile (52b) Compound 52b was prepared according to the procedure reported in step-1 of scheme-11, 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), Cul (0.309 g, 1.625 mmol), K2CO;s (4.49 g, 32.5 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiO» gel (40 g), eluting with EtOAc in hexane from 0-30%] 2-amino-6-bromo-1H-indole-3- carbonitrile (52b) (2.06 g. 54% yield) as a yellow solid: "H NMR. (300 MHz, DMSO-d) & 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). Step-2: Preparation of 7-bromo~9H-pyrimido[4,5-b]indol-4-amine (52¢) Compound 52¢ was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-~6-bromo-1H-indole-3-carbonitrile (32h) (2 g. 8.47 mmol) using trimethyl orthoformate (17.98 g. 169 mmol). AcOH (2.54 g, 42.4 mmol) and NHsOAc (3.27 g. 42.4 mmol). This gave after workup 7-bromo-9H-pyrimido[4,3-b]indol-4-amine (52¢) (2.29 g, 84% yield) as a pale yellow solid; 'H NMR (300 MHz, DMSO-ds) § 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 (5, 2H), 1.92 (s, 3H). Step-3: Preparation of tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-bJindol-9-yl)acetate (52d) Compound 52d was prepared according to the procedure reported in step-2 of scheme-16, from AcOH salt of 7-bromo-9H-pyrimido[4.5-b)indol-4-amine (52¢) (2.2 g, 6.81 mmol) n DMF (75 mL) using tert-butyl 2-bromoacetate (1.056 g, 7.15 mol), Cs2CO: (4.88 g. 14.98 mmol) stirring at RT for 15 h, followed by the addition of K2CO3 (0.941 g, 6.81 mmol), fers butyl 2-bromoacetate (1.006 mL. 6.81 mmol) and stirring for 3 h at RT. This gave after workup ferr-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,3-b]indol-9-yhacetate (52d) (1.25 g, 49% vield) as a pale yellow solid; 'H NMR (300 MHz, DMSO-ds) 8 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). Step-4: Preparation of 2~(4-amino-7-bromo-9H-pyrimido[4.5-bJindol-9-yl)acetic acid (52e) Compound 52e was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2~(4-amino-7-bromo-9H-pynmido[4,3-b]indol-9-yl)acetate (52d) (0.3 g. 0.793 ramol) using 20% TFA in DCM (4.56 mL, 11.93 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-7-bromo-9H-pyrimido[4,3-b]indol-9-yl)acetic acid (52¢) (0.31 2, 90% vield) TFA salt as a white solid: 'H NMR (300 MHz, DMSO-d) 5 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). Step-5: Preparation of (1R,38,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-blindol-9- vl)acetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (52[) Compound 52f was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-7-bromo-9H-pyrimido[4,5-bJindol-9-yl)acetic acid (52e) (75 mg, 0.172 mmol) in DMF (2 mL) using TFA salt of (1R,3S.5R)-N-(6-bromopyridin-2~y})-2~ azabicyclof3.1.0Jhexane-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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 ~ 100%] followed by purification using reverse phase column chromatography [C18 column (50 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%)] (1R.38,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-ylacetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (52f) (79 mg. 78 % yield) HCI salt as a white solid: 'H NMR (300 MHz, DMSO-ds) 3 10.79 (s, 1H, Dz0 exchangeable), 8.70 (s, 2H, D20) exchangeable), 8.64 (s, 1H), 8.49 (d,.J = 8.5 Hz. 1H), 8.08 ~ 7.97 (m, 2H), 7.71 (tJ = 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 He, TH), 5.42 (d, J = 17.3 Hz, 1H), 4.43 (dd. J= 9.0, 5.5 Hz, 1H), 3.90 (ddd, J = 7.6, 54,24 Hz. 1H), 239 = 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); Analysis calculated for C23H:sBraN-02.2H>0.1HCL: 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. Scheme 53 X TFA Uy Xo BocN: NH a )- N A oO 7 0 Se A { “5c Br 53a Rib COOH X HN L0H i NS —N N ee HN tle GF, ————————— TY \ YY HN Sn dN HATU, DIPEA - Br A id 3c NH; ° 53d Preparation of (S)-5-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-bindol-9-yhacetyl)~ N-(6-bromopyridin-2-y1)-5-azaspito[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)-3-(terr-butoxycarbonyl)-5-azaspiro[2.4]heptane~6~carboxyhic acid (53a) (0.5 g, 2.072 mmol) in DCM (15 mL) was added 1-methyl-1H-imidazole (0.413 mL, 5.18 mmol) at 0-5 °C under a nitrogen atmosphere. The reaction mixture was stirred for 10 ruin at 0-5 °C, added methanesulfonyl chloride (0.192 mL, 2.487 ramol) followed by stirnng at 0-3 “C for 1 h. To this mixture was added 6-bromopyridin-2-amine (0.359 g, 2.072 romol) and stirred for 18 h at RT. Water (30 mL) was added to the reaction mixture, layers were separated, and aqueous laver was extracted with DCM (3 x 30 mL). The combined organics were washed with IN HCl (30 mL), Sat. aqueous NaHCO: (30 mL), brine (30 mL), dried, filtered and concentrated in vacuum to afford (S)-fert-butyl 6-((6-bromopyridin-2- vl)carbamoyl)-S-azaspiro| 2.4 ]heptane-3-carboxylate (53b) (0.8 g, 97 % yield); H NMR (300 MHz, DMSO-ds) 6 10.90 (d. J = 18.6 Hz, 1H), 8.11 (dd, J= 13.0, 8.1 Hz, 1H), 7.75 (g.. / = 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 =273, 12.8, 8.3 Hz, 1H), 1.83 (ddd, J = 35.1, 12.6, 5.2 Hz, 1H), 1.33 (d, J = 36.8 Hz, 9H), 0.68 — 0.41 (m, 4H): MS (ES+): 396.00 (M+1). Step-2: Preparation of (S)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (53¢) Compound 53¢ was prepared according to the procedure reported in step-2 of scheme-1, from (8)-tert-butyl 6-((6-bromopyridin-2-yl)carbamoyl)-3-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 RT. This gave after workup (S)-N-(6-bromopyridin-2-y1)-3- azaspiro|2.4]heptane-6-carboxamide (53¢) (0.55 g, 92% vield) TFA salt: 'H NMR (300 MHz, DMSO-ds) § 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, / = 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 (M1) Step-3: Preparation of (S)-3~(2~(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9~ yhacety!)-N-(6-bromopyridin-2-v1)-5-azaspiro[2. 4 Theptane-6-carboxamide (53d) Compound 53d was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of (8)-N~(6-bromopyridin-2-vi)-5-azaspiro| 2.4] heptane-6-carboxamide (53c) (72.5 mg, 0.177 mmol) in DMF (2 mL) using TFA salt of 2~(4-ammo-6-(trifluoromethyl)- 9H-pyrimido[4,5-bJindol-9-v]acetic acid (11e) (75 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol), DIPEA (0.154 mL, 0.884 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (8)-5- (2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-vDacetyl)-N-(6-bromopyridin-2- vh)-5-azaspiro[2.4]heptane-6-carboxamide (53d)) (89 mg, 86% yield) HCI salt as a white solid: 'H NMR (300 MHz, DMSO-ds) (a mixture of two rotamers) 8 11.25 and 10.82 (2s, 1H, D»0 exchangeable), 8.96 (s, 1H), 8.59 and 8.57 (2s, 1H), 8.52 (s, 2H, D»0 exchangeable), 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=7.7Hz. 1H), 5.45 (d,J= 2.4 Hz, 2H), 4.65 (dd, / = 8.5, 5.0 Hz, IH), 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-d) § -58.70. MS (ES+): 588.1 (M1); (ES-): 586.1 (M-1); Analysis calculated for C2sHuBrFaN-Oz 1.5H0.1.1HCI: C, 45.81: H. 3.86; C1, 5.95: N, 14.96; Found: C. 45.85; H, 3.73; C1, 5.91: N, 14.70. Scheme 54 COM C- N NC CN (CF3C0O)0 Et;N x42 NNH OMe Cul, K,CO5 Nl an 7 NH ome CF, Br (CF;C0),0 7 \ NH -_ ZEN OMe 54a Xe AcOH aay Cs,C03, Ky;COa N, [7 N—NH No J OMe HN OMe Ey oo 54a SL 54b C ° 54¢ N o. ANS nw > Br oN HC(OMe)s, NHOAC Ng] OMe YT NN id lid Li errs J AcOH 5,00, KO; ( 30 Mt Cu 4d NH, 54g OH 2 H Br SL MS ay “ H CAH Ny, Br "TJ A HATU, DIPEA NH, 5a NH, 54g Preparation of (1R,38,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-blindol-9-yDacety1)- N-(6-bromopyridin-2-vl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (54g) Step-1: Preparation of N-(2-bromo-6-methoxyphenyl)-2,2.2-trifluoroacetamide (54b) Compound 54b was prepared according to the procedure reported in step-1 of scheme-~46, 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 acid anhydride (5.16 mL, 37.1 mmol) and stirring at RT for 16 h. This gave after workup N-(2-bromo-6-methoxyphenyl)- 2.2, 2-trifluoroacetamide (54b) (7.35 g. 100% yield) as a pale yellow solid and was used as such for next step; 'H NMR (300 MHz, DMSO-dk) 6 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). Step-2: Preparation of 2-amino-7~-methoxy-~1H-indole-3~carbonitrile (54¢) Compound S4¢ was prepared according to the procedure reported in step-1 of scheme-11, from N-~(2-bromo-6-methoxyphenyl)-2.2,2-trifluoroacetamide (54b) (7.2 g, 24.16 mmol) in DMSO (20 mL) and using malononitrile (1.826 mL, 29.0 mmol), L-proline (0.556 g, 4.83 mmol), Cul (0.460 g, 2.416 mmol), K2COs (6.68 g, 48.3 mmol) and stirring at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOz gel (40 g), eluting with EtOAc in hexane from 0-50%) 2-amino-7-methoxy-1H-indole-3-carbonitrile (54¢) (2.308 g, 51% yield) as a yellow solid; H NMR (300 MHz, DMSO-ds) 3 10.81 (s, 1H), 6.92 (t.J=7.9Hz, IH), 6.77 (d, / = 7.7 Hz. IH), 6.59 (d,J=7.9 Hz, 1H), 6.37 (5, 2H), 3.86 (s. 3H): MS (ES+): 188.1 (M-+1): (ES-): 186.0 (M-1). Step-3: Preparation of 8-methoxy-9H-pyrimido[4.5-bindol-4-amine (54d) Compound 54d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-methoxy-1H-indole-3-carbonitrile (54¢) (2.3 g, 12.29 mmol) using trimethyl orthoformate (26.1 g, 246 mmol), AcOH (3.51 mL, 61.4 mmol) and NH:OAc (4.74 g, 61.4 mrool). This gave after workup 8-methoxy-9H-pyrimido[4.5-blindol-4-amine (54d) (2.7 g, 80% vield) AcOH salt as a pale yellow solid; 'H NMR (300 MHz, DMSO-ds) 6 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 (5. 3H), 1.91 (5. 3H). Step-4: Preparation of fert-butyl 2-(4-arnino-8-methoxy-9H-pyrimide[4,5-bindol-9- vhacetate (54e) Compound S4e was prepared according to the procedure reported in step-2 of scheme-16, from 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 fert-butyl 2-bromoacetate (1.471 mL, 9.95 mmol), Cs2C0: (6.80 g, 20.86 mmol), stirring at RT for 15 h, followed by the addition of tert-butyl 2-bromoacetate (1.401 mL, 9.48 mmol), K2CO: (1.31 g, 9.48 munol) and stirring for 3 h. The solid separated was filtered and dried to give ferr-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9- vhacetate (54e) (1.87 g, 60% yield) as a pale vellow solid: 'H NMR (300 MHz. DMSO-de) § 8.28 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H). 7.26 (s, 2H), 7.20 (t..7 = 7.9 Hz, 1H), 7.01 (d, J= 8.0 Hz, 1H), 5.19 (s, 2H), 3.89 (s, 3H), 1.42 (s, 9H). Step-35: Preparation of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) Compound 54f was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4.5-b]indol-9-yl)acetate (54¢) (0.9 g. 2.74 mmol) using 20% TFA in DCM (15.73 mL, 41.1 mmol)) and stirring at RT for 16 h. This gave after workup afford 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) (0.46 g, 43% vield) TFA salt as a white solid; 'H NMR (300 MHz, DMSO-ds) & 8.51 (s, 1H), 8.20 (s, 2H), 8.05 (d.J=7.9 Hz, 1H), 7.32 (t. / =8.0 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 5.32 (s, 2H). 3.92 (s, 3H). Step-6: Preparation of (1R.38,5R)-2~(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9- yhacetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (54g) Compound 54g was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4~amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34f) (75 mg. 0.194 mmol) in DMF (2 mL) using TFA salt of (1R.3S,5R)-N~(6-bromopyridin-2-yt)-2- azabicyclof3.1.0]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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,3$,5R)-2~(2-(4-amino-8-methoxy-9H-pyrimido[4.5-bJindol-9-vl)acetyl)-N-(6- bromopyridin-2~y1)-2~azabicyclo[3.1.0]hexane-3-carboxamide (54g) (85 mg, 82% yield) asa white solid; "H NMR (300 MHz. DMSO-d) 3 10.74 (s. 1H, D20 exchangeable), 8.60 (s, 1H), 8.37 (s, 2H, D20 exchangeable), 8.08 (d, J= 7.9 Hz, 1H), 8.02 (d,J=8.2 Hz, 1H), 7.71 (tJ = 8.0 Hz, 1H), 7.40 ~ 7.24 (m, 2H). 7.15 (d. J = 8.0 Hz, IH), 5.81 (d, J = 17.0 Hz, 1H). 5.59 (d.J=169 Hz, 1H), 4.43 (dd, J=18.9, 5.6 Hz. 1H), 3.94 (5. 3H). 3.85 (td, / =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 = 53,24 Hz. 1H). MS (ES+): 336.1 (M+1); (ES-): 534.1 (M-1); Analysis calculated for C2aH2zBeN-0:.2H20. [HCL C, 47.34: H, 4.47: C1, 5.82: N, 16.10; Found: C, 47.34; H, 4.40; Cl, 548: N, 15.94. Scheme 55 Nad 8a Me HATU, DIPEA - H | Hy 8 N, , J Cr 8a Ca ee HATU, DIPEA I’ rs N, Me NH 4: ts NOM N. A NH; 30e oc 58a Preparation of (1R,38,5R)-2-(2-(4-amino-8-methy]-9H-pyrimido[4,5-blindol-9-yl)acetyl)-N- (6-bromopyridin-2-v1)-3-methyl-2-azabicvelo[3.1.0]hexane-3-carboxamide (55a) Compound 55a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2~(4-amino-8-methy!-9H-pyrimido[4,5-b}indol-9-yl)acetic acid (30e) (50 mg. 0.135 mmol) in DMF (2 mL) using 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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g). eluting with DMA-80 in DCM from 0 - 100%) followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R.38.5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N~(6- bromopyridin-2-yl1)-5-methyl-2-azabicyclo[3.1.0]hexane-~3-carboxamide (55a) (47 mg, 65% yield) HCl salt as a white solid; 'H NMR (300 MHz, DMSO-de) 5 10.75 (s, 1H, D20 exchangeable), 8.51 (s, 1H), 8.35 (s, 2H, D;0 exchangeable), 8.24 (dd, / = 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, IH). 431 (dd. J=9.0, 6.1 Hz, 1H), 3.63 (dd, / = 5.6. 2.3 Hz, IH), 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,.]= 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); Analysis calculated for C2sH24BrN-Q» 1.5H20.0.9HCL: C, 50.53; H, 4.73; Cl, 5.37: N, 16.50; Found: C, 50.38; H, 4.74; C1. 5.68: N. 16.43. Scheme 56 Me MH AcOH EtN NH Cul, K;CO4 by [com N i H ~ Rents Cul, K, CF, H HNN, x, an HNTSNH CO Ne Na ACOH 1 Me Or (CF4C0),0 EN NH, : 56a 58h 56¢ 56d H \ [ al f AN N. 4a ‘BuQ;C” Br Na Ny. TRA no JNO vO d w@ ¢ Vem cco NN CNA YY hat DeEA (ood 1 0 7D NHMé s6e 86f Te. 589 Preparation of (IR,38,5R)-2-(2-(4-amino-~5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N~ (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (56g) Step-1: Preparation of 2,2,2-trifluoro-N-(2-iodo-3-methylphenyl)acetamide (56b) Compound 56b was prepared according to the procedure reported in step-1 of scheme-46, 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 acid anhydride (4.47 mL, 32.2 ramol) and stirring at RT for 16 h. This gave after workup 2.2.2-trifluoro-N-(2-iodo-3- methylphenylacetamide (56b) (6.9 g, 21% yield) as a pale yellow solid and was used as such for the next step; "H NMR (300 MHz, DMSO-~ds) 6 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). Step-2: Preparation of 2-amino-4-methyl-1H-indole-3-carbouitrile (56¢) Compound S6¢ was prepared according to the procedure reported in step-1 of scheme-11, from 2,2,2-trifluoro-N-(2-iodo-3-methylpheny 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), Cul (0.284 g, 1.489 mmol) K>CO: (4.12 g, 29.8 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOz gel (80 g), eluting with EtOAc in hexane from 0-50%] 2-amino-4-methyl-1H-indole-3-carbonitrile (56¢) (0.81 2, 32% vield) as a brown solid; ’H NMR (300 MHz, DMSO-d) 6 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). Step-3: Preparation of S-methyl-9H-pyrimido[4,5-blindol-4-amine (56d) Compound 56d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-4-methyl-1H-indole-3-carbonitrile (56¢) (0.8 g, 4.67 mmol) in ethanol (30 mL) using formamidine acetate (3.93 g. 37.4 mmol) and refluxing for 22 h. This gave after workup and purification by reverse-phase column chromatography [C18 column (275 g). eluting with ACN in water (containing 0.1% HCI) from 0-100%] to afford 5-methyl-9H- pyrimido[4,5-blindol-4-amine (56d) (114 mg, 12% yield) HCI salt as a pale yellow solid; 'H NMR (300 MHz, DMSO-ds) & 13.15 (s, 1H). 8.65 (s, 1H), 8.03 (s, 2H), 7.49 ~ 7.32 (m, 2H), 722-705 (mn, TH), 2.94 (s. 3H); MS (ES+): 199.10 (M+1). 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 according to the procedure reported in step-2 of scheme-16, from HCI salt of 5-methyl-9H-pyrimido[4,5-bJindol-4-amine (56d) (110 mg, 0.469 mmol) in DMF (3 mL) using tert-butyl 2-bromoacetate (0.076 mL, 0.516 mmol) Cs2C0s (336 mg, 1.031 mmol) and stirring at RT for 1.5 h. This gave after workup ferf-butyl 2-(4-amino-3- methyl-9H-pyrimido|4,5-bJindol-9-yl)acetate (56e) (130 mg, 89% yield) as a pale yellow solid; 'H NMR (300 MHz, DMSO-d) 3 8.27 (s, 1H), 7.42 — 7.24 (mn, 2H), 7.04 (d, J=7.1 Hz, 1H), 6.79 (s. 2H), 5.11 (s. 2H). 2.96 (s, 3H), 1.41 (5, 9H); MS (ES+): 313.20 (M+1) Step-5: Preparation of 2-(4-amino-3-methyl-9H-pyrimido[4,5-b|indol-9-vlacetic acid (56f) Compound 56f was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-S-methyl-9H-pyrimido[4,5-b)indol-9-yl)acetate (56e) (100 mg, 0.320 mmol) using 20% TFA in DCM (1837 pL, 4.80 mmol)) and stirring at RT for 16 h. This gave after workup 2-(4-amino-3-methyl-9H-pyrimido[4.5-blindol-9-yl)acetic acid (56f) (115 mg, 97% vield) TFA salt as a white solid: MS (ES+): 257.10 (M+1). Step-6: Preparation of (1R,38,5R)-2-(2-(4-amino-5-methyl-9H-pyrimido[4.5-b]indol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicy¢lo[3. |. 0]hexane-3-carboxanmde (56g) Compound 56g was prepared according to the procedure reported in step-3 of scheme-1., from TFA salt of 2-(4-amino-5-methyl-9H-pyrimido[4,5-blindol-9-yl)acetic acid (56f) (50 mg, 0.135 ramol) in DMF (1.5 mL) using TFA salt of (1R,3$,5R)-N-(6-bromopyridin-2-y1)-2- azabicyclof3.1.0Thexane-3-carboxamide (4a) (53.5 my, 0.135 mmol), HATU (77 mg, 0.203 mmol), DIPEA (0.118 mL, 0.673 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2-(2~(4-amino-5-methyl-9H-pyrimido[4,5-blindol-9-y])acety])-N~(6- bromopyridin-2-yl)-2-azabicyclo[3. 1 OThexane-3-carboxamide (56g) (34 mg. 48% yield) HCI salt as a white solid: '"H NMR (300 MHz, DMSO-de) 5 10.76 (s, 1H, D»0 exchangeable), 8.60 (s. 1H), 8.01 (d, . / = 8.2 Hz, 1H), 7.79 - 7.65 (m, 3H, 2H D:0 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). Scheme 57 CF, ©CFco0 © JH EtsN bo Cul, K,C03 MeO CFy H HN HaN TY SP com en 2 A 0 (CFC0);0 TN AN EtN a Cul, KCO, Ph Med Med Med 57a 57c CO, Bu N Fi ANS SN ~ AN N= TFA HN NH, ry Br” “CO,Bu #3 JPA, eon wat LA. 3 ,CO; HN AcOH HN Ja) CsCOs bb 57d §7e o ol / M NN Aa i Oy vl Ao © w / a 2, -N, 6 J Ny 4a == L: J HATU, DIFEA HoN Ral §7F 2.4 57g Preparation of (1R,38,5R)-2-(2-(4~amino-5-methoxy-9H-pyrimido[4.5-blindol-9-yDacetyl)- N-(6-bromopyridin-2-y1)-2-azabicyclo[3. 1 O]Jhexane-3-catboxamide (37g) Step-1: Preparation of 2.2,2-trifluoro-N-~(2-iodo-3-methoxyphenyl)acetamide (57b) Compound S7b was prepared according to the procedure reported in step-1 of scheme-46, from 2-iodo-3~-methoxyaniling (87a) (5 g. 20.08 mmol; CAS # 98991-09-4) in DCM (75 mL) using triethylamine (4.76 mL, 34.1 mmol), trifluoroacetic acid anhydride (4.19 mol, 30.1 mmol) and stirring at RT for 16 h. This gave after workup 2,2,2-trifluoro-N-~(2-iodo-3- methoxyphenyl)acetamide (57b) (6.8 g, 98% yield) as a dark oil and was used as such for next step; MS (ES-): 343.90 (M-1). Step-2: Preparation of 2-amino-4-methoxy-1H-indole-3-carbonitrile (57¢) Compound 57¢ was prepared according to the procedure reported in step-1 of scheme-11, from 2,2.2-trifluoro-N-(2-iodo-3-methoxyphenyhacetamide (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), Cul (0.281 g, 1.478 mmol), K2COs (4.12 g, 29.8 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification by flash column chromatography [SiO: gel (80 g), eluting with EtOAc in hexane from 0-30%)] 2-amino-4- methoxy-1H-indole-3-carbonitrile (57¢) (1.35 g, 49% yield) as a gray solid: 'H NMR (300 MHz. DMSO-de) § 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 (5. 3H): MS (ES+): 188.10 (M+1); (ES): 186.10 (M-1). Step-3: Preparation of 5-methoxy-9H-pyrimido[4.5-bJindol-4-amine (57d) Compound 57d was prepared according to the procedure reported in step-2 of scheme-29, 2- amino-4-methoxy-1H-indole-3-carbonitrile (57¢) (1.3 g, 6.94 mmol) in ethanol (45 mL) using formanmidine acetate (5.84 g, 55.6 mmol) and refluxing for 22 h. This gave after workup and purification by reverse phase column chromatography [C18 column (275 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] 5-methoxy-9H- pyrimido[4,5-blindol-4-amine (57d) (0.9 g, 61% yield) HCl salt as a pale yellow solid; 'H NMR (300 MHz, DMSOQ-ds) § 12.97 (s, 1H), 8.60 (s, 2H), 8.35 (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); Step-4: Preparation of tert-butyl 2-(4-amino-3-rmethoxy-9H-pytimido[4.5-b]indol-9- vhacetate (57¢) Compound 57e was prepared according to the procedure reported in step-2 of scherne-16, from HCI salt of 3-methoxy-9H-pyrimido[4,5-bindol-4-amine (57d) (810 mg, 3.23 mmol) in DMEF (20 mL) using tert-butyl 2-bromoacetate (0.525 mL, 3.55 mmol). Cs2C0s (2316 mg. 7.11 mmol) and stirring at RT for 1.5 h. This gave after workup tert-butyl 2-(4-amino-3- methoxy-9H-pyrimido[4,5-blindol-9-vl)acetate (57¢) (990 mg, 93% vield) as a pale vellow solid: '"H NMR (300 MHz, DMSO-de) § 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 (5, 3H), 1.41 (s, 9H): MS (ES+): 329.20 (M+1). Step-3: Preparation of 2-(4-amino-5-methoxy-9H-pyrimide[4,5-bJindol-9-yDacetic acid (57f) Compound 57f was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-5-methoxy-9H-pyrimido[4,5-blindol-9-yl)acetate (57¢) (200 mg, 0.609 mmol) using 20% TFA in DCM (3496 pL, 9.14 mmol)) and stirring at RT for 16 h. This gave after workup 2-(4-amino-3-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) (225 mg. 96% vield) TFA salt as a white solid; 'H NMR (300 MHz, DMSO-ds) 6 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). Step-6: Preparation of (1R.38,5R)-2~(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9- yhacetyl)-N-(6-bromopyridin-2-y1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (57g) Compound 57g was prepared according to the procedure reported in step-3 of scheme-1, from 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 TFA salt of (1R,3S,5R)-N-(6-bromopyridin-2-y1)-2~ azabicyclof3.1.0]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 RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g). eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (1R,38,5R)-2~(2-(4-amino-5-methoxy-9H-pyrimido[4.5-bJindol-9-y)acetyl)-N~(6- bromopyridin-2~y1)-2~azabicyclo[3.1.0]hexane-3-carboxamide (57g) (35 mg, 50% yield) HCl salt as a white solid; 'H NMR (300 MHz. DMSO-de) 3 10.74 (s. 1H, D20 exchangeable), 8.53 (s, 1H), 8.42 - 8.19 (m, 3H, 2H D;0 exchangeable), 8.02 (d, J = 8.2 Hz, 1H), 7.71 (1, J = $.0 Hz, 1H), 7.33 (d, / = 7.7 Hz. 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.04 (dd. J = 8.7, 2.2 Hz. 1H), 571(d,J= 17.2 Hz, 1H), 5.42 (d.J = 17.2 Hz, 1H), 442 (dd, J = 9.0, 5.6 Hz, 1H), 3.97 — 3.86 (mn, 4H). 2.28 (m, 2H), 1.99 = 1.86 (m, 1H, 1.08 (m, 1H), 0.81 ~ 0.70 (m. 1H). MS (ES+): 336.1 (M+1); 558.1 (M+Na); (ES-): 534.1 (M-1); Analysis calculated for C2aH2:BeN-0: 1.5H:0. IHC C, 48.05: H, 4.37; CL, 5.91; N, 16.34; Found: C. 48.01; H, 4.33; Cl, 597: N, 16.16. Scheme 58 [CH5(CH2)3)aSnC(OC He )=CH, LiOH, Pd(PPhs)s A 3 NH, ot NH, 48a 58a HH da ary H Ney 4 © 2 HATU. DIPEA NH, 2 H = Br 3 Fei 0 hy 0 NH, 580 NH, 58¢c Preparation of (1R,38,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-blindol-9-yDacety])-N- (6-bromopyridin-2-yl)-2-azabicvelo[3.1.0}hexane-3-carboxamide (58¢) Step-1: Preparation of ethyl 2-(6-acety]-4-amino-9H-pyrimido[4,5-b]indol-9-yDacetate (58a) To a suspension of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-blindol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in toluene (8 mL) was added tributyl(]-ethoxyvinyl)stannane (0.279 mL, 0.802 mmol) and the mixture was degassed and filled with nitrogen followed by addition of Pd(PPhs)s (132 mg, 0.115 mmol) and heating for 14 h at 120 °C. Reaction mixture was cooled to RT. diluted with ethyl acetate (150 mL), treated with IN HCI (30 mL), water (30 mL) followed by stirring at RT for 15 min. The mixture was treated with 2 M K»CO3, extracted. and separated. The organic layer was washed with brine (60 mL), dried. filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatograph [silica gel (24 g), eluting with methanol in DCM (0-5%)] to afford ethyl 2-(6- acetyl-4-amino-9H-pyrimido[4,5-blindol-9-yl)acetate (58a) (20 mg. 11% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) & 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, 2H), 5.29 (s, 2H), 4.14 (gq, J= 7.1 He, 2H), 2.71 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H): MS (ES+): 313.10 (M+1). Step-2: Preparation of 2-(6-acetyl-4-amino-9H-pyrimido[4,5-blindol-9-y1)acetic acid (58b) Compound 58b was prepared according to the procedure reported in step-4 of scheme-17, from ethyl 2-(6-acetyl-4-amino-9H-pyrimido[4,5-blindol-9-yDacetate (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 stirring at RT for 14 h. This gave after workup 2-(6-acetyl-4-amino-9H-pyrimido(4,3-blindol-9-yvl)acetic acid (58b) (17 mg, 100 %) which was used as such in next step-3 without further purification; MS (ES+): 285.10 (M+1), (ES-): 283.0 (M-1) Step-3: Preparation of (LR38,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9~ yhacety!)-N-(6-bromopyridin-2-v1)-2-azabicyclo[3.1.0]hexane-3-carboxamide (58¢) Compound S8¢ was prepared according to the procedure reported in step-3 of scheme-1, from 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yacetic acid (58b) (17 mg, 0.058 mmol) in DMF (8 mL) using HCI salt of (1R,38,5R)-N=(6-bromopyridin-2-y1)-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 stirnng at RT for 20 h. This gave after workup and purification by flash coluron chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%) followed by conversion of product obtained to HCI salt by dissolving in acetonitrile (2 mL) and 0.1% ag. HC! (15 mL) and lyophilization (1R,3S,5R)-2-(2-(6-acetyl- 4-ammo-9H-pyrimido[4,3-b]indol-9-vDacetyl)-N-(6-bromopyridin-2-y1)-2- azabicyclof3.1.0]hexane-3-carboxamide (58¢) (27 mg. 85% vield) HCI salt as an off-white solid; 'H NMR (300 MHz, DMSO-ds) § 10.76 (s, 1H, D>0 exchangeable), 9.09 (d, J = 1.6 Hz. 1H), 8.73 — 8.50 (m, 3H. 2H D20 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 (mn, 1H), 1.14 ~ 1.01 (m. 1H), 0.89 — 0.71 (ro, LH); MS (ES+): 548.10 & 550.10 (M+1): MS (ES-): 546.00 & 548.10 (M-1). Scheme 59 o oA [A IN. i Pd(PPha)s NN HOH, KoCO3 MN A vo Br NH; » NH, 48a 59a H Q Ne, Ji atl ie! 5 Nes” o no “Nia HATU, DIPEA & . ~N Bi. NN 0) N= NH, NH, A8b 50c¢ Preparation of (1R,38,5R)-2-(2-(4-amino-6-vinyl-9H-pyrimido[4,5-b)indol-9-y1)acetyl)-N- (6-bromopyridin-2-v1)-2-azabicyclo[3.1.0thexane-3-carboxamide (59¢) Step-1: Preparation of ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-blindol-9-yl)acetate (59a) To a degassed solution of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-blindol-9-yl)acetate (482) (200 mg, 0.573 mmol) in dioxane (8 mL) was added potassium vinyltrifluoroborate (153 mg, 1.146 mmol), Pd(PPhs)+ (132 mg, 0.115 mmol). a solution of K2CQOz (158 mg, 1.146 mmol) in water (2.3 mL) and heated at 80 °C for 20 h under nitrogen. The reaction mixture was dilated with ethyl acetate (100 mL), washed with water (50 mL), brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel (25 g) eluting with 10% methanol in ethyl acetate in hexanes from 0 — 50%] to afford ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4.5-blindol-9- vhacetate (59a) (82 mg, 48% yield) as a light vellow solid; "H NMR (300 MHz, DMSO-d6) 58.49 (s. 1H), 8.28 (s, 1H). 7.56 (d. J= 8.5 Hz, 1H), 7.50 (dd, / = 8.8. 1.5 Hz. 1H), 7.38 (s, 2H). 6.84 (dd. J=17.7, 11.0 Hz, 1H), 6.03 — 5.95 (m, 1H), 529 - 5.16 (m...

Claims

CLAIMS What is claimed is: 3 A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof: Ra J 3, R3 : | N ~~ 0 . Ay R2 m: wherein, independently for each occurrence: X is a bond or C(R¥)z; Y is a bond. C(RY)2. or ~N(RP) ~: Gis S or C(RY):2; Ra and R® are each independently H or (Ci-Ce)alkvl; R! represents optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl; R? represents optionally substituted bicyclic or tricyclic heteroaryl; R'is independently for each occurrence H, halogen, ~CN, ~NHz, ~CH:2NHz, (Ci- Ce)alkoxy or (Ci-Ces)alkyl; or two vicinal occurrences of R? taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C3-Cr)eveloalkyl or (Ce)arvl: or two geminal occurrences of R? taken together with the carbon atom to which they are bonded form an optionally substituted spiro (C3-Cr)eycloalkyl: or two hominal occurrences of R? taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (Ca-Cr)cycloalkyl; R¥ is independently for each occurrence H. (Ci-Ce)alkyl, or (C:-Cr)eyeloalkyl; RY is independently for each occurrence H, (Ci-Co)alkyl, or (Ci-Cr)eveloalkyl; or an occurrence of RY and a substituent on R? taken together with the intervening atoms form a ring; optional substituents on R! or R? each independently represent halogen, CN, =NOa, ~ORY, ~NR¥R!" ~C(O)RE, ~C(O)OR?, ~C(O)NRERM™, ~OC(0)R, ~NREC(0)RY, ~OC(O)NRERY ~0CO)ORY, ~NREC(O)ORH, —NRBC(O)NR7RM, —0S(0)p(R). -SR'? —=NRPS(0)x(R'), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxvalkvl. aryloxvalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl. aryloxy, cycloalkyl, (cycloalkylalkyl, heterocycloalkyl, or (heterocycloalkylalkyl: or wherein two substituents on R! or two substituents on R?, taken together with the intervening atoms, form a ring: R™ and R™, independently for each occurrence, represent H or optionally substituted alkyl. haloalkyl. alkenyl. alkvnvl. aryl, or heteroaryl: and pis0,1,0r2. Z The compound of claim 1, wherein Y represents C(RY):.

3. The compound of claim 1 or 2, wherein Y represents CHa, 4. The compound of any one of claims 1-3, wherein X represents a bond. § The compound of any one of claims 1-3, wherein X represents CHa.

6. The compound of any one of claims 1-5, wherein R! represents optionally substituted aryl or heteroaryl. 2 The compound of any one of claims 1-5, wherein R’ represents optionally substituted heteroaryl.

8. The compound of any one of claims 1-3, wherein R! represents optionally substituted phenyl (e.g., 3-halophenyl. or 2,3-dihalophenyl), (C:-Cs)eycloalkyl, alkenyl, pyridinyl (¢ g., 6-halopyridin-2-yl), or pyrazinyl (e.g., 6-halopyrazin-2-yl).

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

10. The compound of any one of claims 1-7, wherein R! represents optionally substituted pyridinyl.

11. The compound of any one of claims 1-7 and 10, wherein R! represents optionally substituted 2-pyridinvi. 12 The compound of any one of claims 1-7. 10, and 11, wherein R! represents WN Br oJ 13. The compound of any one of claims 1-6, wherein R! represents optionally substituted phenyl. F < 14. The compound of any one of claims 1-6 and 13, wherein R! represents 15. The compound of any one of claims 1-14, wherein R? represents : zi 100 2 n 2 7 7 zz! Ea I I PY \ RA) (Rn | SZ 75 x 10) FNS , Rm or 2 x >, Ol ~ (Rm, Z' represents N or CR'%; Z% represents N or CR%%; Z? represents N or C: Z* represents N or CR*; 7° represents N or CR; Z8 represents N or CR%Z; 27 represents N or CR%; Z8 represents C; 2° represents N or C; k is an integer from 1-4; m is an integer from 1-3; and each occurrence of RY, R?Z RZ R¥ R® RZ R independently represents H, halogen, ~CN, ~NO,, ~ORB, ~NR¥RM, ~C(O)RY, ~C(O)OR3, ~C(O)NRERM, ~OC(O)R!, ~NRBEC(O)RH, ~OC(O)NRERY, ~OC(0)OR, ~NREC(0)ORM, —NRBC(O)NRIRH, —QS(0)p(R), -SR'?, -NRBS(O)p(R'), or optionally substituted alkyl, alkenyl. alkynyl. haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, arvloxyalkyl, aralkyl, heteroaralkvl, heteroaryl, aryl, aryloxy, cvcloalkyl, (cycloalkylalkyl, beterocyeloalkyl, or (heterocyeloalkylalkyl: or wherein an occurrence of R% and an occurrence of R™ taken together with the intervening atoms form a ring; or wherein an occurrence of RY and an occurrence of R* taken together with the intervening atoms form a ring.

16. The compound of claim 15, wherein 2°, Z°, Z*, and Z° represent N.

17. The compound of claim 15, wherein Z*, Z*, and Z¢ represent N.

18. The compound of claim 13, wherein Z°, Z*, and Z° represent N.

19. The compound of claim 15, wherein Z* and Z* represent N.

20. The compound of claim 15, wherein Z*, Z?, Z%, and Z° represent N. won, cr nas 52 / ~ NA ~~ \ RZ <= 21. The compound of claim 15, wherein R? represents (Rx, 22. The compound of claim 21, wherein R? represents oar rt RR, Sg % its.

23. The compound of claim 21 or 22, wherein k represents 2. wh, ad 52 7 ~Y NA 5 24. The compound of claim 15, wherein R? represents R7% Li wh, RENN hi | wn Naw / 25. The compound of claim 15, wherein R? represents R7* RZ on, 52 7 A N CX) N 26. The compound of claim 15, wherein R? represents R# wh, 27. The compound of claim 26, wherein R? represents NH; A 5; id RY PLN NN az Nan A " I Tid bp 7z RZ 28 The compound of claim 15, wherein R? represents R : on, RZ N { hid N, Nog Ad 17.

29. The compound of claim 15, wherein R? represents RZ R 1 Aa, N N z= | NH, 30 The compound of claim 29, wherein R? represents 31. The compound of any one of claims 13-21, 24-26, 28. and 29, wherein RZ represents ~NRERM™.

32. The compound of any one of claims 15-21, 24-26, 28, and 29, wherein R™ represents —NH:.

33. The compound of any one of claims 15-20, wherein R% represents ~C(O)R*, —C(O)OR, —C(O)NRURY, or hydroxyalkyl.

34. The compound of any one of claims 15-21, 24-26, 28, and 29, wherein R* represents alkyl, halo, or ~NRR, 35. The compound of any one of claims 15-20, 25, 28, and 29. wherein R'® represents ~ CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, ~C(O)R*, ~SRY, ~-NRUR!, ~OR*, ~C(0)OR™, ~C(Q)NR“R™, or “NREC(O)RM, 36. The compound of any one of claims 15-24, wherein each occurrence of R* independently represents —CN, “NO, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, ~C(O)RY, ~C(O)ORY, -NRPC(O)OR™, ~SRY, -NRURM, ~OR, ~C(O)NRERHM, or -NREC(O)RM.

37. The compound of any one of claims 1-36, wherein G is C(RY). 38 The compound of any one of claims 1-37, having the structure of formula (Ia): RS R3 [=&] 8 " R! } w R NX x }] O Ag R2 (la).

39. The compound of any one of claims 1-38, wherein two vicinal occurrences of R? taken together with the carbon atoms to which they are bonded form an optionally substituted fused Cs~cyeloalkyl.

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

41. The compound of any one of claims 1-39, wherein at least one occurrence of R? is fluoro.

42. The compound of any one of claims 1-39, wherein at least one occurrence of RY is methyl, 43. The compound of any one of claims 1-39, wherein two vicinal occurrences of R® taken together with the carbon atoms to which they are bonded form an optionally substituted fused Ca-cycloalkyl and another occurrence of R® is methyl.

44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the following table: J J 9 | # Structure # Structure 75d ~ 24a 1 oN Ng or | ~~, © Tr rr | oe NHCH; NH, Qu, TT nN N. XN , 50f } i Naw, Br yd Ar NHCH; NH, F 77b / BN 157a K H CA _N__Br \ % ® OU Sy NN. C0 OH NH, / M Z H NANA Ng Br | ATL A . | oe NH, 78a ar ey 158e java A of Co “ H py ho o Pa Ai 0 \ © F ® N mY, © z N, oN, LX Con CNH; NH, 79a Pr 32 2 W N N. 7 Br AY CN 5 H New Br TV 7 AN ! N Se NH; NN (> (< 3” F NH; ¥ 80a ~~ 43a wr. Hn Br Cy Ng.-Br AT N (YO A . i. NN / Lo 1 A NH, NH; 81a Pa. Co asf i pd AY rl “1 Ng {8 b Z oe fee dai NH, Ly 82a A~ 30f 3 Ron Br | N \ Koo 0 he Ff fo 7 NT - N ro N J NHCH; Nas Nkd NH, 83d Zt | 4g pee Br # So hv N \ 2 © 97) coocH, ~~ NH, : i Ns ¥ a Lr Ho Na Br YT a Joe oN I _ NN COOCH; 1 NH, 7 HN 84a Ey 48d i BE cap alBF BE H ATO" 0 ZF N © Ll oh le ( o Ts 850 op ' 38e OS 2 y H 0 & N © N co NH, . So Ne 0 LY 3 NH, OMe 86h mm BN 51g A I oy | ( NH, 5 H = Br CJ a New N NH, | Le yy 87fF 2 Mr 52f % H o ZZ N 0 HNN, 1 AJ NH, N No © ~ 0 New N NH, 88f Pry 54g H OL A To a ® g5 _ 3 Hy "0 H; 2 89h | Pop ' Ada HH wy Br ~~ I N N Ny Br | ATL A ww FEN NN ha ae) 5 NH; 2 CoH “ood — Ye wy RB ey d Naw Br LC % H N N Or Br | y ~~ oC Z ~~ oo Ao | on Fe So * To Ne : 4% NH, N= = NH; 91a 91a 4" 22 d wy Br rN PY 2c an pr HONE 22d 2 H x Br Ohl = N Me ~o of No.N ~ IT ™ > NN oh oro ve Ney CT ve NH, (+) and (-) isomer 92b 4 2 330 ro. % H Q ZZ N Q av a ~ 0 HNN NY oF Le A v F NH, 1" Or NH; E 93a % 49¢c SI, ~~ £ 3 N § H N° A WANA | YY {0° NA N Ny—N, N NH, } } NH, oN NH; NH; wl rrr ed rr —— - Bi SQ / Ne-N 5 Cr NH; NH, 95¢ Lr 59¢ I SK “ \ ry NN (30 hos ST Ne low A 17f 4 Hoong oY ~v av gre No NH; ow N Sy fr Cr N= NHBoc NH- NH, 97b oi Poy 18a my yr I q Nao Br Ao 4 Ne -N 'S Cx NH, fi 7 N rt NA \ NH NL == NH, 98h Poe 31f H A, 0 Ao © / Ng N, (Le N A N NH, £ N ne N A NH, N= 99h 2" 60c 47 H N Ny AoC : ~o oA Ny oN, S NH, S| N N ¢ Bs NH, NH; o 100b 5 = 2 61a 2 HH oy RNs 0 a AT oA NH, ff NyN, mY No ~N NH; I 101b | Pp ie 129f oy 129f Nia TNL 101b H A SAO ~~ << 1 H LY - rr rS No Ns N Le LY NH, \ NH, 102b | 2 ' aeg 102b 3 4 = : HN or 6g Br H a HS la A ” ~~ 8 5 N Ns” OF 0 oN N, Ne. eX TY Nex a= NH; COOCH;CHa f Ng N (Le NZ NH; 103b | om Clo 62¢ 2 cl ci of A, o i Ms YO I NeN, mY» NN NH; 7 NN 4, NH, 7 Fa TTT oH NB Cer Hn B WO % AG, AY * | fo 7 N N, N " Je a ' Hy NH; NH; { NH» 105b | Ss al 53d H YN Sofi / 8 NID A, 0 i f: No N N Cx NH; NH, Ng N x NH; NH, 107b | Lr 56g my H Br a Na gee 4 H . W Or 3 5 0 N NH, N, N. = N ( ! (0 NH, tie 108b | fr 57g + c 57g OS Na Br X H ¥ a) J Ao oN 1 NeyN, 'S Lx NH, Ra NH, O_ Fee TT OS 159 7 Cong! " ’ NN, 'S 0x NH, N : Nil OMe NH; 110d | F ' 160a He 110d F, 160a * t a amet Ho Br 3 H A, AO F A, 0 Ff NN 2 NS if Dr {Ld NH, NN 30 Ls vo Br NH. Su WC LI YY Th WZ Ao F: Ne? Ao x £1 A 0 NaN g Cy A Ne Ny! 7 N, NH, N. = NH _ _ -— ln 112b | Por 172a ¥ Qu 72a Ho NB ” NN 8 TA «J | ra’ Qo J ee by \ J Ao f NaN, S Sel NH, nd Lo NH 0 Nt NH; O CH; Br . HN DY N H { | AL, Ao § F In © alia i! Ny, (Le NAAN NH, OO joi Ch ¢ > ~ Hs 161a 1 120c <L A, LL 4 § A No—N 'S [5 NH, NH, 121d | 4 174g INF; oT FT TT Tem TTT ee ae ee ot Ay 0 No H A CL \, N. ; YN A, TY Nes Br Px A> (50 Ned J NaN, S [£2 NH. NH, 122¢ ET ' 175%a MH Fol = Bf . | Oy 5 NaN, x NAN NH, Bi 0 CF; OTN N_ / NH, ] Br 176a y ey : ., - oF vy NTT x Lp of (3D NH, Sr 118a | % 169f wy Br A ol N FO IL -0 NH, vn | af Tard “No, 17d v5 um CT ~ 4 Ne, Br ~ YJ A Lv Hy ge, [ ia Ns N 0 NH, ‘ CF, 9 NC, 116b 5 ob 178d oN - eH NG WY al Ao oo rr N._~ NH; CF3 Arlo Br y H cl 162g x HN 115e fi : 3 ( p CA Ao o A © - lr N__N oy NH, 114f F cl 163g ” H Br EL a Ns hy ~~ cl No. H N N. Q ~~ NG 0 NH, =N Sonal _ 113a | i 164a H AY Or / Ny —N (Xe | No NH, NH» 66h | Ba ZN 1 165a ; 4 u 165a ? oN N N Cl | NA 0 F N ~~ Ng N. 0 r~ N b O Or ” ZN J po | ox “y HN Wy : COH 124b 170c 2" | a) HN | H 170c 1 u 3 By yy As | (0 doo se Or To HN Fi ih © nb gy 68a | E 'o179d F Cn Ns - . wy A t £ H N N Ba Cyr e © Z \ / NN, (Le N_ AN NH, N \ | Oo So (3X N Nl Ye CFy NH, iz T ty x 1 67c ; | 180e HN, . ~~ 8 re NY \ / oe Ao © PW, 0 3 NN, 1 > NAN NH, No De No NH, CF 65a : 166a B IN 166a rp H ~ qx 5 CA N Cl 0 N.. 0° Ny Ay NH, JAY = NH; Ny | NH, OH 64a F 167a ew Ww wy Br F 5 2 H < Br A Ao A E ! ! vi 130e | 4 RN 168g mH Ny o gy Ns No © A N, | ov Ny 5 NF NH; 130e FE 168g mr HON Br Cn Eo NN No 0 - Br ay 5 SAA LI NH, rr Re NSN “0 Ny NH, SX 4 ae (X NH, CN HN—( 'N dl 131e FE 18% Br 3 ” © wry Ho ONG AC WYN | oO F a c a H No Br 131e | F | 187 x OF <Y Sg” ~~ 0 F i NN © oY [0 0 i Na N Co NH, NH, 132d | Fy IN ! 188g id Sa = 132d ys 188g of Hone H "a, N Qu, | ONS | HCN, ro © F oN ° NN + HE 0 LE 4 Nh? Ne re ¢ N= NH, NO, Vip li a a cf 133b | E 195¢ iy MM P LO ) ro if a = os NY o IY NN ¢ \ NH "NH _ = N OH J NH, eed] 208 | | ! 1982 Loy y" Ao FF 1 7 6 4 “0 Wl ¢ 1 VA N Wi Nz AN NH, 134b | 5 N 199a W U 0 A J Wk L., NH, 1353 | kK BN 200a pp Nr ea Ie, NH (TO ( Pp Br NH, 136a | Fo RN 194a y 1 N N. ¢ \ Nas INTE CFa NH, 137b | F RN 201e . YY el ~~ HN, a H NB = WOU oO 0 ON rr © 7 NAA NHy CF; 140a | E Cl 211e HoNH,C 5 cl z oA Pants I E Cl SAH > N =, © N, ie Ad NI Hy SNH Non ra No NH, CF3 141a o Cl 212e HaNH,C, | F w I PN oA Hl 8 Ne BF al So NN IF Ta % F LIGH = © 0 0 a Ng J NaN, i "5 = NH NH, “SNH, CF, 138d ~ an 181a 1 hr. TL pha 138d 18% FE, aay i ® 1 Hog Br FE 7 R Hf ne WS he - hi © 0 ~ \Y So 0 N. N. B00 Naz ==N Lo ZZ NH, pr NH; NH; Coo 138b | FE 182a E z Cf Os & oyu NON oe NiLd — } / M NR d ATT . > ry | NAY NH, / 3 NH y TT. ATT. 5 F 4 H WA ~~ O A oO oY Lo SO F I NG N CU, Ng NH, F NH; © NH2 _ ids FE 22 126f F ow 207b ~A LT / IN, © AS ci Roo. H \ N. Oo 5 f, A, if N. N ob 0 i Ny—Br e Cr A HaN ¥ ory "OY oA N H E Ey 142d % Co 208d NM oH NLS t SNe = 0 F Lid HaC _N, | YS Ny N A NH, 143d | = Cl 203a 143d FE 2 cl i F. 00 N ~~ ° 8 Ney - Nex = _o NH, 7 “I Tf HN NH; ¢ 144 E cl 204a 8 | i ES w— HH Cl Tr JO N N. < ~~ a Cr any LJ 0 NH; i FF NH, Hn | | CH; 1453 | R 184g 2 - - H Naw Br Ao HN bo v Es, NH, CFy “ya5a | TF Tigsa TT OS A ~ 0 F a | ho fA rs Sd Sb WoT yr 0 No -N LM NH, ie 5 HN: Cm 146a | c Cl 186a F 3 E Cl S00 N N. A ° ct 147a | F of 206 ER NE . LE xX ¢ 0 NES) = NH, (OCH; NH, a0 | A, © Ny oN la | woo LID O NH ~h3 148d 5 209b E. J Suk 4 [2 Yl wm [Ty po ray o Te | spf NS ANIL LT HoN 0) N, | Ad NH, 19a F 210d 3 MN" 2 jo 4 N ~~ N Cr Ne | NN 3 A 4 Neer J HN HN wo) A a N © N HN wh 3b F 189g wr HH N Br F 3 oy H < Br Ag ° i ~, J ye ~ go fi NN QM \ | pad N_ AS! & { N | HN N= NH Me 1 0 SN eS _—— F 149b | 3 nN 193a H F 3 Ml PEN YY Ce (nT 1. 0 As oF Ag NeoN \ Br NH» i oO ort | | N Ad NH, J™NH 2 ab wu a Br 190a go Br ONY | Py [ Ad N No INS NH, Ed A 2 Na NH COE 2 wv 2} Newent | frre td Se F 191a 1 ow H YW ~~ hs or | r Bi |g (30 \ Ao Me l ro | n PN NH; NH; 150d | g ' 192g ie 150d E 192; - H Br % CR 8 2T\ N Nes J N YY ( Ye ~ Na (30 (_ oo Br i ae (Xe NH, Me NH, 69a F 196d \ NO oN ay N Non ATT \ Ng A Fr NH, HN, CH, Lisi 70a Mp 197¢ A NN NH, 2d Pa. 214b 2 N oo H Br a No N- N. J AL NH foes grmeemmereeeen em———— 7 = H N NE od UJ IN YL LY HN NH; 72a % 215g K H N NON gr xy N., 0 ox Ny 22 NH; ? 7 NH; I 9a 7 216g i a b 2 NT 3 &LOk Rs Cy” HoN C J : Wy J § A N. Me Na NH; CoMe 151a | F RN 217a 3 CAA 2 N » cl | —h 0 E A J rh | on LL O NH NH, 152d | E '220a wor rete boa TTT TTT Te 1 nN nr \ No Nay oO Pa H Bi Je Ho Ns™ oY J Ao v \ HOY W NA] cl N oe F TY pon Nod NH, A N COgH NTI NH, H 1e 7 Ho NaS 202a " Br o Ao © A h\ 0 0 Nes. N. (3D NZ NM NH, 3 NN ¢ \ Ne \ NO, NH, [1 ape HN LBP 205¢ ON N \_s Q Ao 3 NH; ie NH, vo oy (0 NH; Y CH, I R cl N F PN 0 Ao AJ CS N \ NZ \ Me NH, [ QQ oY C NH, COM N 2 Win NH, wis 2 rl | EOC TOO EEE 21a EF 236f F 3 NH = Na NH, 1 NN NE H ~ Tye | ~ = ’ | HN Me 73a | » ' 237a NH, Be | (J © NH RE 74a bed 238g en OH NE - i 75 H N N_N__Br Are | I ory | Nz J NH, i 1533 I 2 a 2393 tL 153a 5% cl 239a dm OH NB Via 3 Ho oNB LY N- sr . X av! oA 7 FE SO N N LY Co (0 NH, 4 NaN, ry N= J NH, / ~OH 27a sy As x LO Nag ™ xy A 296a | New N QQ Yug. CF3 NH, rE NH, rT a N, Me Ny NH; CFy 25a EB 2 240g a < Br DS / H Cl Ao 1 YL \ CFs NH, NH; NA Co NaN il 0 \_ / B NH; 3 nO 26a | £ bo2a1g 3 N N: H , CY | ~ = ’ | HN N, (TY Pr HN N = LN " CFy NH, 8b o oo 242a HH NH, NH, 28s - ~~! 283a A y 5 N \ Nt Nd CFy NH, rR, NH, 10b o . 244d Cody a = ro | “Ph Ne Naw NH, CH, NH; 11f i. oo 245a DS Ne ® IS Ao NH, rv He N. ~ NH; CF3 ve 12a - 42a - BN 2 Ho Ng A ha 2 Ho NG Noon 3 N 5 ~~ 0 0 4 Fo N. = NH. (oo A ¢_ CO,Me NH. ore Ly oS 1283 | pe— Hn Br | 36e © N gp (0 | U0 " = CF3 NH, o Bi 361 - H Br N N . 0 / I 0 7 - Bi TINNY ' N 3 7 0 NTO Q No Ng N oO A ¢ \ ( J OMe Ad NH. 154e | were Ha Br | 309f i Br 154e H N \ HON Bi 39f a x JA ., Nee 4 No Noa” rag TBE " of Ne ® i ; - - Ao 0 AV [I po Ns N Ne 2 0 N=, NH, SMe Lo COMe 346 ww RW we: BF 23f 2 so Ns” PS re Oy 30 C Me a NH; NH, rr 0 N “7 N Ny NH, he Br Dl a wy PE Ala 1 “aah | oo 4 .. Br 1 aa VY 13b — H a Br 40a 1 N Av 7 0 NH, A € nom NH, COMe LLzvie 14a E 156e ~~ F, ' 156e = * H o Z N © / Q@ N oI Ho NH, NH, ls] iy Lo Ne pb er. 15a were HM oa JB YY aged 2 H Na Br a ev! Ao HoN | Nee - CF, x a NH, tre Lo,Et 155¢ PR 41f gH K H AT o nN © i a N, oN OH NHp 2 ET PF 2 xd (yoo Nes 37a ~ nN 221¢ H WO I ) » ir SY (Oo NH, rr Lo] I HyCOGC 218a pH NBT 250b HCOCC ateadi FN {oN kl Ao 0) Q N ¢ i CN Na NH. NH, Co 2 rn NH, Yo NN Me as, Na ih COH even o | 223a yu mr 270a uo Br BH x JBr i pee Loyd «" Toy 1 © Ls A A il GOOCH; N (30 Ns Nd NH; NH; MD No NH; 0 Nt 274 5 271 b i c er OH NBT HN) FUN n= N Bb - » Br v 1 =o \ N $ \ N { COM ‘NH, N NH, 0 CH FE 225e py NBT 249a H Bar «87a NH Nx” | ude HH Oy <5" N " 0 _] © Sate oO 226¢ oN 252a / N H = Da \—Br HoN ONT ! Qo / So New N NH; 2 ) NH; SN 21% oo 253a Cy MH No Br i pee MH 1 0 21%a Ot 0 Br \ Ao i © Cy Or N / NN ¢ Na \ CoH 227¢ 8 | 254a : N \ " 4 ( A = Ty . 0 PP. £ NN C] O-0 NH, NH; 228a Cy La 263c H 2 Ho Ne B® av N VY WL Ao wi Are id Na NJ (> NH, Nz 2 a) -— Nr 251f om Ho 272¢ oR oh oN Nf CL 0 ci Quer ~N 2 0 7 A ¢ of \ | CFj NH, 233h 255¢ Br Ct SNH ho Dey a, Ne NSA ¢ fs = Me ~~ NH AN, id font NH 7 N—N ? N = J HN 229¢ wr Hn Br 256 Za < NH, 0 Me NH, weoo Lo. {| 230a NL a. 273¢ H NH, x 3 § CT Fa | we TT ae 4 Y 0 ~ Ao 7 oo N I oo Ar CX" N - NH; NH, N 2 2 vr, OMe 246b £ 258a - iy | 2) i Nes Br Pa Y I 3 A N_ / N yy Bo VN | Ne. - | HN & rN MM 4 TT foo N= LA y A N, Me | a HN x CF; NH, OMe CO Fy 247d Hy % 259d on AY ~ =N HyCO 7 H A N N 0 0 J o | os ~ FN oo HN SN ol Y he CF 248d HCQ 260a on TY A N, a o Cr | { Bb NY - HaN | HN _ 232a Cy Br 261d a CO.H HN N \_ / @ ° CoH NH, 234a | we H Nn Br! 262a | — MH Fa pry Ho NE Fez | pr HN BY | 2 H Ns, Br oo 0 No QS Na NH, NH, Ne— £ 7 7 2643 oJ) Hn o AS ET 4 HoN J = AN pe TY r] HN Na oF NH, 7 oN. OLY” N VY Ls Ao cy \ oo Me N— Ia Ny % N rd CF, BR _— rv wl QD A N Me CFy Na NH; OH 269¢ Ni 266b PN 0 HuN 3 N N 0 0 I cl | > Uy ! | HN INT N, / { fT N—~N © N= HN J. CFa mr Ny N © N = HoN CF; ~3 e—_ a -g 2 275¢ 2" oN 2 o=( N 275¢ | oN N R oN H No rs HN a HN J a To ey Br (o~" " Lv 276g | N. ug N= | «08a 7 ] N Me | Ha o | Oa ry 33% / Nar Hh © yr | 284a ow mr H NB By Nes ' vy J o N N Ao — N, Cr LT EI [2772 | Po HN ~o a 0 p NH, - Ha — —_ 3 J Br 10 ’ 2, BoM - 3 vig | |286a A 0° | 2862 au. 50 Ns 0 NH, I NL _N | 0 NH, N= Me H 7 Ho Ng %] NN , N. 2 TN Py \®) 0 Aq° wea | [0% [2872 | MNoN we {iT N Me Na NH, CFy NH, 2 RS Ao 280 | Nae A 288¢ NH, li eh N Me Ng 2 NH, ’ \ = / EL T mmm H < Br + H Na Br | 281a | Ie D- |280a CC 7 H Nae Br N. F NH: NH, “NN = “3 Ye NN 18 N= NH; 7 SN Fatt Qe | 290 282a | og N= N= \ Br NH; (30 - Yo... OH NH, le > re wo... LS Nee w J o Sed Aq 0 Me 283g - Ce 291a N Me (30 Ny NE NH, ~ ro NN Me | WS Na NH, or, H Loy <y" Ao 292a 293a and 293b NN Fo NH, N= Br / HN FE, a NT Neo BT NS A vl 294 | Yo - | | 295 lf a“ N, Me LES NH; CF, a Nigel NW a — Ty =r 2'y ™ Ao 3 N H il “yA Ny ir CO | 207d | wr No ad | 298 HN NH, bai Ia N 3 0 SN Ne HN wale oD Ny. NHCH. Noy 4 0 fromm de] H o Hs” YL aa ONY Ay | 200a | NNN 300a NH, gr Ns N Me N. = NH, CF, rer Lo eh] % HN Br WD kK o H Br HN Lol, os N PS AK, Bue 0 oF 301a |. 302a | i 0 302a roe Ns No Me | Ns No Me NZ N # NH, NH; CF CF, ONY N 3 # o 2 H Ne Br CoS A, be 3032 | ON. NO 307¢ NH, ¥ rhs NO Me as, H, Ms tr, fmm b———————————————————————————— F, * ! F, y H N. Br Hy N Br Nog Ns Nes A a $ N \. N \ 5 A o = A 2 Le o ages | N 0 AS e rl 2 3042 | o 3053 | . o MN , 3 > 05a | 0° ry r NA - NH; - CFy - CFy = 1 1 i Ww Br N 4 N Aq.° Ao N Ue 1 Ye 308 | NewrNsod 309a | wn NO J a 1 © ~~ Ge a 309a Nex Ai NH. Jn NH, Jn v= n= Me Me Me NTN Me oO 2 H Br UN Ne | 2 Ho NB N \ ? Hat" A YE 0 Me ° re Ao md 3102 | 4. WL 311a NH \ NH, fT No -N 7 ] Me Ny NH, ’ AN N, Me Ny NH 7 Ne" NN Nex Me A % 5 Me H 1 I 1 . ll % N = % LT IS Ao CF Ao 317¢ | ON. 318 | ON. -, a: N Le oy A 318¢ | N, [re NA \ : TC Nz CF Ne CCF CFs 2 PL Lg = # Hoong A N \ 5 Be A b N \_J ’ AY Ir a30r | NB 0 [oo pL s20¢ | 9 So > ry C Ne? CFs NH, CF; FE, H MS oe 0 PE Mp oo [ © N 322¢ Ns N AA | (0 No N 2 NH; NH CF, os H o=( 2 HNP bai oy N= H = N OCF» r $e=N oN 2 I Tr ass | NN HN NH ®, OCF, . 2 H Ns, Br pI H Br 5 Na, {ON % N N \ Fay tL hs A o N le | N ° Jo 33 | oN. 314a | No TU 2 ) N o 314a | [oo a Me Loe NH, . CFy . . is Mes Me Me rm E, H Hei I~ Br a Ao © Fo.) 3 i Ne Ns a \ J Ao © 0 i J LE IN A r e O . NaN pe Ao 312a | r T y= 3233 | 7° i / 0 \ Nt do CFa NH5 [A N N Mh J Ny NH; ¢ \ N=( Me H XY ! Br ' H I § NN L N- 0 0 © 3243 | 0 306a | dy a i 5 \ Net Xo CF NH; 3% . . NH» pn Ho Ns Cl OCS Ty; g i 0, © : 325¢ | re 326c | 1 N No bo x N nN #eB% N NJ CST § 5 Nd NH. CF3 NN CF, NH, v3 NH. ~S N \ J A 0 N No 0 © 327¢ | ro 328f | L Na, N / (= N NH, “73 NH; roms) 5 H i Br 3293 | No 330f | z H Br N 5 Va Q N, N. ! = Q NH, hb NH, i ~ Neo ( F N-Z NH; ? 2 + vl Rs J N i | 0 / o=< o Jer 331 No 336 i = a | ON c | rN. HN NH, ju) 337a | aoaN 315a Br ®) N. NH, 2 >, e=t y H Cl BS Ns xy a N Qe N- CEI Ys, a NH; IN n= Me 316a | a NO 3433 Ff HL NB Ful Ho Ne yO ai’ sea | oO Se 43a | N Cy " 3 ee = ~ 344c | Que OMe 345 2 H Ne Br A Qe OMe | vie N N (30 Na NL CFy F # Ro MeO ( Pa a ® N Qe 0 (3 NH, CF, NH A CFy NH; LL Ne Tf Ne BT Lo Ls oy AV 346g | ~ Qe 347a | Aq, N Me N ¢ VJ ON rE Nos, CFs; N W\ A Ae CC (3C (3 Yd CF3 ! ER NH, NH; ¥ " Pa Yr o=( ~ N_ Rr 3 NN, o= sv TT 3 Ns 338e | [TN Nel 339g Li i. v °C J Ig HN A” HN NJ XR io o NR | Ne “oo” oy H CF. jy H CF. LIN" i 3 CNS 3 N Al N A o A o 0 3a8c | See sac | oon. No ig: L Ye 349¢ NON Me Nee ‘ | 1 le Ny ¢ Be CF. NH, NH; 2 CFa je Bi z Ho Nee™ N L #7 A oN 30a | [© 351a LS » Aq.0 i 359» | AN N Me 3512 | " & “Me nH Nii CFs T= H Nee Br WTO 332¢ | A 0 © 333¢ | oA © 1 1 of No Yiii. CFy NH, wry NH, F, F. So 4 By Br N \_~F 0 Ao 1 a, cl , . "oN s Ho Nes 0 365¢ | A o 366c | = 0, N A 0 / 0 Nese N NL CF3 i 1! oe Nr NL CFy NH, wis NH, Be 7] H Br 5 Ho Ns xl Ne Ns x wD ~ 0 Ao 359¢ | AN Me 3533 | NON Me dg N Id ] N Me Ny NH, \-O A HNP 5 H 3 Ho Ns y N- a A A 5 A Q © 0 N N. sac | For Me 366s | ZNO Me NH, l= No NC Me ea NHp _ { Mecry == For | nN o=( INN =N 7 30a | =N_ . / CJ 341¢ Bet Na HoN Cote £0 Ns 0d 0) N { HN o ll TL 1 > Coy" Ay WS av = - NaN Me 3423 | CO . wee | LL NH, wha TI Na yd w Br Ao © Me 37a | | || DO Hever 388 | ZN Me i Ro Msc® ” Br LY N \, No by C 0 © 359c | NN me 360c | NN Me NH, fl N 7 ] No Me Ng NH; J Q 2 2 H Na. Br {, ~ phy N \ T / 0 ¢ 361a | NN Me 367g | - A J " N I QO 5 po D AL CF4 NH, So NSN Me Cs NH, 2 I Br Aa. N \ A © # 368 © a | 369g | oF Of NA Xfici.c CF3 NH, non ro N_2 NH; o CF CNT DY ~ Br 362 | 9 3633 | Ag N Ne N 30 N= N= ithe CF; ©n jh)! 3 A 0 (ee (33 N INI" N CFs NH, 79 NH, H %Z H Na, Cl 364e | Aa 364d Cog, Al nN BN \ aN N Qe (30 Wo NM CFs S04C | | Ve vad | N Me Neg N N ¢ 3 N= =, NH, OF NH, CF TI. II IIIT ITI IIIT Hi. TTI II, N i a (EY 381 | = Read 382a N H = NA = 0 Oy N om 3 Zn HN a A HoN E F Rw i - N = S| FF NN Ne HN ), — B asa | Ah Uy 384g | 2 wd O= I NN TN 8 N J 0 Oy 384g | AN ol [ N Ng HN F HN F v 1 1 rrr eee] o=( \ H <n a oye IN F - - ¥ Nd J TN-Br 0 r h NL 7 N_ 7 NS = 387a Ay Ny J Nao Jl HN F HoN F F “ 3 F = L ~ ¥ Fa o=( Hy vy AY | ak ye 3s | NS Na b F F tO wo SN oo 388a | ~~ N Ng J No | HN o’ Ho rd F F H o= <r N= o= N, he © Ye IN nil: é 7 NN Br QO of IH ANN - 390 | A { Ny J N. J x HN F HN F Br i y Br TL ————— 5 yA Na he 4 o= ° Uy 377a | Pi No, { = ay ree | a HN ww / HN UN 4 % o / ZN Ne F HN Br . . Br H o=(_ AY nn. r pl Br Br A 3 J NN Br O = I ~N N og 380a | ~~ wi Ng J Ny J HN HN Br Br on, | jae . Q rs N N N ar IN $ ; ° © Oy 375a | r Ye N ’ i. 4 57a | J N g Br h: i 4 Br 7, Eye =I PN i 3753 | A Ny J Na / HN o HN o Br ; g Br bee eee] H bY 0 ~ 1 = 391g | oF 39223 Br N 7 0 oN E OR O oA | F N N ¢ \ N=, o_o nN TT N. J 0 (0 NE Ne NH, NH; ee ee L 8 g on, N- N OJ NY o o oN oN 370a | ON 378¢ | ao 378¢c NH, RS wy H nN Br 4 N oo Oy oN N N ¢ \ ss Q NH; L) Id NE Loe oN NN 22. N= N NH, IS HH Cf < a + Me | 7 SN 372a as —— a Oy nd 373a 45. A pharmaceutical composition. comprising the compound of any one of the preceding claims, or a pharmaceatically acceptable salt thereof and a pharmaceutically acceptable carrier.

46. A method of treating or preventing a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-44, ora pharmaceutically acceptable salt thereof. 47 The method of claim 46, wherein the disease or condition characterized by aberrant complement system activity is an immunological disorder, 48. The method of claim 46. wherein the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system.

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

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

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

53. The method of claim 46, wherein the disease or condition characterized by aberrant 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-deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome.

54. The method of claim 46, wherein the disease or condition characterized by aberrant complement system activity is selected from the group consisting of adult respiratory distress syndrome, myocardial infarct, Jung inflammation, sepsis, cardiopulmonary bypass, bums, asthma, restenosis, multiple organ dysfunction, Guillain-Barré syndrome, hemorrhagic shock, slomenilonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility. Alzheimer’s disease. multiple sclerosis, platelet storage, and hemodialysis.

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

57. The method of claim 46, wherein the disease or condition characterized by aberrant complement svstem activity is an ocular disorder or an eye disorder. 58 The method of claim 46, wherein the disease or condition characterized by aberrant 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, a comeal neovascularization disease, post-corneal transplant rejection, a corneal dystrophic disease, an autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, an environmental dry eye disease, Fuchs’ endothelial dystrophy, retinal vein occlusion, or post- operative inflammation.

59. The method of claim 46, wherein the disease or condition characterized by aberrant compleraent system activity 1s selected from the group consisting of obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, and neuropathy. 60 The method of claim 46, wherein the disease or condition is angioedema.

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

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

63. 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 noctumal hemoglobinuria. and thrombotic microangiopathy.

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

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

67. 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. The method of claim 46, wherein the disease or condition is atheroscerosis.

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

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

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

74. 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 bums, 75. 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, ¢.g., kidney transplant.

76. 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. The method of claim 46, wherein the disease or condition is selected from the group consisting of antibody-mediated rejection, antiphospholipid syndrome, Berger's disease, C3 glomerulonephritis, cold agglutinin disease. cardiopulmonary bypass, dense deposit disease, delayed graft function, geographic atrophy, granulomatosis with polyangiitis, graft versus host disease, hematopoietic stem cell transplant-related thrombotic microangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy. microscopic polyangitis, pyoderma gangrenosurm, Stargardt Disease 1, and warm type autoimmune menolytic anemia.

78. The method of claim 46, wherein the disease or condition characterized by aberrant 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, Parkinsons disease, schizophrenia, periodontitis, Crohn's disease, C3 glomerulopathy, membranous nephropathy, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, of ischemia / reperfusion injury, acute kidney injury, and organ transplantation, ¢.g., kidney transplant, systemic inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, Berger's disease, delayed graft function, granulomatosis with polyangiitis, graft versus host disease, hematopoietic stem cell transplant-related thrombotic ruicroangiopathy, immune complex-mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy. microscopic polyangitis. pyoderma gangrenosum. and Stargardt Disease 1.