Compounds and composition for targeting tp53-y220c mutants

Abstract

Provided are compounds of Formula (I) and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with the activation of p53.

Description

COMPOUNDS AND COMPOSITION FOR TARGETING TP53-Y220C MUTANTSRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. provisional application No. 63 / 432,074, filed December 13, 2022, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] The transcription factor TP53 functions as a tumor suppressor and is inactivated via mutation in about 50% of all tumors. TP53 regulates a host of intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence. The Y220C mutation is a frequent TP53 missense mutant and is associated with over 100,000 new cancer cases per year worldwide, predominantly breast and ovarian cancer. The Y220C mutation causes major structural changes in the TP53 protein and is known to form a new protein cavity reckoned to accommodate small molecule drug candidates. Critically, the mutation-induced crevice is distant from the TP53 surfaces involved in DNA recognition or protein-protein interactions, allowing for the development of targeted chemical agents that stabilize the DNA-binding domain without interfering with binding of its natural substrates. Stabilization allows for restoration of TP53 function, thereby reactivating TP53 tumor suppressor pathways and shrinking or killing the tumor.SUMMARY

[0003] Provided herein are compounds having the Formula I:and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, R3, R4, X, and p are as described herein. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof act as covalent modifiers of TP53 Y220C. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof stabilize TP53 Y220C. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof restore wild-type tumor suppressor protein TP53 (WT TP53) function. In one aspect, it is believed that the described compounds are covalent modifiers of TP53 Y220C which lead to stabilization of the mutant protein and may restorewild-type function to the dysfunctional mutant protein. See e.g., the exemplification section below.

[0004] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the disclosed compounds of Formula I, as well as methods for their preparation are also included.DETAILED DESCRIPTION1. General Description of Compounds

[0005] In a first embodiment, provided herein is a compound of Formula I:R1is selected from optionally substituted alkyl;R2is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRaRb, -ORC, -NHC(O)RC, -C(O)NRdRe, -C(O)Rf, and -SRg;R3is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRalRbl, -ORcl, -NHC(O)Rcl, - C(O)NRdlRel, -C(O)Rfl, and -SRgl;R4is halo, cyano, optionally substituted alkyl, and optionally substituted alkoxy;X is selected from halo, -S(O)2alkyl, and -S(O)alkyl;Ra, Ral, Rb, Rbl, Rc, and Rclare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted heterocyclyl;Rd, Re, and Rgare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’, -C(O)OR’, -C(O)NR’R”, -S(O)R’, and -S(O)2R’ ; or Rdand Retogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;Rdl, Rel, and Rglare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’1, -C(O)OR’1, -C(O)NR’1R”1, -S(O)R’1, and -S(0)2R’1; or Rdland Reltogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;Rfand Rflare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;R’ R’^ R”, and R”1are each independently selected from hydrogen and optionally substituted (Ci-C4)alkyl; and p is 0, 1, or 2.2. Definitions

[0006] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NRaRbmeans that the point of attachment for this group occurs on the nitrogen atom.

[0007] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0008] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical.

[0009] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0010] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0011] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHF2 or -OCF3.

[0012] The term oxo means the group =0.

[0013] The term “heteroaryl” used alone or as part of a larger moiety refers to a 5- to 12- membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclicheteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.

[0014] The term “heterocyclyl” means a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (e.g., in the case of an optionally substituted heterocyclyl or heterocyclyl which is optionally substituted).

[0015] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0016] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0017] The term “bridged” refers to two rings that share three ring atoms with one another.

[0018] The term “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that whenspecified, optional substituents on a cycloalkyl or cycloaliphatic group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

[0019] The term “optionally substituted” means that one or more hydrogens of the designated moiety may be replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group as valency permits. Optional substituents include, but are not limited to, one or more groups selected from cyano (-CN), halo, imino (=NH), nitro (-NO2), oxo (=0), - 0(0)^, -0(0)0^, -C(0)NRiiRiii, -QOSR1, -C(NRi)NRiiRiii, -QS)^, -0(8)0^, - C(S)NRiiRiii, -OR1, -00(0)^, -00(0)0^, -0C(0)NRiiRiii, -00(0)8^, -GUNR'iNR'k". -OQS)^, -00(8)0^, -0C(S)NRiiRiii, -0P(0)(0Rii)0Riii, -08(0)^, -08(0)2^, - 0S(0)NRiiRiii, -0S(0)2NRiiRiii, -NR''R''', -NR^CO)^, -NRiC(0)0Riv, -NRiC(0)NRiiRiii, - NRaC(0)SRlv, -NRiC(NRiv)NRiiRiii, -NRiC(S)Riv, -NRiC(S)0Riv, -NRiC(S)NRiiRiii, - NR^CO)^, -NRiS(0)2Riv, -NRiS(0)NRiiRiii, -NRiS(0)2NRiiRiv, -SR1, -8(0)^, -8(0)2^, - S(O)NRUR1V, -S(0)2NRUR1V, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each R1, R11, R111, and R1Vis independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qaor R11and R111together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each Qais independently selected from cyano, halo, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, Ce-14 aryl, heteroaryl, heterocyclyl, -C(O)RV, -C(0)0Rv, -C(0)NRviRvii, -C(O)SRV, -C(NRv)NRviRvii, - C(S)RV, -C(S)ORV, -C(S)NRviRvii, -ORV, -0C(0)Rv, -0C(0)0Rv, -0C(0)NRviRvii, - OC(O)SRV, -0C(NRv)NRviRvii, -OC(S)RV, -OC(S)ORV, -0C(S)NRviRvii, -0P(0)(0Rv)0Rvl, -OS(O)RV, -OS(O)2RV, -0S(0)NRviRvii, -0S(0)2NRvRvii, -NRviRvii, -NRvC(0)Rviii, - NReC(0)0Rvl, -NRvC(0)NRviRvii, -NRvC(0)SRvl, -NRvC(NRviii)NRviRvii, -NRvC(S)Rviii, - NRVC(S)ORV1, -NRvC(S)NRviRvii, -NRvS(0)Rviii, -NRvS(0)2Rviii, -NRvS(0)NRviRvii, - NRvS(0)2NRviRvii, -SRV, -S(O)RV, -S(O)2RV, -S(0)NRviRvii, and -S(0)2NRviRvii; wherein each Rv, RV1, Rvu, and RV1Uis independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; or (iii) RV1and Rvmtogether with the N atom to which they are attached form heterocyclyl.

[0020] In certain aspects, where specified, one or more hydrogen atoms on a disclosed compound may be replaced with deuterium. Such deuterated compounds may have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent “un-deuterated” compound.

[0021] One or more of the compounds described herein may exist in various tautomeric forms and are part of the present disclosure. The terms “tautomers” or “tautomeric” refer to two or more interconvertible compounds / substituents resulting from at least one formal migration of a hydrogen atom and at least one change in valency. All such isomeric forms of such compounds are expressly included. Thus, when a compound herein is represented by a structural formula or designated by a chemical name herein, all tautomeric forms which may exist for the compound are encompassed by the structural formula.

[0022] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. A “geometric isomer” refers to isomers that differ in the orientation of substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers to substituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0023] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.“Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0024] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicatedgeometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture.

[0025] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0026] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0027] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0028] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0029] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0030] For use in medicines, the salts of the compounds described herein refer to nontoxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0031] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg / kg body weight / day. 3. Compounds

[0032] In a second embodiment, p in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 0, wherein the remaining variables are as described above for Formula I.

[0033] In a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from chloro, bromo, fluoro, -SO2CH3, and -SOCH, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, as part of a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from chloro, bromo, fluoro, and - SO2CH3, wherein the remaining variables are as described above for Formula I or the second embodiment. In another alternative, as part of a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is chloro, wherein the remaining variables are as described above for Formula I or the second embodiment.

[0034] In a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyano(C1-C4)alkyl, and -(C1-C4)alkyl(C3-C6)cycloalkyl), wherein the remaining variables are as described above for Formula I or the second or third embodiment. Alternatively, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl and halo(C1-C4)alkyl, wherein the remaining variables are asdescribed above for Formula I or the second or third embodiment. In another alternative, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -CH2CH3, -CH2CF3, -CH2CF2CH3, -CH2CF2CF3, - CH2CN, and -CH2-cyclopropyl wherein the remaining variables are as described above for Formula I or the second or third embodiment. In another alternative, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -CH2CH3, -CH2CF3, -CH2CF2CH3, and -CH2CF2CF3, wherein the remaining variables are as described above for Formula I or the second or third embodiment. In yet another alternative, as part of a fourth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -CH2CF3, wherein the remaining variables are as described above for Formula I or the second or third embodiment.

[0035] In a fifth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, - (C1-C4)alkyl[4- to 6-membered heterocyclyl], -NRaRb, -ORc, -(C1-C4)alkylORc, -C(O)Rf, - C(O)NRdRe, -(C1-C4)alkylNRdRe, -(C1-C4)alkylC(O)Rf, -(C1-C4)alkylC(O)NRdRe, and -SRg, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5(alternatively, R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1- C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, - (C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], -NRaRb, -ORc, -(C1-C4)alkylORc, -C(O)Rf, -C(O)NRdRe, -(C1-C4)alkylNRdRe, -(C1-C4)alkylNRaC(O)Rb, -(C1-C4)alkylC(O)Rf, - (C1-C4)alkylC(O)NRdRe, and -SRg, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5); Ra, Rb, and Rcare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, - (C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6;Rd, Re, and Rgare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -(C1-C4)alkylOR’, -(C1-C4)alkylNR’R’’, -(C1-C4)alkylC(O)NR’R’’, -(C1- C4)alkylC(O)R’, -(C1-C4)alkylC(O)OR’, -(C1-C4)alkylS(O)R’, -(C1-C4)alkylS(O)2R’, (C1- C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], -C(O)R’, -C(O)OR’, -C(O)NR’R’’, -S(O)R’, and -S(O)2R’, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7; or Rdand Retogether with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7; Rfis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8; Ra, R6, R7, and R8are each independently selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -NR’R’’, -(C1- C4)alkylNR’R’’ -(C1-C4)alkylC(O)NR’R’’, oxo, -(C1-C4)alkylOR’, -C(O)R’, -S(O)R’, and - S(O)2R’ (alternatively ; and R’ and R’’ are each independently selected from hydrogen, (C1-C4)alkyl, and (C3- C6)cycloalkyl, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments.

[0036] In a sixth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NRaRb, -ORc, -C(O)NRdRe, -(C1-C4)alkylNRdRe, and -(C1-C4)alkylC(O)NRdRe, wherein for each occurrence of 5- to 7- membered heteroaryl, phenyl, (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. Alternatively, as part of a sixth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, - NRaRb, -ORc, -C(O)NRdRe, -(C1-C4)alkylNRdRe, -(C1-C4)alkylNRaC(O)Rb, and -(C1- C4)alkylC(O)NRdRe, wherein for each occurrence of 5- to 7-membered heteroaryl, phenyl,(C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. Alternatively, as part of a sixth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NRaRb, -ORc, -C(O)NRdRe, -(C1- C4)alkylNRdRe, -(C1-C4)alkylNRaC(O)Rb, and -(C1-C4)alkylC(O)NRdRe, wherein said cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R5, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. Alternatively, as part of a sixth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C1-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NRaRb, -ORc, -C(O)NRdRe, -(C1- C4)alkylNRdRe, and -(C1-C4)alkylC(O)NRdRe, wherein said cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R5, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments.

[0037] In a seventh embodiment, Ra, Rb, and Rcin the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, and -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl, said groups are each optionally substituted with 1 to 3 groups selected from R6, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of a seventh embodiment, Ra, Rb, and Rcin the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], (C3-C6)cycloalkyl, phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, and -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of 5- to 7- membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl, said groups are each optionally substituted with 1 to 3 groups selected from R6, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments.

[0038] In an eighth embodiment, R5and R6in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from (C1-C4)alkyland halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments. Alternatively, as part of an eighth embodiment, R5and R6in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from halo, (C1-C4)alkyl,halo(C1-C4)alkyl, -(C1- C4)alkylOR’, and S(O)2R’, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments.

[0039] In a ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3,variables are as described above for Formula I or any one of the second to eighth embodiments. Alternatively, as part of a ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3, -CH2NHC(O)CH3, -CH2NHSO2CH3, -CH2C(O)NHCH3, - CH2C(O)N(CH3)2, -CH2C(O)NHCH2CF3, -CH2C(O)NHCH2OCH3, -CH2C(O)NH2, - CH2C(O)N(CH3)(CH2CF3), -CH2C(O)NH(CH2)2SO2CH3, -C(O)N(CH3)2, -C(O)NHCH3,,remaining variables are as described above for Formula I or any one of the second to eighth embodiments. Alternatively, as part of ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, chloro, and - OCH2CF3, wherein the remaining variables are as described above for Formula I or any one of the second to eighth embodiments. In another alternative, as part of a ninth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second to eighth embodiments.

[0040] In a tenth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylORc1, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -NRa1Rb1, - NHC(O)Rc1, -ORc1, -(C1-C4)alkylORc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1- C4)alkylC(O)Rf1, -(C1-C4)alkylC(O)NRd1Re1, and -SRg1, wherein for each occurrence of (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5a; Ra1, Rb1, and Rc1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a; Rd1, Re1, Rg1, and Rh1, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, -(C1-C4)alkylC(O)OR’1, -(C1-C4)alkylS(O)R’1, -(C1-C4)alkylS(O)2R’1, (C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6- membered heterocyclyl], -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, -S(O)R’1, and -S(O)2R’1, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7a; or Rd1and Re1together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7a; Rf1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8a; R5a, R6a, R7a, and R8aare each independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, cyano, -NR’1, - (C1-C4)alkylNR’1R’’1, -(C1-C4)alkylC(O)NR’1R’’1, oxo, -(C1-C4)alkylOR’1, -C(O)R’1, - S(O)R’1, and -S(O)2R’1; andR’1and R’’1are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, and 4- to 7-membered heterocyclyl, wherein the remaining variables are as described above for Formula I or any one of the second to ninth embodiments. Alternatively, as part of a tenth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1- C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylORc1, -(C1-C4)alkylphenyl, 4- to 10-membered heterocyclyl, -(C1-C4)alkyl[4- to 10-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -ORc1, -(C1- C4)alkylORc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1-C4)alkylC(O)Rf1, -(C1- C4)alkylC(O)NRd1Re1, and -SRg1, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, and 4- to 10-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5a; Ra1, Rb1, and Rc1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a; Rd1, Re1, Rg1, and Rh1, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl,)alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, -(C1-C4)alkylC(O)OR’1, -(C1-C4)alkylS(O)R’1, -(C1-C4)alkylS(O)2R’1, (C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 8-membered heterocyclyl, -(C1-C4)alkyl[4- to 8- membered heterocyclyl], -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, -S(O)R’1, and -S(O)2R’1, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7a; or Rd1and Re1together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7a; Rf1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8a;R5a, R6a, R7a, and R8aare each independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, cyano, -NR’1R’’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkyC(O)OR’1, -(C1- C4)alkylC(O)NR’1R’’1, oxo, -(C1-C4)alkylOR’1, -C(O)NR’1R’’1, -OR’1, C(O)OR’1, -C(O)R’1, -S(O)R’1, -S(O)2R’1, 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R’1; and R’1and R’’1are each independently selected from hydrogen, (C1-C4)alkyl, (C3- C6)cycloalkyl, and 4- to 7-membered heterocyclyl, wherein the remaining variables are as described above for Formula I or any one of the second to ninth embodiments.

[0041] In an eleventh embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -(C1-C4)alkyl[5- to 7-membered heteroaryl], 4- to 6-membered heterocyclyl, - (C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, and -(C1- C4)alkylNRg1Rh1, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 6- membered heterocyclyl, and 4- to 9-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. Alternatively, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -(C1- C4)alkyl[4- to 10-membered heterocyclyl], -(C1-C4)alkyl[5- to 7-membered heteroaryl], 4- to 10-membered heterocyclyl, -(C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, - C(O)NRd1Re1, and -(C1-C4)alkylNRg1Rh1, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 10-membered heterocyclyl, and 4- to 9-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. Alternatively, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -(C1-C4)alkylORc1, 4- to 10-membered heterocyclyl, -(C1-C4)alkyl[4- to 10-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1- C4)alkylNRg1Rh1, wherein each 4- to 10-membered heterocyclyl are optionally substituted with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. Alternatively, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from -(C1- C4)alkylORc1, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, wherein said 4- to 6-membered heterocyclyl and 4- to 9-membered heterocyclyl are each optionally substitutedwith 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. In another embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from - (C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, - (C1-C4)alkyl[piperazinyl], -(C1-C4)alkyl[piperidinyl], -(C1-C4)alkyl[morpholinyl], -(C1- C4)alkyl[pyrrolindyl], -(C1-C4)alkyl[diazepanyl], -(C1-C4)alkyl[azetindinyl], piperazinyl, and tetrahydropyridinyl, wherein said piperidinyl, morpholinyl, pyrrolindyl, diazepanyl, tetrahydropyridinyl, azetindinyl, and each occurrence of piperazinyl are optionally substituted with 1 to 3 groups selected from R5a, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments.

[0042] In a twelfth embodiment, R5ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- C6)cycloalkyl, -NR’1R’’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkylOR’1, and -C(O)R’1, wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments. Alternatively, as part of a twelfth embodiment, R5ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, -N[(C1-C4)alkyl]2, -(C1-C4)alkylN[(C1-C4)alkyl]2, -(C1- C4)alkylOH, -(C1-C4)alkylO(C1-C4)alkyl, and -C(O)(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments.

[0043] In a thirteenth embodiment, Rc1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, Rc1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is piperidinyl or pyridinyl, each optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to twelfth embodiments.

[0044] In a fourteenth embodiment, R6ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to thirteenth embodiments.

[0045] In a fifteenth embodiment, Ra1and Rb1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein for each occurrence of 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to fourteenth embodiments. Alternatively, as part of a fifteenth embodiment, Ra1and Rb1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and -(C1-C4)alkyl[5- to 7-membered heteroaryl], wherein said 5- to 7-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to fourteenth embodiments. In another alternative, as part of a fifteenth embodiment, Ra1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen and Rb1is -(C1-C4)alkyl[pyridinyl], wherein said pyridinyl is optionally substituted with 1 to 3 groups selected from R6a, wherein the remaining variables are as described above for Formula I or any one of the second to fourteenth embodiments.

[0046] In a sixteenth embodiment, Rf1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R8a, wherein the remaining variables are as described above for Formula I or any one of the second to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, Rf1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is piperazinyl optionally substituted with 1 to 3 groups selected from R8a, wherein the remaining variables are as described above for Formula I or any one of the second to fifteenth embodiments.

[0047] In a seventeenth embodiment, R8ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to sixteenth embodiments.

[0048] In an eighteenth embodiment, Rd1and Re1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, - (C1-C4)alkylNR’1R’’1, (C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein said 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, Rd1and Re1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkylNR’1R’’1, (C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 8-membered heterocyclyl, wherein said 5- to 7-membered heteroaryl, and 4- to 8-membered heterocyclyl, are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, Rd1and Re1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkylN[(C1- C4)alkyl]2, (C1-C4)alkyl[pyridinyl], and piperidinyl, wherein said pyridinyl and piperidinyl, are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to seventeenth embodiments.

[0049] In a nineteenth embodiment, Rg1and Rh1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR’1, -(C1-C4)alkylNR’1R’’1, -(C1- C4)alkylC(O)NR’1R’’1, -(C1-C4)alkylC(O)R’1, (C1-C4)alkylphenyl, -(C1-C4)alkyl[5- to 7- membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein said phenyl, 5- to 7- membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments. Alternatively, as part of a nineteenth embodiment, Rg1and Rh1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, (C1-C4)alkylphenyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 8-membered heterocyclyl, wherein said phenyl, 5- to 7-membered heteroaryl, and 4- to 8- membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments. Alternatively, as part of a nineteenth embodiment, Rg1and Rh1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1- C4)alkyl[pyridinyl], -(C1-C4)alkylO(C1-C4)alkyl, (C1-C4)alkylphenyl, -(C1-C4)alkylN[(C1- C4)alkyl]2, pyridinyl, piperidinyl, pyrrolidinyl, -(C1-C4)alkylC(O)N[(C1-C4)alkyl]2, halo(C1- C4)alkyl, -(C1-C4)alkylC(O)(morpholinyl), wherein said phenyl, pyridinyl, piperidinyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments. Alternatively, as part of a nineteenth embodiment, Rg1and Rh1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1- C4)alkyl[pyridinyl], -(C1-C4)alkylO(C1-C4)alkyl, (C1-C4)alkylphenyl, -(C1-C4)alkylN[(C1- C4)alkyl]2, piperidinyl, pyrrolidinyl, -(C1-C4)alkylC(O)N[(C1-C4)alkyl]2, halo(C1-C4)alkyl, - (C1-C4)alkylC(O)(morpholinyl), wherein said phenyl, pyridinyl, piperidinyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R7a, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments. In another alternative, as part of a nineteenth embodiment, R7ain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, (C1-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second to eighteenth embodiments.

[0050] In a twentieth embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from –CH2NHCH3, –CH2N(CH3)2,\ , wherein the remaining variables are as described above for Formula I or any one of the second to nineteenth embodiments.

[0051] Compounds having the Formula I are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included.4. Uses, Formulation and Administration

[0052] The compounds and compositions described herein are generally useful for modulating the activity of TP53. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein are covalent modifiers of Y220C. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein stabilize TP53. In some aspects, the compounds,pharmaceutical acceptable salts, and pharmaceutical compositions described herein restore wild-type tumor suppressor protein p53 (WT TP53) function.

[0053] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition associated with TP53 function. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition responsive to the activation of TP53 function. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition responsive to the restoration of TP53 function, e.g., where protein function has been lost due to mutation such as a Y220C mutation.

[0054] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a cancer. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a cancer expressing a TP53 mutant (e.g., a cancer harboring a Y220C mutation)

[0055] Specific cancers treatable by the present compounds, salts, and compositions include, but are not limited to, solid tumors, heme malignancy, ovarian, esophageal, colorectal, head and neck, larynx, lung, leukemia (e.g., acute myeloid leukemia (AML)), sarcoma, testicular, melanoma, cervical, breast, pancreatic, glioma, glioblastoma, endometrial, esophageal, gastric cancer, prostate, bladder, myelodysplastic syndromes (MDS), sarcoma, and melanoma.

[0056] Use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a described condition is also provided. Further provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a described condition.

[0057] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceuticalcompositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0058] In some aspects, the pharmaceutical compositions are administered orally.

[0059] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.EXEMPLIFICATIONChemical Synthesis

[0060] The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention.

[0061] Scheme 1.

[0062] 4-chloropyrimidoindoles like S10 may be prepared via a nine-step process beginning with the appropriate fluorocynaobenzoate ester or fluorocyanonicotinate ester represented by SI. Nucleophilic aromatic substitution of SI with a glycinate ester providesintermediate S2 which can be converted to 3-amino-indole derivative S3. Condensation of S3 with dimethylformamide dimethylacetyl followed by treatment with ammonia yields the hydroxypyrimidoindole intermediate S5. S5 can be converted to the chloride intermediate S6 with phosphorousoxychloride. Alkylation of S6 with the appropriate electrophile provides S7. Reduction of S7 provides the benzylic alcohol intermediate S8 which is converted to the benzylic chloride intermediate S9 with thionyl chloride. Alkylation of the appropriate amine with S9 provides the target compounds like S10.CF3S14

[0064] 4-chloropyrimidoindoles like S14 may be prepared via a three-step process from intermediates like Sil. Saponification of Sil provides the acid intermediate S12 which can be converted to amide target compounds like S14 via conversion to the acid chloride intermediate S13 followed by reaction with an amine.

[0065] Scheme 3.

[0066] 4-chloropyrimidoindoles like S17 may be prepared via a two-step process from intermediates like S15. Oxidation of S15 provides intermediate S16 which can be converted to target compounds like S17 via reductive amination.

[0067] Scheme 4.

[0068] 4-chloropyrimidoindoles like S22 may be prepared via a four-step process from intermediates like S18. Treatment of S18 with trimethylhydroxytin provides an acid intermediate like S19 which can be converted to the amine intermediate S21 via a two-step process involving a Curtins rearrangement and acid mediated removal of the Boc protecting group. Derivatization of S21 with a reductive amination or an amide coupling provides target compounds represented by S22.

[0069] Scheme 5.

[0070] Chloropyrimidoindoles like S32 may be prepared via a nine-step process starting with an appropriate cyano-fluoro-iodo- benzene like S23. Nucleophilic aromatic substitutionof S23 with ethyl glycinate provide S24 which can be converted to a 3-amino-indole intermediate S25 by treatment with BOC2O and DMAP. In an analogous manner to Scheme 1, S25 can be converted to intermediate S29 via a four-step process. Treatment of S29 with sodium methoxide yield methoxyp yrimidoindole intermediates like S30. Palladium catalyzed amination provides iodide intermediate S31 which can be converted to target compounds like S32 by treatment with phosphorousoxychloride.

[0071] Scheme 6.

[0072] Dichlorop yrimidoindoles like S40 may be prepared via a seven- step process starting with an appropriate bromo-cyano-fluoro-benzene like S33. Treatment of S33 with aminoacetamide followed by base mediated cyclization provides 3-amino-indole intermediates like S35. Treatment of S35 with triphosgene provides a dihydroxypyrimidoindole intermediate like S36, which can be converted to the desired target compound like S40 via four-step sequence similar to that described in Scheme 1.

[0073] Scheme 7.

[0074] Chloropyrimidoindoles like S46 may be prepared via a five-step sequence starting with intermediate S41. Alkylation of S41 with electrophile provides intermediate S42.Selective displacement of the chloride with sodium methoxide provides intermediate S43. S43 can be converted to S45 via a Suzuki coupling with a boronic acid or ester to provide intermediate S45 which can be subsequently converted to the target compounds S46 by treatment with phenylphosphonic dichloride.

[0075] Scheme 8.

[0076] Chloropyrimidoindoles like S55 may be prepared via an eight-step sequence starting with intermediate S47. Diamide S48 can be prepared by coupling Boc-glycine with the 3-aminoindole S47. Base-mediated cyclization of S48 provides the hydroxpyrimidinolintermediate S49 which can be converted to the chloropyrimidine S50 with POCh. After protection of the free amine in S50 with a Boc group the indole can be alkylated with an electrophile to provide intermediate S52. Suzuki coupling of S52 with potassium ((dimethylamino)methyl)trifluoroborate followed by treatment with POCh provides intermediate S54, which can be converted to target compounds like S55 by amide coupling with a carboxylic acid or reaction with an acid chloride.

[0077] Scheme 9.

[0078] Chloropyrimidoindoles like S64 may be prepared via an eight-step sequence starting with intermediate S56. Reaction of 3-amino-2-carboxamideindole intermediate S56 with diethyl malonate provides intermediate S57 which can be converted to the chloropyrimidine intermediate S58 using POCh. Alkylation of S58 with an electrophile provides intermediate S59. Displacement of the chloride with sodium methoxide provides S60 which can be converted to the 7-diaminomethylpyrimidoindole intermediate S61 via a Suzuki coupling with potassium ((dimethylamino)methyl)trifluoroborate. Treatment of S61 with POCh provides intermediate S62. Hydrolysis of ester S62 with trimethyl tin hydroxide provides the carboxylic acid intermediate S63 which can be coupled with amine nucleophiles to provide target compounds like S64.

[0079] Scheme 10.

[0080] Chloropyrimidoindoles like S73 may be prepared via an nine-step sequence starting with intermediate S65. Reaction of 3-amino-2-carboxamideindole intermediate S65 with diethyl oxalate provides intermediate S66 which can be converted to the methoxypyrimidine intermediate S67 by sequential treatment with POCh and sodium methoxide. Alkylation of S67 with an electrophile provides intermediate S68 which can be converted to the 7-diaminomethylpyrimidoindole intermediate S69 via a Suzuki coupling with potassium ((dimethylamino)methyl)trifluoroborate. Sequential treatment of S69 with oxalyl chloride and then methanol provides the methyl ester intermediate S70 which can be selectively demethylated with trimethylsilylchloride and sodium iodide to provide the hydroxyp yrimidoindole intermediate S71. Sequential treatment of S71 with POCh and trimethylhydroxy tin provide the carboxylic acid intermediate S73 which can be converted to target compounds like S74 via an amide coupling.

[0081] Scheme 11.

[0082] Chloropyrimidoindoles like S77 may be prepared via an two-step sequence starting with intermediate S75. Alkylation of amines with intermediate S75 provides intermediate S76 which can be converted to target compounds like S77 via treatment with hydrochloric acid.

[0083] Scheme 12.

[0084] Chloropyrimidoindoles like S80 may be prepared via an two-step sequence starting with intermediate S78. Reductive amination with intermediate S75 provides intermediate S79 which can be converted to target compounds like S80 via treatment with hydrochloric acid.

[0085] Scheme 13.

[0086] Chloropyrimidoindoles like S90 may be prepared via a nine-step sequence starting with intermediate S81. SNAT reaction of S81 with para- methoxybenzylamine followed by deprotection with TFA provides aniline intermediate S83. Reductive amination of S83 with ethyl glyoxalate provides S84. Treatment of S84 with Boc-anhydride and 4- dimethylaminopyridine induces a cyclization reaction which yield the indole intermediate S85. Sequential treatment of S85 with DMF-DMA and ammonia yields the hydropyrimidinol intermediate S87. Treatment of S87 with POCh provides chloropyrimidoindole intermediate S88. Alkylation of S88 with an electrophile followed by Suzuki coupling with potassium ((dimethylamino)methyl)trifluoroborate provides target compounds like S90.

[0087] Scheme 14.

[0088] Chloropyrimidoindoles like S94 may be prepared via one of two different two- step sequences starting with intermediates like S91. Palladium-catalyzed cross coupling of S91, when X = OMe, with a boronic acid or boronic ester provides intermediate S92 which can be converted to target compounds like S94 by treatment with POCh. Palladium-catalyzed borylation of S91, when X = Cl, followed by Suzuki coupling with a boronic acid or boronic ester provides target compounds like S94.

[0089] Abbreviations:ACN = acetonitrileAcOH = acetic acidBOC2O = di-tert-butyl dicarbonateDCM = dichloromethaneDCE = 1,2-dichloroethaneDIEA = N,N-diisopropylethylamineDMAP = 4-dimethylaminopyridineDMF = dimethylformamideDMF-DMA = N,N-dimethylformamide dimethyl acetalDPP A = diphenylphosphoryl azideEtOAc = ethyl acetateEtOH = ethanolIPA = isopropanolMeOH = methanolTEA = triethylamineTFA = trifluoroacetic acidTHF = tetrahydrofuranTMSC1 = trimethylsilyl chlorideTMSBr = trimethylsilylbromideExample L l-(4-chloro-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine

[0090] Scheme 1, step 1, methyl 3-cyano-4-r(2-ethoxy-2-oxo-ethyl) aminolbenzoate:

[0091] To a solution of ethyl 2-aminoacetate hydrochloride (8.6 g, 62.2 mmol, 1.0 equiv.) in ACN (110 mL) was added K2CO3 (20.4 g, 148.1 mmol, 2.5 equiv.) and methyl 3-cyano-4- fluorobenzoate (10.6 g, 59.1 mmol, 1.0 equiv.). The mixture was stirred at 90°C for 4 hours. The reaction mixture was poured into H2O (80 mL) and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (3: 1 petroleum ether : ethyl acetate) to afford the title compound (3.7 g, 14.1 mmol, 24% yield) as a white solid.

[0092] JH NMR (400 MHz, CHLOROFORM-d) 5 8.09 - 8.06 (m, 1H), 7.99 (dd, J = 2.0, 8.8 Hz, 1H), 6.49 (d, J= 8.8 Hz, 1H), 5.53 (t, J= 4.4 Hz, 1H), 4.22 (q, J= 7.2 Hz, 2H), 3.97 (d, 7= 5.2 Hz, 2H), 3.81 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0093] LCMS [M-l] = 261.1.

[0094] Scheme 1, step 2, l-(fert-butyl) 2-ethyl 5-methyl 3-amino-lH-indole- 1,2,5- tricarboxylate:

[0095] To a solution of methyl 3-cyano-4-[(2-ethoxy-2-oxo-ethyl)amino]benzoate (2.7 g, 10.3 mmol, 1.0 equiv.) in DCM (1.0 mL) was added TEA (1.06 g, 10.4 mmol, 1.4 mL, 1.0 equiv.), BOC2O (2.7 g, 12.4 mmol, 1.2 equiv.) and DMAP (125.7 mg, 1.0 mmol, 0.1 equiv.). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reducedpressure. The resulting residue was purified by silica gel column chromatography (4.5:1 petroleum ether: EtOAc) to afford the title compound (4.4 g, crude) as a white solid.

[0096] 1HNMR (400 MHz, CHLOROFORM-d) δ 8.37 - 8.30 (m, 1H), 8.23 (dd, J = 2.0, 8.4 Hz, 1H), 7.61 (s, 1H), 4.36 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 1.54 - 1.40 (m, 9H), 1.34 - 1.27 (m, 3H).

[0097] LCMS [M-55] = 307.2.

[0098] Scheme 1, step 3.1-(tert-butyl) 2-ethyl 5-methyl 3-(((dimethylamino)methylene) amino)-1H-indole-1,2,5-tricarboxylate:

[0099] To a solution of 1-(tert-butyl) 2-ethyl 5-methyl 3-amino-1H-indole-1,2,5- tricarboxylate (3.4 g, 9.3 mmol, 1.0 equiv.) in DMF (34 mL), was added DMF-DMA (1.6 mL, 12.2 mmol, 1.3 equiv.) and then the mixture solution was stirred at 100°C for 4 hours. The reaction mixture was poured into H2O (50 mL) and was extracted with EtOAc (3 × 30 mL). The organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (4.5:1 petroleum ether: EtOAc) to afford the title compound (4 g, crude) as a white solid.

[0100] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.39 (s, 1H), 8.12 - 8.03 (m, 2H), 7.93 (s, 1H), 4.30 (q, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.11 (d, J = 9.4 Hz, 6H), 1.63 (s, 9H), 1.33 (t, J = 7.2Hz, 3H).

[0101] LCMS [M+1] = 418.4.

[0102] Scheme 1, step 4. methyl 4-oxo-3,5-dihydropyrimido[5,4-b]indole-8-carboxylate:

[0103] To a solution of 1-(tert-butyl)-2-ethyl-5-methyl-3- (((dimethylamino)methylene)amino)-1H-indole-1,2,5-tricarboxylate (3.6 g, 8.6 mmol, 1.0 equiv.) in EtOH (40 mL) was added NH3·H2O (40 mL). The mixture was stirred at 70°C for 16 hours. The reaction mixture was filtered and the filter cake was concentrated in vacuum to afford the title compound (1.2 g, crude) as a white solid. This material was used in the next step without further purification.

[0104] 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 2H), 8.62 (s, 1H), 8.11 - 7.99 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H).

[0105] LCMS [M+1] = 244.2.

[0106] Scheme 1, step 5. Methyl 4-chloro-5H-pyrimido[5,4-b]indole-8-carboxylate:

[0107] A solution of methyl 4-hydroxy-5H-pyrimido[5,4-b]indole-8-carboxylate (900.0 mg, 3.7 mmol, 1.0 equiv.) in POCl3(18.0 mL) was stirred at 110°C for 20 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crudeproduct was triturated with ACN at 20°C for 10 minutes to afford a residue. The residue was triturated with H2O at 20°C for 2 minutes to afford the title compound (600 mg, 62% yield) as a yellow solid.

[0108] 1H NMR (400 MHz, CHLOROFORM-d) δ 12.8 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.27 (d, J = 8.8 Hz 1H), 7.85 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H).

[0109] LCMS [M+1, M+3] = 262.2, 264.2.

[0110] Scheme 1, step 6. Methyl 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole-8- carboxylate:

[0111] To a solution of methyl 4-chloro-5H-pyrimido[5,4-b]indole-8-carboxylate (500.0 mg, 1.9 mmol, 1.0 equiv.) in dry DMF (5.0 mL) in a dried round bottom flask was added NaH (115 mg, 2.8 mmol, 60% purity, 1.5 equiv.) at 0°C. The reaction mixture was stirred at 20°C for 0.5 hours under nitrogen and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (887 mg, 3.8 mmol, 2.0 equiv.) was added to the reaction mixture. After stirring at 20°C for 16 hours, the reaction mixture was quenched by the addition of H2O (10 mL) at 0°C. The mixture was extracted with EtOAc (20 mL) and the organic extract was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to afford the title compound (330 mg, 50% yield) as a white solid.

[0112] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.30 (s, 1H), 8.99 (s, 1H), 8.46 (dd, J = 1.6, 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 5.39 (q, J = 8.0 Hz, 2H), 4.01 (s, 3H).

[0113] LCMS [M+1] = 344.2.

[0114] Scheme 1, step 7. (4-Chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido [5,4-b] indol-8- yl)methanol:

[0115] A 100 mL three-necked flask equipped with a stirred bar was charged with methyl 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole-8-carboxylate (5.0 g, 14.5 mmol, 1.0 equiv.) and toluene (60 mL). The suspension was degassed under vacuum and purged with N2three times. The solution was cooled to -60°C and then a solution of DIBAL-H (1 M, 29.1 mL, 2.0 equiv.) was added dropwise over 15 minutes. The resulting solution was stirred at -60°C for 1 hour under N2. The reaction mixture was quenched by the addition of EtOAc (500 mL) and then diluted with a saturated aqueous solution of potassium sodium tartrate (500 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100:1 to 0:1 petroleum ether: EtOAc) to afford the title compound (3.0 g, 65% yield) as an off-white solid.

[0116] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.78 (s, 1H), 8.27 (s, 1H), 7.71 (dd, J = 1.2, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 5.26 (q, J = 8.4 Hz, 2H), 4.75 (s, 2H).

[0117] LCMS: [M+1] = 316.1.

[0118] Scheme 1, step 8.4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole:

[0119] To a solution of (4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8- yl)methanol (2.5 g, 7.9 mmol, 1.0 equiv.) in toluene (40 mL) was added SOCl2(3.8 g, 31.6 mmol, 4.0 equiv.) at 0°C under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 1 hour. Most of the SOCl2 was removed under reduced pressure and then the mixture was quenched by the dropwise addition of H2O (20 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100:1 to 0:1 petroleum ether: EtOAc) to afford the title compound (2.0 g, 76% yield) as an off-white solid.

[0120] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 1H), 8.42 (d, J =1.2 Hz, 1H), 7.82 (dd, J = 1.6, 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 5.34 (q, J = 8.0 Hz, 2H), 4.81 (s, 2H).

[0121] LCMS: [M+1] = 334.1.

[0122] Scheme 1, step 9.1-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8- yl)-N,N- dimethylmethanamine:

[0123] To a solution of 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b] indole (500.0 mg, 1.5 mmol, 1.0 equiv.) in ACN (10.0 mL) was added dropwise dimethylamine (2 M, 1.5 mL, 2.0 equiv.) and then the mixture was stirred at 30°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with ACN (3 × 10ml) at 25 ℃ for 30 minutes to afford the title compound (1.1 g, 72% yield) as white solid. Further purification of a 100 mg sample was achieved by preparative HPLC (column: Phenomenex Luna (80 × 30 mm × 3 um); mobile phase: 5% - 35% ACN in water (HCl)) to afford the HCl salt of the title compound (50.0 mg) as a white solid. The HCl-salt of the title compound (50.0 mg) was converted to the formic acid salt by treatment with formic acid (6.3 mg, 132 umol, 1.0 equiv.). The mixture was stirred at 25 °C for 5 minutes. The white solid was re-crystallized from water and dried by lyophilization to afford the formic acid salt of the title compound (35.0 mg, 66% yield) as a white solid.

[0124] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 1H), 8.50 (s, 1H),8.34 (s, 1H), 7.91 (dd, J = 1.6, 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 5.36 (q, J = 8.0 Hz, 2H), 3.92 (s, 2H), 2.47 (s, 6H).

[0125] LCMS: [M+1] = 343.0. Example 2.1-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl-N-(3- pyridylmethyl)methanamine

[0126] Scheme 1, step 9. 1-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]- N-methyl-N-(3-pyridylmethyl)methanamine:

[0127] To a solution of 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (100 mg, 299 μmol, 1.0 equiv.) in ACN (5 mL) was added TEA (83 μL, 599 μmol, 2.0 equiv.) and N-methyl-1-(3-pyridyl)methanamine (73.1 mg, 599 umol, 2.0 equiv.). The mixture was stirred at 50°C for 6 hours and concentrated. The resulting residue was purified by preparative TLC (10:1 DCM: MeOH) to afford the title compound (20.0 mg, 15% yield) as a yellow solid.

[0128] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 1H), 8.61 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.37 (s, 1H), 7.92 - 7.74 (m, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.33 - 7.28 (m, 1H), 5.35 (q, J = 8.0 Hz, 2H), 3.78 (s, 2H), 3.64 (s, 2H), 2.26 (s, 3H).

[0129] LCMS: [M+1, M+3] = 420.1, 422.2. Example 65.1-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl-N-(3- pyridylmethyl)methanamine

[0130] Scheme 1, step 9. 4-chloro-8-|(2-mcthylpyrimidin-5-yl )oxymcthyl |-5-(2.2.2- trifluoroethyl)p yrimido [ 5 ,4-b] indole:

[0131] A mixture of 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (80.0 mg, 239.4 pmol, 1.0 equiv.), 2-methylpyrimidin-5-ol (21.0 mg, 191.5 pmol, 0.8 equiv.), and CS2CO3 (234 mg, 718 pmol, 3.0 equiv.) in acetonitrile (1.0 mL) was stirred at RT for 2 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch diol 150mm x 25mm x 5pm; mobile phase: 5-50% ethanol in heptane) to afford the title compound (15.7 mg, 15% yield) as a white solid.

[0132] LCMS: [M+l, M+3] = 408.1, 410.1.

[0133] JH NMR (400 MHz, DMSO-tfe) d 8.83 (s, 2H), 8.67 (s, 1H), 8.38 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 1.6, 8.8 Hz, 1H), 5.70 (q, J = 8.8 Hz, 2H), 5.04 (s, 2H), 2.70 (s, 3H).Example 66. 4-chloro-8-r(4-methylimidazol-l-yl)methyl]-5-(2,2,2- trifluoroethyl)p yrimido [ 5 ,4-b] indole

[0134] Scheme 1, step 9. 4-chloro-8-r(4-methylimidazol-l-yl)methyl]-5-(2,2,2- trifluoroethyDpyrimido [ 5 ,4-b] indole:

[0135] To a solution of 4-methyl-lH-imidazole (29.4 mg, 359 pmol, 0.6 equiv.) in THF (2.0 mL) was added NaH (72 mg, 1.80 mmol, 3.0 equiv.; 60% dispersion in oil) at 0°C. After hydrogen evolution ceased, 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (200 mg, 599 pmol, 1.0 equiv. ) was added and the mixture was allowed to warm to RT and stirred for 2 hours under an atmosphere of nitrogen. The reaction mixture was quenched by with H2O (5.0 mL), and then diluted with EtOAc (6.0 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Ultimate XB NH2 10 x 100 x 30 mm; mobile phase: 10-15% isopropanol in heptane) to afford the title compound (17.5 mg, 7.3% yield) as a white solid.

[0136] LCMS [M+l, M+3] = 380.1, 382.1.

[0137] ’ H NMR (400 MHz, CHLOROFORM-d) 3 = 9.14 (s, 1H), 8.49 (d, J= 1.2 Hz, 1H), 7.89 (s, 1H), 7.84 (dd, J= 2.0, 8.4 Hz, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.16 (s, 1H), 4.84 (s, 2H), 4.70 - 4.62 (q, J= 8.0 Hz, 2H), 2.42 - 2.38 (s, 3H).Example 67, l -| |4-chloro-5-(2.2.2-trifluorocthyl )pyrimido|5.4-b|indol-8-yl |mcthyl |-4- methyl-piperazin-2-one

[0138] The title compound was prepared in a similar manner to that described for example 66.

[0139] LCMS: [M+l, M+3] = 412.1, 414.1.

[0140] JH NMR (400 MHz, DMSO-tfc) 6 8.94 (s, 1H), 8.18 (s, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.73 (dd, J = 1.6, 8.8 Hz, 1H), 5.74 (q, J= 8.8 Hz, 2H), 4.73 (s, 2H), 3.26 (t, J= 4.8 Hz, 2H), 3.05 (s, 2H), 2.58 (br d, J= 5.2 Hz, 2H), 2.21 (s, 3H).

[0141] Table 1. The examples in Table 1 were prepared in a similar manner to those described for Example 1, Example 2, or Example 65 using scheme 1.Example 35. [4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-yl1-(4-methylpiperazin-1-yl) methanone

[0142] Scheme 2, step 1, 4-hydroxy-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indole-8- carboxylic acid:

[0143] To a solution of methyl 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carboxylate (500.0 mg, 1.5 mmol, 1 equiv.) in THF (4 mL) and H2O (1 mL) was added LiOH-thO (67.2 mg, 1.6 mmol, 1.1 equiv.) and the reaction mixture was stirred at 25°C for 15 hours. The pH of the mixture was adjusted to ~1 with aqueous HC1 (IM, 1 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (500 mg, crude) as a yellow solid. This material was used in the next step without further purification.

[0144] LCMS: [M+l] = 312.0.

[0145] Scheme 2, step 2, 4-chloro-5-(2,2,2-trifluoroethyl )pyrimido|5.4-b|indolc-8- carbonyl chloride:

[0146] A solution of 4-hydroxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carboxylic acid (50.0 mg, 160.7 pmol, 1 equiv.) in SOCh (1 mL) was stirred at 60°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (50 mg, 89% yield) as yellow solid. This material was used in the next step without further purification.

[0147] LCMS: [M+l] = 344.0 (The reaction was quenched with MeOH and analyzed by LCMS).

[0148] Scheme 2, step 3. [4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-ylT(4- methylpiperazin -1-yl) methanone:

[0149] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8-carbonyl chloride (80.0 mg, 229.8 pmol, 1 equiv.) in THF (1.5 mL) was added TEA (128 pL, 919 pmol, 4 equiv.) and 1 -methylpiperazine (23 pL, 207 pmol, 0.9 equiv.) and then the reaction was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150mm x 40mm x 10pm; mobile phase: 25-55% ACN in water (+NH4HCO3 modifier)) to afford the title compound (24.5 mg, 26% yield) as a white solid.

[0150] JH NMR (400MHz, DMSO-ri6) 8 8.98 (s, 1H), 8.31 (d, J= 1.6 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.88 (dd, J= 1.6, 8.8 Hz, 1H), 5.79 (q, J = 8.8 Hz, 2H), 3.55 (s, 4H), 2.35 (s, 4H), 2.21 (s, 3H).

[0151] LCMS: [M+l, M+3] = 412.1, 414.1.

[0152] Table 2. The examples in Table 2 were prepared in a similar manner to that described for example 35 using scheme 2.Example 43. l-|4-chloro-5-(2.2.2-trinuorocthyl) b|indol-8-yl|-N-mcthyl-methanamine

[0153] Scheme 3, step 1, 4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indole-8- carbaldehyde:

[0154] To a solution of [4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8- yl]methanol (0.2 g, 634 pmol, 1 equiv.) in DCE (2 mL) was added MnCE (550.8 mg, 6.34 mmol, 10 equiv.). The mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:0 to 10:1 petroleum ether: EtOAc) to afford the title compound (0.3 g, crude) as a yellow solid. This material was used in the next step without further purification.

[0155] LCMS: [M+H] = 314.0.

[0156] Scheme 3, step 2, l-[4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-yl1-N-methyl- methanamine:

[0157] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carbaldehyde (90.0 mg, 287 pmol, 1 equiv.) in DCE (1 mL) was added methanamine (2 M, 287 pL, 2 equiv.) and AcOH (33 pL, 574 pmol, 2 equiv.) and the mixture was stirred at RT for 0.5 hours. NaBH(OAc)3 (152 mg, 717 pmol, 2.5 equiv.) was added to the mixture, and the mixture was stirred at 25 °C for 1 hour. The reaction was filtered and the solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 (150mm x 40mm x 10pm); mobile phase: 15-50% ACN in water (+NH4HCO3 modifier)) to afford the title compound (54.6 mg, 57% yield) as a white solid.

[0158] JH NMR (400MHz, CHLOROFORM-d) 5 8.92 (s, 1H), 8.34 (s, 1H), 7.79 (dd, J = 1.6, 8.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 5.35 (q, J = 8.0 Hz, 2H), 3.98 (s, 2H), 2.51 (s, 3H).

[0159] LCMS: [M+H, M+3] = 329.0, 331.1.

[0160] Table 3. The examples in Table 3 were prepared in a similar manner to that described for Example 43 using Scheme 3.Example 51. N.N-dimcthyl- l - mcthylsullbnyl-5-(2.2.2-ti%luorocthyl )pyrimido|5.4-b|indol-8-yllmethanamine

[0161] To a solution of l-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]- N,N-dimethyl-methanamine (30.0 mg, 87.5 pmol, 1.0 equiv.) in DMA (1.0 mL) was added NaSCEMe (60.0 mg, 587.7 pmol, 6.7 equiv.). The mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to RT and purified by preparative HPLC (column: Phenomenex luna C18 80cm x 40mm x 3 mm; mobile phase: 15-55% ACN in water (+ formic acid modifier)) to afford the title compound (4.2 mg, 12% yield) as white solid.

[0162] JH NMR (400 MHz, DMSO-tfc) 8 9.28 (s, 1H), 8.27 (s, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.85 (dd, J = 1.6, 8.8 Hz, 1H), 5.95 (q, J= 8.8 Hz, 2H), 3.65 (s, 3H), 3.62 (s, 2H), 2.20 (s, 6H).

[0163] LCMS [M+l] = 387.0.Example 52, l-(4-bromo-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine

[0164] A mixture of l-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N,N- dimethyl -methanamine (30.0 mg, 87.5 pmol, 1.0 equiv.) and TMSBr (79.5 pL, 612.7 pmol, 7.0 equiv.) in ACN (2.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 40°C for 16 hours under an atmosphere of N2. The reaction mixture was quenched by the addition of saturate aqueous NaHCOa solution (5 mL), diluted with H2O (5 mL), and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna (80mm x 30mm x 3pm); mobile phase: 1-40% ACN in water (+TFA modifier)) to afford the title compound (8.5 mg, 25% yield) as a white solid.

[0165] JH NMR (400 MHz, DMSO-tfe) 8 8.90 - 8.85 (m, 1H), 8.22 (s, 1H), 8.19 - 8.15 (m, 1H), 8.03 - 7.96 (m, 1H), 7.83 - 7.76 (m, 1H), 5.84 - 5.73 (m, 2H), 3.67 (s, 2H), 2.23 (s, 6H).

[0166] LCMS: [M+l, M+3] = 387.1, 389.1.Example 53. l-[4-fhioro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-yl1-N,N-dimethyl- methanamine

[0167] To a solution of l-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]- N,N-dimethyl-methanamine (50.0 mg, 146 pmol, 1.0 equiv.) in ACN (1.0 mL) was added 1,4,7,10,13,16-hexaoxacyclooctadecane (3.9 mg, 14.6 pmol, 0.1 equiv.) and cesium fluoride (66.5 mg, 438 pmol, 3.0 equiv.) and tetramethylammonium chloride (1.6 mg, 14.6 pmol, 0.1 equiv.). The mixture was stirred at 60°C for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters XbridgePrep OBD C18 (150 x 40 mm x 10 pm); mobile phase: 30-55% ACN in water (+NH4HCO3 modifier)) to afford the title compound (20.4 mg, 21% yield) as a white solid.

[0168] ’ H NMR (400 MHz, DMSO-tfe) 3 8.81 (s, 1H), 8.18 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 5.52 (q, J = 9.2 Hz, 2H), 3.60 (s, 2H), 2.19 (s, 6H).

[0169] LCMS [M+ 1 ] = 327.1.Example 54, 4-fluoro-8-((4-methylpiperazin- l-yl)methyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido^5,4-b]indole

[0170] To a mixture of 1,4,7,10,13,16-hexaoxacyclooctadecane (10.6 mg, 40.2 umol, 0.1 equiv.) and cesium fluoride (183 mg, 1.2 mmol, 3.0 equiv.), tetramethylammonium chloride (4.4 mg, 40 umol, 0.1 equiv.) in ACN (4 mL) was added 4-chloro-8-[(4-methylpiperazin-l- yl)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (160 mg, 402 umol, 1.0 equiv.) in one portion at 25°C under an atmosphere of N2. The mixture was stirred at 60°C for 0.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 (100mm x 25mm x 5pm); mobile phase: 5-35% ACN in water (+ NH4HCO3 modifier)) to afford the title compound (37.0 mg, 24% yield) as a yellow solid.

[0171] JH NMR (400 MHz, CHLOROFORM-d) 3 8.81 (s, 1H), 8.34 (s, 1H), 7.77 (dd, J =1.2, 8.4 Hz, 1H), 7.53 (d, J= 8.8 Hz, 1H), 5.03 (q, J= 8.2 Hz, 2H), 3.74 (s, 2H), 2.82 - 2.42 (m, 8H), 2.37 (s, 3H).

[0172] LCMS [M+l] = 382.4.Example 120, 4-Fhioro-8-r(2-methyl-2,7-diazaspiro[3.51nonan-7-yl)methyl]-5-(2,2,2- trifluoroethylln yrimido [ 5 ,4-b] indole

[0173] Step 1, 4-chloro-8-r(2-methyl-2,7-diazaspiror3.51nonan-7-yl)methyl]-5-(2,2,2- trifluoroethyllp yrimido [ 5 ,4-b] indole:

[0174] 4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8-carbaldehyde (250 mg, 797 pmol, l.O equiv.), 2-methyl-2,7-diazaspiro[3.5]nonane hydrochloride (211 mg, 1.2 mmol, 1.5 equiv.) and AcOH (91 pL, 1.5 mmol, 2 equiv.) were combined in DCE (3.0 mL) and stirred at RT for 30 minutes. Then NaBH(OAc)3 (507 mg, 2.3 mmol, 3.0 equiv.) was added and the mixture was stirred at RT for 2 hours. The pH of the mixture was adjusted to pH = 9 with solid NaHCOa. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiCE, 10:1 DCM: MeOH) to afford the title compound (130 mg, 37% yield) as light- yellow solid.

[0175] LCMS: [M+l, M+3] = 438.3, 440.3.

[0176] Step 2, 4-fluoro-8-r(2-methyl-2,7-diazaspiro[3.51nonan-7-yl)methyl]-5-(2,2,2- trifluoroethyDpyrimido [ 5 ,4-b] indole:

[0177] A mixture of 4-chloro-8-[(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methyl]-5- (2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (75.0 mg, 171.2 pmol, 1.0 equiv.), 1,4,7,10,13,16- hexaoxacycloo ctadecane (4.5 mg, 17.1 pmol, 0.1 equiv.), cesium fluoride (78 mg, 514 pmol, 18.9 pL, 3.0 equiv.) and tetramethylammonium chloride (1.8 mg, 17.1 pmol, 0.1 equiv.) in acetonitrile (0.5 mL) was degassed with nitrogen and then the mixture was stirred at 60°C for 2 hours under an atmosphere of nitrogen. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x 10pm; mobile phase: 25-40% acetonitrile in water (+10 mM NH4HCO3)) to afford the title compound (2.0 mg, 1.3% yield) as a white solid.

[0178] LCMS: [M+l] = 442.3.

[0179] 1H NMR (400 MHz, CHLOROEORM-d) 5 = 8.81 (s, 1H), 8.30 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 5.03 (q, J = 8.0 Hz, 2H), 3.66 (s, 2H), 3.17 (s, 4H), 2.43 (s, 3H), 2.39 (br s, 3H), 1.81 (m, 5H).Example 121, N- fluoro-8-r(4-methylpiperazin-l-yl)methyl1-5-(2,2,2-trifhioroethyl)pyrimido [5, 4-b]indol-2-yl] methyl] -l-methyl-pyrazole-4-carboxamide

[0180] Example 121 was prepared in a similar manner as that described for Examples 54 and 120.

[0181] LCMS: [M+l] = 519.2.

[0182] ’ H NMR (400 MHz, DMSO-tfc): 3 8.78 (t, J= 6.0 Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J= 8.4 Hz, 1H), 5.49 (q, J= 8.8 Hz, 2H), 4.70 (d, J= 6.0 Hz, 2H), 3.87 (s, 3H), 3.65 (s, 2H), 2.49 - 2.17 (m, 8H), 2.14 (s, 3H).Example 55. 4-chloro-8-((pyridin-4-yloxy)methyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- bl indole

[0183] To a solution of pyridin-4-ol (8.5 mg, 89.7 pmol, 0.5 equiv.) and K2CO3 (74.4 mg, 539 pmol, 3.0 equiv.) in DMF (0.5 mL) was added 4-chloro-8-(chloromethyl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole (60.0 mg, 178 pmol, 1.0 equiv.) at 25°C. The mixture was stirred at 25 °C for 16 hours. The mixture was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150mm x 25mm x 10pm; mobile phase: 15-45% ACN in water (+formic acid modifier)) to afford the title compound (23.7 mg, 32% yield) as a white solid.

[0184] JH NMR (400 MHz, CHLOROFORM-d) 3 8.97 (s, 1H), 8.32 (s, 1H), 7.69 - 7.59 (m, 2H), 7.44 (d, J= 7.5 Hz, 2H), 6.47 (d, J= 7.6 Hz, 2H), 5.38 (q, J= 8.1 Hz, 2H), 5.17 (s, 2H).

[0185] ECMS [M+l, M+3] = 393.0, 395.0.Example 56. l-[4-chloro-2T2,2,24rifhioroethoxy)-5T2,2,2-trifluoroethyl)pyrimido[5,4- bl indol- 8-yll -N,N -dimethyl-methan amine

[0186] Step 1, 8-|(dimcthylamino)mcthyl |-5H-pyrimido|5.4-b|indolc-2.4-diol:

[0187] To a solution of 8-bromo-5H-pyrimido[5,4-b]indole-2,4-diol (2.0 g, 7.1 mmol, 1.0 equiv.) in 2-methylbutan-2-ol (24.0 mL), H2O (6.0 mL) was added CS2CO3 (4.6 g, 14.2 mmol, 2.0 equiv.) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'- amino-l,r-biphenyl)]palladium(II) methanesulfonate (614.4 mg, 714.0 pmol, 0.1 equiv.), and potassium[(dimethylamino)methyl]trifluoroborate (2.3 g, 14.2 mmol, 2.0 equiv.) under an atmosphere of nitrogen. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (100 mL) and H2O (100 mL), the aqueous layer was extracted with EtOAc (2 xlOO mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with EtOAc (5 mL) at 20°C for 30 minutes to afford the title compound (1.1 g, 60% yield) as a white solid.

[0188] JH NMR (400 MHz, DMSO-tfe) 5 11.69 - 11.04 (m, 3H), 7.83 (s, 1H), 7.53 - 7.16 (m, 2H), 3.42 (s, 2H), 2.14 (s, 6H).

[0189] Step 2, l-(2,4-dichloro-5H-pyrimido[5,4-b]indol-8-yl)-N,N-dimethyl- methanamine:

[0190] To a solution of 8-[(dimethylamino)methyl]-5H-pyrimido[5,4-b]indole-2,4-diol (1.1 g, 4.2 mmol, 1.0 equiv.) was added dichlorophosphorylbenzene (8.0 mL, 57.1 mmol, 13.4 equiv.). The mixture was stirred at 140°C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCOa (50 mL). The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and H2O (100 mL) and the aqueous layer was extracted with EtOAc (2 xlOO mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, 10:1 THE: MeOH) to afford the title compound (280.0 mg, crude) as yellow oil. This material was used in the next step without further purification.

[0191] LCMS [M+l, M+3] = 295.3, 297.3.

[0192] Step 3. l -|4-chloro-2-(2.2.2-trinuorocthoxy)-5-(2.2.2-trinuorocthyl )pyrimido|5.4- b]indol-8-yl]-N,N-dimethyl-methanamine:

[0193] To a solution of l-(2,4-dichloro-5H-pyrimido[5,4-b]indol-8-yl)-N,N-dimethyl- methanamine (35.0 mg, 118.5 pmol, 1.0 equiv.) in DMF (0.5 mL) was added NaH (14.2 mg, 355.7 pmol, 60.0% purity, 3.0 equiv.) at 0°C, and then was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (55.0 mg, 237.1 pmol, 2.0 equiv.) at 20°C for 2 hrs. LC-MS showed 1 / 3 of starting material was remained and one main peak with desired mass was detected. The reaction mixture solution was quenched by H2O 5 mL at 0°C, and extracted with EtOAc (8 mL) and the organic layers was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x 10pm; mobile phase: 40-70% ACN in water (+NH4HCO3 modifier)) to afford the title compound (3.1 mg, 5.8% yield) as a white solid.

[0194] JH NMR (400 MHz, DMSO-ri6) 8 8.09 (s, 1H), 7.92 (d, 7= 8.8 Hz, 1H), 7.74 (dd, J= 1.2, 8.8 Hz, 1H), 5.46 (q, J= 8.8 Hz, 2H), 5.32 (q, J= 8.8 Hz, 2H), 3.59 (s, 2H), 2.19 (s, 6H).

[0195] LCMS [M+l, M+3] = 440.8, 442.Example 57, 4-chloro-N-(4-pyridyl methyl )-5-(2.2.2-tiriluorocthyl )pyrimido| 5.4-b I indol-8-

[0196] Scheme d, step L 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b] indole-8- carboxylic acid:

[0197] To a solution of methyl 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido [5,4-b]indole-8- carboxylate (1.4 g, 422 pmol, 1 equiv.) in DCE (15 mL) was added hydroxy (trimethyl) stannane (6.1 g, 3,375 pmol, 8 equiv.) and the mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched by the additiona of an aqeous solution of FK (10 mL) and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reducedpressure. The resulting residue was triturated with HC1 (1 M, 50 mL) which resulted in a precipitate that was filtered off to afford the title compound (600 mg, 43% yield) as a white solid.

[0198] JH NMR (400 MHz, DMSO-tfc) 3 13.15 (s, 1H), 9.00 (s, 1H), 8.84 (s, 1H), 8.36 (dd, J= 1.6, 8.8 Hz, 1H), 8.13 (d, J= 8.8 Hz, 1H), 5.79 (q, J= 8.4 Hz, 2H).

[0199] LCMS: [M+l, M+3] = 330.0, 331.9.

[0200] Example 58, Scheme 4, step 2, tert-Butyl N-[4-chloro-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indol-8-yl1carbamate:

[0201] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carboxylic acid (200 mg, 607 pmol, 1 equiv.) in t-BuOH (4 mL) was added TEA (253 pL, 182 pmol, 3 equiv.) and DPPA (250.44 mg, 910.0 pmol, 197.20 pL, 1.5 equiv.). The mixture was stirred at 90°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x 1 pm; mobile phase: 50-70% ACN in water (+ NH4HCO3 modifier)) to afford the title compound (23.5 mg, 21% yield) as a white solid.

[0202] 1H NMR (400 MHz, DMSO-tfc) d 9.64 (s, 1H), 8.90 (s, 1H), 8.48 (s, 1H), 7.94 (d,J= 9.2 Hz, 1H), 7.83 (dd, J= 2.0, 8.8 Hz, 1H), 5.68 (q, J= 8.6 Hz, 2H), 1.52 (s, 9H).

[0203] LCMS: [M+l, M+3] = 401.4, 403.4.

[0204] Example 59, Scheme 4, step 3. 4-chloro-5-(2,2,2-trifluoroethyl) pyrimido[5,4- b]indol-8-amine:

[0205] To a solution of tert-butyl N-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl] carbamate (80 mg, 200 pmol, 1 equiv.) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 20°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Phenomenex luna C18 100mm x 40mm x 5pm; mobile phase: 5-35% ACN in water (+formic acid modifier)) to afford the title compound (19.8 mg, 29% yield) as a yellow solid (formic acid salt).

[0206] ’ H NMR (400 MHz, DMSO-tfc) d 8.80 (s, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.16 (dd, J= 2.0, 8.8 Hz, 1H), 5.60 (q, J= 8.8 Hz, 2H), 5.27 (br s, 2H).

[0207] LCMS: [M+l, M+3] = 301.0, 302.8.

[0208] Scheme 4, step 4A. 4-chloro-N-(4-pyridylmethyl)-5-(2,2,2- trifluoroethyDpyrimido [ 5 ,4-b] indol- 8-amine:

[0209] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-amine (80.0 mg, 266.0 pmol, 1 equiv.), pyridine-4-carbaldehyde (57 mg, 532 pmol, 2 equiv.) andAcOH (30 pL, 532 pmol, 2 equiv.) in DCE (1 mL) was added NaBH(OAc)3 (197 mg, 931 pmol, 3.5 equiv.). The mixture was stirred at 25°C for 1 hour. The pH was adjusted to ~9 by addition of a saturated aqueous solution of NaHCOa. The mixture was extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water, dried over NaaSCU, filtered, and concentrated. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x 10pm; mobile phase: 35-55% ACN in water (+ NH4HCO3 modifier)) to afford the title compound (40.0 mg, 38% yield) as yellow solid.

[0210] 1H NMR (400 MHz, DMSO-tfe) 8 8.77 (s, 1H), 8.50 (d, J = 6.0 Hz, 2H), 7.78 (d, J= 8.8 Hz, 1H), 7.41 (d, J= 6.0 Hz, 2H), 7.29 (dd, J = 2.0, 8.8 Hz, 1H), 7.13 (d, J= 2.4 Hz, 1H), 6.66 (t, J= 6.4 Hz, 1H), 5.60 (q, J= 8.8 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H).

[0211] LCMS: [M+l M+3] = 391.8, 393.8.Example 60. N-r4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-yl1-l-methyl- piperidine-4-carboxamide

[0212] Scheme 4, step 4B. N-r4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-yl1- l-methyl-piperidine-4-carboxamide:

[0213] To a mixture of l-methylpiperidine-4-carboxylic acid (41.9 mg, 293 pmol, 1.1 equiv.) in DMF (1.0 mL) was added HATU (152 mg, 399 pmol, 1.5 equiv.), DIEA (185 pL, 1.1 mmol, 4.0 equiv.) and 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-amine (80.0 mg, 266 pmol, 1.0 equiv.) and the mixture was stirred at RT for 2 hours. The mixture was filtered to remove the insoluble materials and concentrated in vacuum. The resulting residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150mm x 40mm x 10pm; mobile phase: 15-45% ACN in water (+NH4HCO3 modifier)) to afford the title compound (22.1 mg, 19% yield) as a white solid.

[0214] ’ H NMR (400 MHz, DMSO-tfc) d 10.14 (s, 1H), 8.91 (s, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.02 - 7.87 (m, 2H), 5.69 (q, J= 8.8 Hz, 2H), 2.88 - 2.79 (m, 2H), 2.35 - 2.28 (m, 1H), 2.16 (s, 3H), 1.88 (dt, 7 = 2.0, 11.2 Hz, 2H), 1.81 - 1.63 (m, 4H).

[0215] LCMS: [M+l, M+3] = 425.8, 427.8.

[0216] Table 4. The examples in Table 4 were prepared in a similar manner as that described for Examples 57 or 60.Example 62, 4-chloro-8-(4-mcthylpipcrazin- l-yl)-5-(2.2.2-trifluorocthyl)-5H-pyrimido|5.4- bl indole

[0217] Scheme 5, step 1, Ethyl (2-cyano-4-iodophcnyl )glycinatc:

[0218] To a solution of 2-fluoro-5-iodobenzonitrile (2.0 g, 8.1 mmol, 1.0 equiv.) in NMP (20.0 mL) was added ethyl glycinate-HCl (2.3 g, 16.1 mmol, 2.0 equiv.) and DIEA (4.2 mL, 24.2 mmol, 3.0 equiv.) at 25°C. The mixture was stirred at 110°C for 12 hours. The mixture was cooled to 25°C and poured into H2O (50 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100:0 to 9:1 petroleum ether:EtOAc) to afford the title compound (1.2 g, 45% yield) as a white solid.

[0219] JH NMR (400 MHz, CHLOROFORM-7) 37.69 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 1.8, 8.8 Hz, 1H), 6.35 (d, 7= 8.8 Hz, 1H), 5.21 (br s, 1H), 4.28 (q, 7 = 7.2 Hz, 2H), 3.96 (d, 7 = 5.4 Hz, 2H), 1.31 (t, 7 = 7.2 Hz, 3H).

[0220] LCMS [M+l] = 331.1.

[0221] Scheme 5, step 2, l-(fert-butyl) 2-ethyl 3-amino-5-iodo-lH-indole-l,2- dicarboxylate:

[0222] A mixture of ethyl (2-cyano-4-iodophenyl)glycinate (1.0 g, 3.0 mmol, 1.0 equiv.), BOC2O (1.3 mL, 6.0 mmol, 2.0 equiv.), DMAP (37.0 mg, 303 pmol, 0.1 equiv.) and TEA (422 pL, 3.0 mmol, 1.0 equiv.) in DMF (10.0 mL) was degassed and purged with N2 3 times at 25°C, and then the mixture was stirred at 50°C for 2 hours under an atmosphere of nitrogen. The mixture was cooled to 25°C and poured into H2O (50 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100:0 to 10: 1 petroleum ether:EtOAc) to afford the title compound (1.2 g, 92% yield) as a colorless oil.

[0223] 1H NMR (400 MHz, CHLOROFORM-7) 37.96 (s, 1H), 7.89 (br d, 7 = 8.4 Hz,1H), 7.38 - 7.28 (m, 1H), 4.24 (m, 2H), 1.63 - 1.49 (m, 4H), 1.44 - 1.39 (m, 5H), 1.33 - 1.24 (m, 3H).

[0224] Scheme 5, step 3. l-(fert-butyl) 2-ethyl 3-(((dimethylamino)methylene)amino)-5- iodo- IH-indole- 1 ,2-dicarboxylate:

[0225] To a solution of 1 -(tert-butyl) 2-ethyl 3-amino-5-iodo-lH-indole-l,2- dicarboxylate (800 mg, 1.86 mmol, 1.0 equiv.) in DMF (8.0 mL) was added 1,1-dimethoxy- N,N-dimethylmethanamine (321 pL, 2.42 mmol, 1.3 equiv.) at 25°C. The mixture was stirred at 100°C for 16 hours. The mixture was cooled to 25 °C and poured into H2O (30 mL). The aqueous phase was extracted with EtOAc (3 x50 mL). The combined organic extracts werewashed with brine (3 x30 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100:0 to 5:1 petroleum ether: EtOAc) to afford the title compound (530 mg, 59% yield) as a yellow oil.

[0226] JH NMR (400 MHz, CHLOROEORM-d) 3 8.00 (s, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.66 (dd, J= 1.8, 8.8 Hz, 1H), 4.29 (q, J= 7.0 Hz, 2H), 3.10 (br d, J= 5.6 Hz, 6H), 1.61 (s, 9H), 1.35 - 1.28 (m, 3H).

[0227] LCMS [M+l] = 486.3.

[0228] Scheme 5, step 4, 8-Iodo-5H-pyrimido[5,4-b]indol-4-ol:

[0229] To a solution of 1 -(tert-butyl) 2-ethyl 3-(((dimethylamino)methylene)amino)-5- iodo-lH-indole-l,2-dicarboxylate (400 mg, 824 pmol, 1.0 equiv.) in EtOH (5.0 mL) was added NH3 H2O (5.0 mL) at 25 °C. The mixture was stirred at 70°C for 16 hours. The reaction mixture was filtered and the filter cake was washed with H2O (30 mL) and dried under reduced pressure to afford the title compound (180 mg, 70% yield) as a white solid.

[0230] ’ H NMR (400 MHz, DMSO-tfe) 3 12.46 - 12.21 (m, 2H), 8.29 (d, J= 1.4 Hz, 1H), 8.01 (s, 1H), 7.71 (dd, J = 1.6, 8.6 Hz, 1H), 7.38 (d, J= 8.6 Hz, 1H).

[0231] Scheme 5, step 5. 4-chloro-8-iodo-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4- blindole:

[0232] To a solution of 4-chloro-8-iodo-5H-pyrimido[5,4-b]indole (130 mg, 395 pmol, 1.0 equiv.) in DME (2.5 mL) was added NaH (47.34 mg, 1.1 mmol, 3.0 equiv.; 60% dispersion in oil) at 0°C and stirred at 20°C for 0.5 hours under an atmosphere of nitrogen. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (183.1 mg, 789.0 pmol, 2.0 equiv.) was added to the reaction mixture. The mixture was stirred at 25 °C for 16 hours under atmosphere of nitrogen. The reaction mixture solution was quenched by the addition of a saturated aqeous solution of NH4CI (10 mL) at 0°C, and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150mm x 25mm x 10pm; mobile phase: 54%-84% ACN in water (+ formic acid modifier)) to afford the title compound (17.7 mg, 11% yield) as a white solid.

[0233] ’ H NMR (400 MHz, CHLOROEORM-d) 3 8.95 (s, 1H), 8.76 (d, J= 1.8 Hz, 1H), 8.02 (dd, J= 1.6, 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 5.33 (q, J = 8.2 Hz, 2H).

[0234] LCMS [M+l, M+3] = 411.8, 413.8.

[0235] Scheme 5, step 6. 8-iodo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- blindole:

[0236] To a solution of 4-chloro-8-iodo-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (100 mg, 243 pmol, 1.0 equiv.) in MeOH (1.0 mL) was added NaOMe (0.6 mL) at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H2O (15 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (90.0 mg, 91% yield) as a white solid.

[0237] JH NMR (400 MHz, CHLOROFORM-d) 3 8.75 - 8.67 (m, 2H), 7.91 (dd, 7 = 1.8, 8.8 Hz, 1H), 7.32 (d, J= 8.6 Hz, 1H), 5.14 (q, J= 8.3 Hz, 2H), 4.24 (s, 3H).

[0238] LCMS [M+l] = 408.0.

[0239] Scheme 5, step 7, 4-methoxy-8-(4-methylpiperazin-l-yl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido[5,4-b]indole:

[0240] To a solution of 8-iodo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (80.0 mg, 196.5 pmol, 1.0 equiv.) and 1 -methylpiperazine (43.5 pL, 393.0 pmol, 2.0 equiv.) in dioxane (1.0 mL) was added sodium tert-butoxide (197 pL, 2.0 equiv.; 2 M in dioxane) and Xantphos Pd G4 (18.9 mg, 19.6 pmol, 0.1 equiv.) at 25°C under an atmosphere of nitrogen. The mixture was stirred at 90°C for 1 hour. The mixture was cooled to 25°C and poured into H2O (20 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the title compound (60.0 mg, 80% yield) as a yellow solid.

[0241] 1H NMR (400 MHz, CHLOROFORM-d) 3 8.69 (s, 1H), 7.79 (s, 1H), 7.44 - 7.41(m, 2H), 5.11 (q, J= 8.3 Hz, 2H), 4.22 (s, 3H), 3.32 - 3.21 (m, 4H), 2.67 - 2.57 (m, 4H), 2.39 (s, 3H).

[0242] Scheme 5, step 8. 4-chloro-8-(4-methylpiperazin-l-yl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido[5,4-b]indole:

[0243] A solution of 4-methoxy-8-(4-methylpiperazin-l-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido [5, 4-b] indole (50.0 mg, 131.7 pmol, 1.0 equiv.) in POCI3 (1 mL) was stirred at 110°C for 16 hours. The reaction mixture was cooled to RT and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 150mm x 25mm x 10pm; mobile phase: 39-89% ACN in water (+ formic acid modifier)) to afford the title compound (21.4 mg, 41% yield) as a yellow solid.

[0244] JH NMR (400 MHz, CHLOROFORM-d) d 8.90 (s, 1H), 7.87 (s, 1H), 7.55 - 7.44 (m, 2H), 5.31 (q, J= 8.2 Hz, 2H), 3.62 - 3.42 (m, 4H), 3.06 (br d, J = 4.4 Hz, 4H), 2.66 (s, 3H).

[0245] LCMS [M+l, M+3] = 384.0, 386.0.

[0246] Table 6. The examples in Table 6 were prepared in a similar manner as was described for Example 62 in scheme 5.Example 63. 4-chloro-8-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido [5, 4-b] indole

[0247] To a solution of 4-chloro-8-iodo-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (80 mg, 194 pmol, 1.0 equiv.) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (52 mg, 233 pmol, 1.2 equiv.) in dioxane (1 mL) and H2O (0.2 mL) was added Na2COa (61.8 mg, 583 pmol, 3 equiv.) and Pd(dppf)Ch (14.2 mg, 19.4 pmol, 0.1 equiv.) at 20°C under an atmosphere of nitrogen. The mixture was stirred at 100°C for 1 hour. The mixture was cooled to RT and then poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150mm x 25mm x 10pm; mobile phase: 11-41% ACN in water (+formic acid modifier)) to afford the title compound (18.6 mg, 14% yield) as a white solid.

[0248] JH NMR (400 MHz, METHANOL-^) d 8.88 (s, 1H), 8.44 (d, J= 1.6 Hz, 1H), 8.00 (dd, J= 1.8, 8.8 Hz, 1H), 7.87 (d, 7 = 9.0 Hz, 1H), 6.30 (td, J= 1.8, 3.3 Hz, 1H), 5.63 (q, J = 8.6 Hz, 2H), 3.74 (br d, J = 2.8 Hz, 2H), 3.35 (t, J = 6.0 Hz, 2H), 3.00 - 2.93 (m, 2H), 2.84 (s, 3H).

[0249] LCMS [M+l, M+3] = 381.0, 383.0.Example 64, l-[2,4-dichloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8-yl1-N,N- dimethyl-methan amine

[0250] Scheme 6, step 1, 2-(4-bromo-2-cyano-anilino)acetamide:

[0251] To a mixture of 5-bromo-2-fluoro-benzonitrile (5 g, 25.0 mmol, 1 equiv.) and 2- aminoacetamide;hydrochloride (3.04 g, 27.5 mmol, 1.1 equiv.) in DMSO (50 mL) was added K2CO3 (10.37 g, 75.0 mmol, 3 equiv.) at RT. The mixture was stirred at 100°C for 3 hours. The mixture was quenched by the addition of H2O (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with H2O (3 x 50 mL), dried with Na2SO4, filtered, and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography (1:0 to 0:1 petroleum ether: EtOAc) to afford the title compound (2.3 g, 36% yield) as a yellow solid.

[0252] JH NMR (400 MHz, DMSO-tfe) 87.72 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 2.4, 9.2 Hz, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.39 (t, J= 5.6 Hz, 1H), 3.75 (d, J = 5.6 Hz, 2H).

[0253] Scheme 6, step 2, 3-amino-5-bromo-lH-indole-2-carboxamide:

[0254] A mixture of 2-(4-bromo-2-cyano-anilino)acetamide (5 g, 19.7 mmol, 1 equiv.) and sodium isopropoxide (1.62 g, 19.7 mmol, 1 equiv.) in IPA (50 mL) was stirred at 95 °C for 1 hour. The mixture was concentrated and diluted with H2O (30 mL). The pH of the mixture was adjusted to 4 with 2 N HC1 and then extracted with EtOAc (15 mL). The organic layer was discarded. The pH of the aqueous layer was adjusted to pH = 8 with solid Na2COa and then extracted with EtOAc (3 x15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduce pressure to afford the title compound (3.0 g, 53% yield) as a red solid.

[0255] ’ H NMR (400 MHz, DMSO-tfc) d 10.39 (s, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.30 - 7.18 (m, 2H), 7.12 (s, 2H), 5.61 (s, 2H).

[0256] LCMS: [M+l, M+3] = 254.0, 256.0.

[0257] Scheme 6, step 3. 8-bromo-5H-pyrimido[5,4-b]indole-2,4-diol:

[0258] To a solution of 3-amino-5-bromo-lH-indole-2-carboxamide (4 g, 15.7 mmol, 1 equiv.) in dioxane (100 mL) was added trichloromethyl chloroformate (4.52 g, 22.8 mmol, 1.45 equiv.) at 25°C. The mixture was stirred at 110 °C for 2 hours. The mixture was quenched by the addition of H2O (40 mL). The resulting precipitate was filtered off and thesolid was concentrated under reduce pressure to afford the title compound (3 g, crude) as yellow solid.

[0259] *H NMR (400 MHz, DMSO-tfc) <5 11.96 (s, 1H), 11.56 (s, 1H), 11.14 (s, 1H), 8.13 (d, J= 1.6 Hz, 1H), 7.46 (d, J= 1.6, 8.8 Hz, 1 H), 7.36 (d, 7=8.8 Hz, 1H).

[0260] Scheme 6, step 4, 8-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole:

[0261] A mixture of 8-bromo-5H-pyrimido[5,4-b]indole-2,4-diol (1.0 g, 3.57 mmol, 1.0 equiv.) in dichlorophosphorylbenzene (6.96 g, 35.7 mmol, 5.01 mL, 10.0 equiv.) was degassed and purged with nitrogen 3 times and then the mixture was stirred at 180°C for 3 hours under an atmosphere of nitrogen. The reaction mixture was quenched by the addition of a saturated aqueous solution of NaHCOa (100 mL) at RT. The mixture was extracted with EtOAc (3 x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (5:1 to 1:1 petroleum ether: EtOAc) to afford the title compound (600 mg, 52% yield) as a light- yellow solid.

[0262] 1H NMR (400 MHz, DMSO-tfc) 8 12.78 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.86(dd, 7= 2.0, 8.8 Hz, 1H), 7.65 (d, 7= 8.8 Hz, 1H).

[0263] LCMS [M+l, M+3] =316.1, 318.1.

[0264] Scheme 6, step 5. 8-bromo-2,4-dichloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4- blindole:

[0265] To a mixture of 8-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole (550 mg, 1.7 mmol, 1 equiv.) in DMF (5.5 mL) was added NaH (174 mg, 4.3 mmol, 2.5 equiv.; 60% dispersion in oil) at 0°C. The mixture was stirred at 25°C for 0.5 hours. Then 2,2,2- trifluoroethyl trifluoromethanesulfonate (1.0 g, 4.3 mmol, 2.5 equiv.) was added and the mixture was stirred at 25 °C for 2 hours. The mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (3 x lOmL). The combined organic extracts were washed with brine (3 xlO mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (1:0 to 0:1 petroleum ether: EtOAc) to afford the title compound (400 mg, 58% yield) as a yellow solid.

[0266] ’ H NMR (400 MHz, DMSO-76) d = 8.49 (d, 7 = 1.2 Hz, 1H), 8.10 - 8.01 (m, 2H), 5.75 (q, 7= 8.8 Hz, 2H).

[0267] LCMS: [M+l, M+3] = 398.0, 400.0.

[0268] Scheme 6, step 6. 2-chloro-8-r(dimethylamino)methyl]-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indol-4-ol:

[0269] To a mixture of 8-bromo-2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (500 mg, 1.25 mmol, 1 equiv.) and potassium[(dimethylamino)methyl]trifluoroborate (414 mg, 2.51 mmol, 2 equiv.) in 2- methylbutan-2-ol (5 mL) was added CS2CO3 (816.6 mg, 2.51 mmol, 2 equiv.) in H2O (1.3 mL) and [ 1 ,1 '-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (81.6 mg, 125.3 pmol, 0.1 equiv.) at 25 °C under an atmosphere of nitrogen. The mixture was stirred at 80°C for 16 hours. The mixture was cooled to RT, filtered, and concentrated under reduce pressure. The resulting residue was purified by preparative TLC (SiCT, 4:1 DCM:MeOH) to afford the title compound (120 mg, crude) as a brown solid. This material was used directly in the next step.

[0270] LCMS: [M+l, M+3] = 359.3, 361.2.

[0271] Scheme 6, step 7, l-[2,4-dichloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8- ylTN,N-dimethyl-methanamine:

[0272] A solution of 2-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-4-ol (110 mg, 307 pmol, 1 equiv.) in POCI3 (2 mL) was stirred at 110°C for 16 hours. The mixture was cooled to RT and poured into saturated aqueous NaHCCL (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried with Na2SO4, filtered, and concentrated under reduce pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x 10pm; mobile phase: 40-70% ACN in water (+NH4HCO3 modifier)) to afford the title compound (14.2 mg, 12% yield) as a brown solid.

[0273] JH NMR (400 MHz, DMSO-d) 3 8.18 (s, 1H), 8.02 (d, J= 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 5.72 (q, J = 8.8 Hz, 2H), 3.62 (s, 2H), 2.21 (s, 6H).

[0274] LCMS: [M+l, M+3] = 376.8, 378.7.Example 148. 1 - [ 4-chloro-5-(2,2,2-trifluoroethyl)-2- [ 4-(trifluoromethyl)phenyl] pyrimido [5,4- b] indol- 8-yl] -N,N -dimethyl-methan amine

[0275] Step 1, 8-r(dimethylamino)methyl]-5-(2,2,2-trifhioroethyl)-2-[4-(trifhioromethyl)- phenyl] pyrimido [ 5 ,4-b I i ndol -4-ol :

[0276] To a mixture of 2-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-4-ol (100 mg, 279 pmol, 1 equiv.) and (114 mg, 418 pmol, 1.5 equiv.) in dioxane (1 mL) and H2O (0.1 mL) was added K2CO3 (116 mg, 836 pmol, 3 equiv.). The mixture was degassed with nitrogen and Pd(PPh3)4 (10.3 mg, 27.9 pmol, 0.1 equiv.) was added. The mixture was stirred at 100°C for 2 hours. The mixture was concentrated under reduce pressure to give a residue which was purified by preparative TLC (SiO2, 10:1 ethyl acetate: methanol) to afford the title compound (100 mg, crude) as a white solid.

[0277] LCMS: [M+l] = 469.2.

[0278] Step 2, l-[4-chloro-5-(2,2,2-trifhioroethyl)-2-[4-(trifhioromethyl)phenyl]-Pyrimido[5,4-b]indol-8-yl1-N,N-dimethyl-methan amine:

[0279] A solution of 8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)-2-[4- (trifluoromethyl)phenyl]pyrimido[5,4-b]indol-4-ol (100 mg, 213.5 pmol, equiv.) in POCI3 (1 mL) was stirred at 110°C for 1 hour. The residue was concentrated under reduce pressure to give a residue. The reaction mixture was cooled to RT and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100mm x 30mm x 5pm;mobile phase: 30-60% acetonitrile in water (+0.2% formic acid)) to afford the title compound (18.8 mg, 18% yield) as a white solid.

[0280] LCMS: [M+l, M+3] = 487.2, 489.2.

[0281] JH NMR (400 MHz, DMSO-d6) 3 8.68 (d, J = 8.4 Hz, 2H), 8.37 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 5.77 (q, J = 8.8 Hz, 2H), 3.76 (s, 2H), 2.31 (s, 6H).Example 149. l-(4-chloro-2-(l-methyl-lH-pyrazol-4-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indol-8-yl)-N,N-dimethylmethanamine

[0282] Scheme 7, step 1, 8-bromo-2.4-dichloro-5-(2.2.2-trinuorocthyl )pyrimido|5.4- blindole:

[0283] To a solution of 8-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole (27 g, 85.2 mmol, 1 equiv.) in DMF (270 mL) was added K2CO3 (23.5 g, 170 mmol, 2 equiv.) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (39.5 g, 170 mmol, 2 equiv.) at RT. The mixture was stirred at RT for 4 hours. The mixture was diluted with water and extracted with ethylacetate. The combined organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (3:1 petroleum ether: ethyl acetate) to afford the title compound (28 g, 82% yield) as a yellow solid.

[0284] LCMS: [M+l, M+3] = 398.1, 400.1.

[0285] Scheme 7, step 2, 8-bromo-2-chloro-4-methoxy-5-(2,2,2- trifluoroethvDp yrimido [ 5 ,4-b] indole:

[0286] To a solution of 8-bromo-2,4-dichloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole in methanl (50 mL) was added NaOMe (1.13 g, 6.27 mmol, 1 equiv.; 30% solution in methanol). The mixture was heated to 60°C for 30 minutes. The reaction was cooled to RT, diluted with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine (5 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (5.1 g, crude) as a lightyellow solid.

[0287] LCMS: [M+l, M+3] = 393.9, 395.9.

[0288] Step 3 , 1 - [ 2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)p yrimido [ 5 ,4-b] indol- 8- yl] -N,N-dimethyl-methanamine:

[0289] To a mixture of 8-bromo-2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)- pyrimido [5, 4-b] indole (4.6 g, 11.7 mmol, 1 equiv.) and potassium ((dimethylamino)methyl)trifluoroborate (2.31 g, 14.0 mmol, 1.2 equiv.) in 2-methylbutan-2- ol (46 mL) was added CS2CO3 (7.60 g, 23.3 mmol, 2 equiv.) in H2O (10 mL) and [1,1 '-bis(di- tert-butylphosphino)ferrocene]dichloropalladium(II) (760 mg, 1.17 mmol, 0.1 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 80°C for 5 hours. The mixture was cooled to RT and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (3.2 g, 68% yield) as a pink solid.

[0290] LCMS: [M+l, M+3] = 373.1, 375.1.

[0291] Scheme 7, step 4, l-[4-methoxy-2-(l-methylpyrazol-4-yl)-5-(2,2,2-trifluoroethyl)- 2,3- dihydropyrimido|5.4-b|indol-8-yl |-N.N-dimcthyl-mcthanaminc:

[0292] To a mixture of l-[2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine (200 mg, 537 pmol, 1 equiv.) and l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (167 mg, 805 pmol, 1.5 equiv.) in H2O (0.2 mL) and dioxane (2 mL) was added Pd(PPh3)4 (62.0 mg, 53.7 pmol, 0.1 equiv.) and K2CO3 (222 mg, 1.61 mmol, 3 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 100°C for 12 hours. The mixture was cooled to RT and water (1 mL) was added and the mixture was extracted with EtOAc (3 x 1 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduce pressure. The residue was purified by preparative TLC (SiCL, 10:1 ethyl acetate: methanol) to afford the title compound (120 mg, 53% yield) as a yellow solid.

[0293] LCMS: [M+l] = 419.3.

[0294] Scheme 7, step 5, l-(4-chloro-2-(l-methyl-lH-pyrazol-4-yl)-5-(2,2,2- trifhioroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N-dimethylmethan amine:

[0295] A mixture of l-[4-methoxy-2-(l-methylpyrazol-4-yl)-5-(2,2,2-trifluoroethyl)-2,3- dihydropyrimido[5,4-b]indol-8-yl]-N,N-dimethyl-methanamine (100 mg, 238 pmol, 1 equiv.) in dichlorophosphorylbenzene (1 mL, 7.14 mmol, 30.0 equiv.) was stirred at 140°C for 2 hours. The mixture was cooled to RT and poured into saturated aqueous NaHCCL (5 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine, dried with Na2SO4 and concentrated under reduce pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100mm x 30mm x 5p m; mobile phase: 15-45% acetonitrile in water (+0.2% formic acid)) to afford the title compound (49.4 mg, 49% yield) as a white solid.

[0296] LCMS: [M+l, M+3] = 423.2, 425.3.

[0297] JH NMR (400 MHz, DMSO-tfe) d 8.47 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 5.68 (q, J = 8.8 Hz, 2H), 3.93 (s, 3H), 3.60 (s, 2H), 2.20 (s, 6H).

[0298] Table 7. The examples in Table 7 were prepared in a similar manner as was described for Example 149 in scheme 7.Example 152, 4-Chloro-2-methyl-8-[(4-methylpiperazin-l-yl)methyl]-5-(2,2,2- tri 0 uorocth y 1 )p y ri m ido [ 5 ,4-b] indole

[0299] Step 1. 2-Chloro-4-mcthoxy-5-(2.2.2-ti%]uorocthyl )-8- vinyl-pyri midol 5.4- blindole:

[0300] To a mixture of 8-bromo-2-chloro-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido [5, 4-b] indole (2.0 g, 5.0 mmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2- vinyl-l,3,2-dioxaborolane (859 mg, 5.58 mmol, 1.1 equiv.) in 2-methylbutan-2-ol (32 mL) and H2O (8 mL) was added CS2CO3 (1.82 g, 5.58 mmol, 1.1 equiv.) and [l,l'-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (330 mg, 507 pmol, 0.1 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred 80°C and stirred for 1 hour. The reaction mixture was cooled to RT and extracted with CH2Q2 (3 x 20 ml). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15- 50% ethylacetate in petroleum ether) to afford the title compound (540 mg, 31% yield) as a white solid.

[0301] LCMS: [M+l, M+3] = 342.0, 344.0.

[0302] JH NMR (400 MHz, CHLOROFORM-d) 3 8.31 (s, 1H), 7.74 (dd, J = 1.6, 8.8 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 6.86 (dd, J = 10.8, 17.6 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 5.31 (d, J= 10.8 Hz, 1H), 5.08 (q, J= 8.4 Hz, 2H),4.24 (s, 3H).

[0303] Step 2, 4-methoxy-2-methyl-5-(2,2,2-trifhioroethyl)-8-vinyl-pyrimido[5,4- blindole:

[0304] To a mixture of 2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl- pyrimido [5, 4-b] indole (540 mg, 1.58 mmol, 1.0 equiv.) and 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (397 mg, 3.16 mmol, 2.0 equiv.) in toluene (5.0 mL) and H2O (1.0 mL) was added Pd(OAc)2 (71 mg, 316 pmol, 0.2 equiv.), tricyclohexylphosphine (89 mg, 316 pmol, 0.2 equiv.) and K3PO4 (1.68 g, 7.90 mmol, 5.0 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 120°C for 16 hours. The reaction mixture was cooled to RT and extracted with CH2CI2 (3 x 25 ml). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3-5% ethyl acetate in petroleum ether to affored the title compound (170 mg, 33% yield) as a green solid.

[0305] LCMS: [M+l] = 322.1.

[0306] Step 3. 4-methoxy-2-methyl-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indole-8- carbaldehyde:

[0307] To a mixture of 4-methoxy-2-methyl-5-(2,2,2-trifluoroethyl)-8-vinyl- pyrimido [5, 4-b] indole (170 mg, 529 pmol, 1.0 equiv.) in dioxane (2.0 mL) and H2O (1.0 mL) was added K2OSO4 2H2O (4.9 mg, 13.2 pmol, 0.025 equiv.), NalCL (566 mg, 2.65 mmol, 5.0 equiv.), 2,6-dimethylpyridine (185 pL, 1.59 mmol, 3.0 equiv.) at RT under and atmosphere of nitrogen. The mixture was stirred at RT for 1 hour. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate to afford the title compound (150 mg, 88% yield) as a white solid.

[0308] LCMS: [M+l] = 324.2.

[0309] ’ H NMR (400 MHz, CHLOROFORM-d) 3 10.13 (s, 1H), 8.85 (d, J = 1.2 Hz, 1H), 8.20 (dd, J = 1.6, 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 5.18 (q, J = 8.4 Hz, 2H), 4.23 (s, 3H), 2.84 - 2.77 (m, 3H).

[0310] Step 4, 4-methoxy-2-methyl-8-r(4-methylpiperazin-l-yl)methyl]-5-(2,2,2- trifluoroethvDp yrimido [ 5 , 4-b] indole:

[0311] To a mixture of 4-methoxy-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-8-carbaldehyde (100 mg, 309 μmol, 1.0 equiv.) and 1-methylpiperazine (69 μL, 619 μmol, 2.0 equiv.) in DCE (1.0 mL) was added AcOH (17.7 μL, 309 μmol, 1.0 equiv.) at RT. Then NaBH(OAc)3 (196.6 mg, 928.0 μmol, 3.0 equiv.) was added and the mixture was stirred at RT for 2 hours. Water (10 mL) was added dropwise into the reaction mixture and the pH was adjusted to pH = 8 with an aqueous saturated solution of NaHCO3. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford the title compound (100 mg, 79% yield) as a yellow solid.

[0312] LCMS: [M+1] = 408.2.

[0313] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1H), 7.67 - 7.61 (m, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.17 - 5.06 (m, 2H), 4.20 (s, 3H), 3.68 (s, 2H), 2.77 (s, 3H), 2.62 - 2.43 (m, 8H), 2.30 (s, 3H).

[0314] Step 5.4-chloro-2-methyl-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole:

[0315] POCl3(1.0 mL) was added to a flask containing 4-methoxy-2-methyl-8-[(4- methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (80 mg, 196 μmol, 1.0 equiv.) in in one portion at RT under an atmosphere of nitrogen. The mixture was stirred at 120°C for 18 hours. The mixture was cooled to RT and quenched by the addition of a saturated aqueous solution of NaHCO3(1 mL). The mixture was extracted with ethyl acetate (3 x10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875mm x 30mm x 3µm; mobile phase: 20-45% acetonitrile in water (+0.04% HCl)) to afford the title compound (10.5 mg) as a white solid.

[0316] LCMS: [M+1, M+3] = 412.2, 414.2.

[0317] 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.14 - 7.96 (m, 2H), 5.74 (q, J = 8.0 Hz, 2H), 4.75 - 4.44 (m, 2H), 3.72 - 3.17 (m, 8H), 2.90 - 2.73 (m, 6H). Example 153.1-[4-chloro-2-methyl-5- (2,2,2-trifluoroethyl)pyrimido [5,4-b]indol-8-yl]-N- methyl-methanamine

[0318] Step 1, 4-chloro-2-mcthyl-5-(2.2.2-trifluorocthyl )-8-vinyl-pyri mido|5.4-b I indole:

[0319] Dichlorophosphoryloxybenzene (10 mL) was added to a flask containing 4- methoxy-2-methyl-5-(2,2,2-trifhioroethyl)-8-vinyl-pyrimido [5,4-b]indole (800 mg, 2.49 mmol, 1.0 equiv.) and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to RT and was quenched by the addition of a saturated aqueous solution of NaHCOa. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (800 mg, crude) as a brown solid.

[0320] LCMS: [M+l] = 326.0.

[0321] Step 2, 4-chloro-2-methyl-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indole-8- carbaldehyde:

[0322] To a mixture of 4-chloro-2-methyl-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrimido[5,4- b]indole (800 mg, 2.46 mmol, 1.0 equiv.) in dioxane (8.0 mL) and H2O (4.0 mL) was added K2OSO4-2H2O (22.6 mg, 61.4 pmol, 0.025 equiv.), NalCL (2.63 g, 12.28 mmol, 5.0 equiv.), 2,6-dimethylpyridine (859 pL, 7.37 mmol, 3.0 equiv.) at RT under an atmosphere of nitrogen. The reaction was stirred at RT for 1 hour. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 43% yield) as a white solid.

[0323] LCMS: [M+l] =326.0.

[0324] Step 3. l-[4-chloro-2-methyl-5- (2,2,2-trifluoroethyl)pyrimido [5,4-b]indol-8-yl1-N-methyl-methanamine:

[0325] To a mixture of 4-chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole- 8- carbaldehyde (40.0 mg, 122 pmol, 1.0 equiv.) and methyl amine (122.0 pL, 244 pmol, 2.0 equiv.; 2M in THF) in DCM (0.4 mL) was added AcOH (21 pL, 366 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 minutes and then NaBH(OAc)3 (78 mg, 366 pmol, 3 equiv.) was added and the reaction was stirred at RT for 2 hours. The reaction was diluted with water and DCM and the layers were separated. The organic layer was dried over Na2SO4, filtered,and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C1880mm x 30mm x 3µm; mobile phase: 5-40% acetonitrile in water (0.04% HCl)) to afford the title compound (12.2 mg, 29% yield; hydrochloride salt) as a white solid.

[0326] LCMS: [M+1, M+3] = 343.2, 345.2.

[0327] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (br s, 2H), 8.50 (d, J = 1.2 Hz, 1H), 8.12 - 8.07 (m, 1H), 7.93 (dd, J = 1.2, 8.8 Hz, 1H), 5.74 (q, J = 8.8 Hz, 2H), 4.34 (s, 2H), 2.78 (s, 3H), 2.59 (s, 3H). Example 154.4-chloro-8-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)-2-methyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole

[0328] Step 1. tert-Butyl 3- chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate:

[0329] To a mixture of 4-chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole- 8-carbaldehyde (80 mg, 244 μmol, 1 equiv.) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (104 mg, 488 μmol, 2 equiv.) in DMF (1 mL) was added TMSCl (186 μL, 1.46 mmol, 6 equiv.). The mixture was stirred at RT for 20 minutes before adding NaBH(OAc)3 (155 mg, 732 μmol, 3 equiv.). The reaction was then stirred for 2 hours at RT. The reaction mixture was quenched with H2O (1 mL) and extracted with EtOAc (3 x 1 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduce pressure. The residue was purified by preparative TLC (SiO2, 1:1 ethyl acetate: petroleum ether) to afford the title compound (80 mg, 61% yield) as a yellow oil.

[0330] LCMS: [M+1, M+3] = 524.3, 526.3.

[0331] Step 2.4-chloro-8-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)-2-methyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole:

[0332] A solution of tert-butyl 3-[[4-chloro-2-methyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-8-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 191 μmol, 1 equiv.) in HCl / dioxane (1 mL) was stirred at RT for 1 hour. The mixture was concentrated under reduce pressure to afford the title compound (80 mg, 89% yield; hydrochloride salt) as a white solid.

[0333] LCMS: [M+1, M+3] = 424.2, 426.2.

[0334] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (br s, 1H), 8.51 - 8.48 (m, 1H), 8.23 - 7.87 (m, 2H), 5.74 (q, J = 8.8 Hz, 2H), 4.75 (br s, 4H), 4.56 - 4.28 (m, 2H), 4.14 (s, 2H), 2.78 (s, 3H), 2.45 - 2.26 (m, 2H), 2.10 - 1.91 (m, 2H). Example 155.4-chloro-8-(3,6-diazabicyclo[3.1.1]heptan-3-ylmethyl)-2-methyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole

[0335] Example 155 was prepared in a similar manner to that described for Example 154.

[0336] LCMS: [M+1, M+3] = 410.1, 412.1.

[0337] 1H NMR (400 MHz, DMSO-d6) δ 12.12 (br s, 1H), 9.90 (br s, 1H), 9.25 (br s, 1H), 8.62 - 7.70 (m, 3H), 5.86 - 5.61 (m, 2H), 4.96 - 4.60 (m, 1H), 4.38 - 4.22 (m, 2H), 4.19 - 3.93 (m, 2H), 3.88 - 3.62 (m, 2H), 3.22 - 3.01 (m, 1H), 2.77 (s, 3H). Example 156. N-((4-chloro-8-((dimethylamino)methyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indol-2-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0338] Scheme 8, Step 1. tert-butyl N-[2-[(5-bromo-2-carbamoyl-1H-indol-3-yl)amino]- 2-oxo-ethyl]carbamate:

[0339] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (6.1 g, 35.2 mmol, 1.5 equiv.) in DMF (40.0 mL) was added TEA (9.5 g, 94.0 mmol, 13.1 mL, 4.0 equiv.), EDCI (9.0 g, 47.0 mmol, 2.0 equiv.) and 1-oxidopyridin-1-ium-2-ol (5.2 g, 47.0 mmol, 2.0 equiv.). Then 3-amino-5-bromo-1H-indole-2-carboxamide (5.9 g, 23.5 mmol, 1.0 equiv.) was added and the mixture was stirred at 30°C for 2 hours. The reaction mixture was quenched with H2O (100 mL). The resulting suspension was filtered through a pad of Celite and the filter cake was washed with ethyl acetate to give the crude product. The filtrate was extracted withethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate at RT for 20 minutes to afford the title compound (6.1 g, 58% yield) as a brown solid.

[0340] LCMS: [M+1, M+3] = 411.2, 413.2.

[0341] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.94 (s, 1H), 7.83 (s, 1H), 7.73 (br s, 1H), 7.40 - 7.22 (m, 4H), 3.78 (d, J = 6.0 Hz, 2H), 1.42 (s, 9H).

[0342] Scheme 8, step 2. tert-butyl N-[(8-bromo-4-hydroxy-5H-pyrimido[5,4-b]indol-2- yl)methyl]carbamate:

[0343] To a solution of tert-butyl N-[2-[(5-bromo-2-carbamoyl-1H-indol-3-yl)amino]-2- oxo-ethyl]carbamate (4.0 g, 9.8 mmol, 1.0 equiv.) in EtOH (50 mL) and H2O (2.5 mL) was added NaOH (8.0 M, 2.5 mL, 2.0 equiv.) at 0°C. The mixture was stirred at RT for 16 hours. The reaction mixture was quenched with water (80 mL). Then the suspension was filtered through a pad of Celite and the filter cake was washed with ethyl acetate. The filtrate was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate at RT for 20 minutes to afford the title compound (3.2 g, 76% yield) as a brown solid.

[0344] LCMS: [M+1, M+3] = 393.1, 395.1.

[0345] 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 2H), 8.05 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 1.6, 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.20 (br t, J = 5.4 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 1.42 (s, 9H).

[0346] Scheme 8, step 3. (8-bromo-4-chloro-5H-pyrimido[5,4-b]indol-2-yl)methanamine hydrochloride:

[0347] A solution of tert-butyl N-[(8-bromo-4-hydroxy-5H-pyrimido[5,4-b]indol-2- yl)methyl]carbamate (4.0 g, 10.1 mmol, 1.0 equiv.) in POCl3(20.0 mL) was stirred at 100°C for 16 hours. The mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in THF and quenched by the addition aqueous NaHCO3 at RT. Once the pH was determined to be 7 the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (3.1 g) as a black solid.

[0348] LCMS: [M+1, M+3] = 311.0, 312.9.

[0349] Scheme 8, step 4. tert-butyl N-[(8-bromo-4-chloro-5H-pyrimido[5,4-b]indol-2- yl)methyl]carbamate:

[0350] To a solution of (8-bromo-4-chloro-5H-pyrimido[5,4-b]indol-2-yl)methanamine (3.4 g, 10.9 mmol, 1.0 equiv.) in THF (20 mL) and H2O (20 mL) was added NaHCO3 (1.8 g, 21.8 mmol, 2.0 equiv.) and Boc2O (1.2 g, 5.4 mmol, 0.5 equiv.). The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-75% ethyl acetate in petroleum ether) to afford the title compound (2.9 g, 55% yield) as a brown solid. LCMS: [M+1, M+3] = 411.2, 413.2.

[0351] 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 2.0, 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 6.2 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 1.43 (s, 9H).

[0352] Scheme 8, step 5. tert-butyl N-[[8-bromo-4-chloro-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]carbamate:

[0353] To a three-necked 100 mL flask was added a solution of tert-butyl N-[(8-bromo-4- chloro-5H-pyrimido[5,4-b]indol-2-yl)methyl]carbamate (2.1 g, 5.1 mmol, 1.0 equiv.) in DMF (20 mL). The solution was degassed with nitrogen and then cooled to 0°C. NaH (306.0 mg, 7.6 mmol, 60% purity, 1.5 equiv.) was added to the mixture in five portions at 0°C under an atmosphere of nitrogen and stirred at 0°C for 1 hour. A solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.8 g, 7.6 mmol, 1.5 equiv.) in DMF (2.0 mL) was added dropwise to the mixture and the resulting mixture was stirred at 0°C for 1 hour. The mixture was quenched by the addition of an aqueous saturated solution of NH4Cl (50 mL). The mixture was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50:1 to 10: 1 petroleum ether: ethyl acetate) to afford the title compound (1.9 g, 76% yield) as a white solid.

[0354] LCMS: [M+1, M+3] = 493.2, 495.2.

[0355] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.54 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 2.0, 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.73 (br s, 1H), 5.31 (q, J = 8.0 Hz, 2H), 4.73 (d, J = 4.8 Hz, 2H), 1.52 (s, 9H).

[0356] Scheme 8, step 6. tert-butyl N- [(dimethylamino)methyl]-4-hydroxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]carbamate.

[0357] To a mixture of tert-butyl N-[[8-bromo-4-chloro-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]carbamate (600 mg, 1.2 mmol, 1.0 equiv.),potassium ((dimethylamino)methyl)trifluoroborate (401 mg, 2.4 mmol, 2.0 equiv.) and Cs2CO3 (792 mg, 2.4 mmol, 2.0 equiv.) in 2-methylbutan-2-ol (5.0 mL) and H2O (1.25 mL) was added dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]- phosphane;methanesulfonate;[2-[2-(methylamino)phenyl]phenyl]palladium(II) (104.5 mg, 121.5 μmol, 0.1 equiv.) in one portion at RT under an atmosphere of nitrogen. The mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50:1 to 10:1 petroleum ether: ethyl acetate) to afford the title compound (350 mg, 64% yield) as a white solid.

[0358] LCMS: [M+1] = 454.4.

[0359] 1H NMR (400 MHz, METHANOL-d4) δ 8.20 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 5.55 (q, J = 8.8 Hz, 2H), 4.32 (s, 2H), 4.07 (s, 2H), 2.59 (s, 6H), 1.49 (s, 9H).

[0360] Scheme 8, step 7. [4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methanamine hydrochloride:

[0361] A mixture of tert-butyl N-[[8-[(dimethylamino)methyl]-4-hydroxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]carbamate (40.0 mg, 88.2 μmol, 1 equiv.) in POCl3 (0.3 mL) was degassed with nitrogen and then the mixture was stirred at 60°C for 16 hours under an atmosphere of nitrogen. The mixture was cooled to RT and then poured into H2O (5 mL). The mixture was stirred for 2 minutes and then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875mm x 30mm x 3µm; mobile phase: 5-30% acetonitrile in water (0.04%HCl)) to afford the title compound (20.0 mg, 55% yield) as a white solid.

[0362] LCMS: [M+1] = 372.1, 374.0.

[0363] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (br s, 1H), 8.70 (br s, 3H), 8.53 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 5.82 (q, J = 8.4 Hz, 2H), 4.52 (d, J = 5.2 Hz, 2H), 4.45 (q, J = 5.6 Hz, 2H), 2.72 (d, J = 4.8 Hz, 6H).

[0364] Scheme 8, step 8. N-((4-chloro-8-((dimethylamino)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indol-2-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide:

[0365] [4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methanamine (200 mg, 538 μmol, 1.0 equiv.) and 1-methylpyrazole-4-carbonyl chloride (156 mg, 1.1 mmol, 2.0 equiv.) were combined in pyrdine (2 mL) and then the mixture was stirred at RT for 30 minutes under an atmosphere of nitrogen. The reactionmixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic extracts were concentrated and the residue was purified by preparative HPLC (column: Waters Xbridge C18150mm x 50mm x 10µm; mobile phase: 15- 45% acetonitrile in H2O (10 mM NH4HCO3)) to afford the title compound (25.4 mg, 9.2% yield) as a white solid.

[0366] LCMS: [M+1, M+3] = 480.1, 482.2.

[0367] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.8 Hz, 1H), 8.17 (s, 1H), 8.16 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.81 - 7.72 (dd, J = 1.2, 8.4 Hz, 1H), 5.71 (q, J = 8.4 Hz, 2H), 4.72 (d, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.63 (s, 2H), 2.21 (s, 6H).

[0368] Table 8. The examples in Table 8 were prepared in a similar manner as was described for Examples 156 following Scheme 8.Example 167, N- chloro-8-r(4-methylpiperazin-l-yl)methyl]-5-(2,2,2-trifluoroethyllpyrimido b1indol-2-yl1 methyl] -l-methyl-pyrazole-4-carboxamide

[0369] Step 1, Ze / 7-Butyl N-| |4-chloro-5-(2.2.2-trinuorocthyl )-8-vinyl-pyrimido|5.4- b]indol-2-yl]methyl]carbamate:

[0370] A mixture of 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.1 g, 7.2 mmol, 1.2 mL, 1.2 eq), tert-butyl N-[[8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methyl]carbamate (3.0 g, 6.0 mmol, 1.0 equiv.), CS2CO3 (2.1 g, 6.6 mmol, 1.1 equiv.), [l,r-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (396 mg, 608 pmol, 0.1 equiv.) in 2-methylbutan-2-ol (120 mL) and H2O (30 mL) was degassed with nitrogen, and then the mixture was stirred at 80°C for 2 hours under an atmosphere of nitrogen. The reaction mixture was cooled to RT and then poured into H2O (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-10% ethylacetate in petroleum ether) to afford the title compound (2.8 g, crude) as a white solid.

[0371] LCMS [M+l, M+3] = 441.2, 443.2.

[0372] JH NMR (400 MHz, CHLOROEORM-d) 5 = 8.40 (s, 1H), 7.85 (dd, J= 1.6, 8.8 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 6.91 (dd, J= 10.8, 17.6 Hz, 1H), 5.89 (d, J= 18.0 Hz, 1H), 5.76 (br s, 1H), 5.38 - 5.28 (m, 3H), 4.74 (br d, J= 4.8 Hz, 2H), 1.53 (s, 9H).

[0373] Step 2, tert-Butyl N- chloro-8-formyl-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-2-yl]methyl]carbamate.

[0374] To a solution of tert-butyl N-[[4-chloro-5-(2,2,2-trifluoroethyl)-8-vinyl- pyrimido[5,4-b]indol-2-yl]methyl]carbamate (2.2 g, 4.9 mmol, 1.0 equiv.) in 1,4-dioxane (80 mL) and H2O (40 mL) was added K2OSO4 H2O (45.9 mg, 124.7 pmol, 0.025 equiv.), NaICU (4.2 g, 19.9 mmol, 4.0 equiv.), and 2,6-dimethylpyridine (1.1 mL, 9.9 mmol, 2.0 equiv.) andthe mixture was stirred at RT for 3 hours. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-50% ethylacetate in petroleum ether) to afford the title compound (2.5 g, crude) as a white solid.

[0375] LCMS [M+1-56, M+3-56] = 387.0, 389.0.

[0376] 1H NMR (400 MHz, CHLOROFORM-d) δ = 10.19 (s, 1H), 8.93 (s, 1H), 8.32 (dd, J = 0.8, 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 5.73 (br s, 1H), 5.39 (q, J = 7.6 Hz, 2H), 4.76 (br d, J = 3.6 Hz, 2H), 1.53 (s, 9H).

[0377] Step 3. tert-Butyl N- chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-2- yl]methyl]carbamate:

[0378] To a solution of tert-butyl N-[[4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)- pyrimido[5,4-b]indol-2-yl]methyl]carbamate (500 mg, 1.1 mmol, 1.0 equiv.) and 1- methylpiperazine (226.1 mg, 2.2 mmol, 250.4 μL, 2.0 equiv.) in DCE (5.0 mL) was added AcOH (129 μL, 2.2 mmol, 2.0 equiv.) and NaBH(OAc)3 (598 mg, 2.8 mmol, 2.5 equiv.) and the mixture was stirred at RT for 1 hour. The reaction mixture was poured into saturated aqueous NaHCO3(20 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 DCM: MeOH) to afford the title compound (1.1 g, 92% yield) as a white solid.

[0379] LCMS [M+1, M+3] = 527.4, 529.3.

[0380] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.33 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 5.78 (br s, 1H), 5.32 (q, J = 8.0 Hz, 2H), 4.73 (d, J = 4.8 Hz, 2H), 3.72 (s, 2H), 2.56 (br s, 8H), 2.34 (s, 3H), 1.53 (s, 9H).

[0381] Step 4. [4-Chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl) pyrimido[5,4-b]indol-2- yl]methanamine hydrochloride:

[0382] To a solution of tert-butyl N-[[4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5- (2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methyl]carbamate (1.1 g, 2.0 mmol, 1.0 equiv.) in dioxane was added HCl (10.0 mL, 19.1 equiv.; 4 M solution in dioxane) and the mixture was stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (1.1 g, crude) as a white solid.

[0383] LCMS [M+1, M+3] = 427.4, 429.4.

[0384] 1H NMR (400 MHz, METHANOL-d4) δ = 8.76 (s, 1H), 8.13 - 8.02 (m, 2H), 5.71 (q, J = 8.4 Hz, 2H), 4.75 (s, 2H), 4.55 (s, 2H), 3.87 - 3.67 (m, 8H), 3.02 (s, 3H).

[0385] Step 5. N- chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]-1-methyl-pyrazole-4-carboxamide:

[0386] A solution of 1-methylpyrazole-4-carboxylic acid (3.0 g, 23.7 mmol, 1.0 equiv.) in SOCl2 (30.0 mL, 413 mmol, 17.3 equiv.) was stirred at 80°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to afford 1-methylpyrazole-4-carbonyl chloride (3.5 g, crude) as a white solid. This material was used in the next phase of the step without further purification.

[0387] To a solution of [4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methanamine hydrochloride (500 mg, 1.0 mmol, 1.0 equiv.) in THF (0.5 mL) was added TEA (600 μL, 4.3 mmol, 4.0 equiv.). The mixture was stirred at RT for 30 minutes before the addition of 1-methylpyrazole-4-carbonyl chloride (156.0 mg, 1.0 mmol, 1.0 equiv.). The mixture was stirred at RT for 10.5 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100mm x 30mm x 10µm; mobile phase: 20-35% acetonitrile in water (+10 mM NH4HCO3)) to afford the title compound (300 mg, 50% yield) as a white solid.

[0388] LCMS [M+1, M+3] = 535.2, 537.2.

[0389] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (t, J = 5.6 Hz, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.82 - 7.66 (m, 1H), 5.70 (q, J = 8.8 Hz, 2H), 4.72 (d, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.64 (s, 2H), 2.47 - 2.19 (m, 8H), 2.15 (s, 3H). Example 168. N-[[4-chloro-8-[[3-(dimethylamino)azetidin-1-yl]methyl]-5-(2,2,2- trifluoroethyl) 2- yl]methyl]-1-methyl-pyrazole-4-carboxamide

[0390] Example 168 was prepared in a similar manner to that described for Example 167.

[0391] LCMS: [M+1, M+3] = 535.2, 537.2.

[0392] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, 1H), 7.93 (s, 2H), 7.73 (dd, J = 1.2, 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 5.32 (q, J = 8.0 Hz, 2H), 4.99 (d, J = 4.8 Hz, 2H), 3.99 (s, 3H), 3.83 (s, 2H), 3.59 - 3.49 (m, 2H), 3.03 - 2.95 (m, 2H), 2.95 - 2.84 (m, 1H), 2.13 (s, 6H). Example 169.2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]-N-methyl-acetamide

[0393] Scheme 9, step 1. Ethyl 3-[(5-bromo-2-carbamoyl-1H-indol-3-yl) amino]-3-oxo- propanoate:

[0394] 3-Amino-5-bromo-1H-indole-2-carboxamide (10.0 g, 39.3 mmol, 1.0 equiv.) and diethyl propanedioate (74.6 mL, 492 mmol, 12.5 equiv.) were combined and heated under solvent-free conditions at 200°C for 30 minutes. Then EtOH (300 mL) was added and refluxed was continued for additional 2 hours. The mixture was cooled to RT and the suspension was filtered through filter paper to afford the title compound (12.5 g, 84% yield) as a brown solid.

[0395] LCMS [M+1, M+3] = 368.2, 370.2.

[0396] Scheme 9, step 2. Ethyl 2-(8-bromo-4-chloro-5H-pyrimido [5,4-b]indol-2- yl)acetate:

[0397] To a solution of ethyl 3-[(5-bromo-2-carbamoyl-1H-indol-3-yl) amino]-3-oxo- propanoate (16.2 g, 44.0 mmol, 1.0 equiv.) in dioxane (160 mL) was added POCl3 (61.5 mL, 660.0 mmol, 15.0 equiv.). The mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. Then the residue was treated with with water and the pH was adjused to pH=8. The suspension was filtered through filter paper to afford the title compound (16.0 g, 89% yield) as a brown solid.

[0398] LCMS [M+1, M+3] = 368.1, 370.1.

[0399] Scheme 9, step 3. Ethyl 2-[8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]acetate:

[0400] To a solution of ethyl 2-(8-bromo-4-chloro-5H-pyrimido [5,4-b]indol-2-yl)acetate (12.0 g, 32.5 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.5 g, 32.5 mmol, 1.0 equiv.) in DMF (150 mL) was added K2CO3(13.5 g, 97.6 mmol, 3.0 equiv.). The mixture was stirred at RT for 12 hours. The reaction mixture was diluted with water (200 mL) and the suspension was filtered through filter paper. The filter cake was triturated with ethyl acetate for 30 minutes to afford the title compound (12.0 g, 69% yield) as a brown solid.

[0401] LCMS [M+1, M+3] = 450.1, 452.1.

[0402] Scheme 9, step 4. Methyl 2-[8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)- pyrimido[5,4-b]indol-2-yl]acetate:

[0403] To a solution of ethyl 2-[8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)-pyrimido[5,4- b]indol-2-yl]acetate (14.0 g, 31.0 mmol, 1.0 equiv.) in MeOH (140.0 mL) was added CH3ONa (5.5 g, 31.0 mmol, 1.0 equiv.; 30% in MeOH). The mixture was heated to 60°C for 30 minutes. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (12.0 g, 65% yield) as a brown solid.

[0404] LCMS [M+1, M+3] = 432.1, 434.1.

[0405] Scheme 9, step 5. Methyl 2-[8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetate:

[0406] To a solution of methyl 2-[8-bromo-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetate (11.5 g, 26.6 mmol, 1.0 equiv.) and potassium ((dimethylamino)methyl)trifluoroborate (8.7 g, 53.2 mmol, 2.0 equiv.) in 2- methylbutan-2-ol (120 mL) and H2O (30 mL) was added Cs2CO3(17.3 g, 53.2 mmol, 2.0 equiv.). Then [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (1.70 g, 2.60 mmol, 0.1 equiv.) was added and the reaction mixture was purged with nitrogen. The mixture was stirred at 90°C for 1 hour under an atmosphere of nitrogen. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate in petroleum ether) to afford the title compound (6.5 g, 52% yield) as a brown solid.

[0407] LCMS [M+1] = 411.1.

[0408] Scheme 9, step 6. Methyl 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetate:

[0409] A mixture of methyl 2-[8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetate (1.50 g, 3.60 mmol, 1.0 equiv.) in POCl3 (60 mL) was degassed and purged with nitrogen, and then the mixture was stirred at 110°C for 12 hours under an atmosphere of nitrogen. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (6.00 g, 81% yield) as a brown solid.

[0410] LCMS [M+1, M+3] = 415.3, 417.3.

[0411] Scheme 9, step 7.2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetic acid:

[0412] To a solution of methyl 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetate (2.00 g, 4.80 mmol, 1.0 equiv.) in DCE (20 mL) was added hydroxy(trimethyl)stannane (5.20 g, 28.9 mmol, 6.0 equiv.). The mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with H2O (3 x 50 mL). The combined aqueous layers were lyophilized to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100mm x 30mm x 5µm; mobile phase: 5-30% acetonitrile in H2O (+0.2% formic acid)) to afford the title compound (200 mg, 10% yield) as a white solid.

[0413] LCMS [M+1, M+3] = 401.2, 403.1.

[0414] 1H NMR (400 MHz, DMSO-d6) δ 13.61 - 11.73 (m, 1H), 8.18 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 1.2, 8.8 Hz, 1H), 5.71 (q, J = 8.8 Hz, 2H), 4.02 (s, 2H), 3.62 (s, 2H), 2.20 (s, 6H).

[0415] Scheme 9, step 8.2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]-N-methyl-acetamide:

[0416] To a solution of 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetic acid (100.0 mg, 249.5 μmol, 1.0 equiv.) in acetonitrile (0.5 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (77.0 mg, 274.4 μmol, 1.1 equiv.), N-methylimidazole (61.6 μL, 773.4 μmol, 3.1 equiv.), and methanamine hydrochloride (20.2 mg, 299 μmol, 1.2 equiv.). The mixture was stirred at RT for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine 15 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters XbridgeBEH C18100mm x 30mm x 10µm; mobile phase: 15-45% acetonitrile in water (+10 mM NH4HCO3)) to afford the title compound (15.8 mg, 15% yield) as a white solid.

[0417] LCMS: [M+1, M+3] = 413.9, 415.9.

[0418] 1H NMR (400 MHz, DMSO-d6) δ = 8.16 (s, 1H), 8.05 (br d, J = 3.6 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 5.70 (q, J = 8.8 Hz, 2H), 3.88 (s, 2H), 3.59 (s, 2H), 2.63 (d, J = 4.8 Hz, 3H), 2.19 (s, 6H). Example 170.2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]-N-methyl-acetamide

[0419] Scheme 9, step 8.2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]-N-(oxetan-3-yl)acetamide:

[0420] To a solution of 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetic acid (60.0 mg, 149.7 μmol, 1.0 equiv) and oxetan-3-amine (13.1 mg, 179.6 μmol, 1.2 equiv.) in THF (1.0 mL) was added DIEA (78.2 μL, 449.1 μmol, 3.0 equiv.) and T4P (216 mg, 299 μmol, 2.0 equiv.; 50% solution in EtOAc). The mixture was stirred at RT for 2 hours. The reaction mixture was poured into H2O (3 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with H2O (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18150mm x 50mm x 10 µm; mobile phase: 20-60% acetonitrile in H2O (+10 mM NH4HCO3)) to afford the title compound (11.4 mg, 16% yield) as a white solid.

[0421] LCMS: [M+1, M+3] = 456.1, 458.1.

[0422] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 6.4 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 5.71 (q, J = 8.8 Hz, 2H), 4.83 (q, J = 6.8 Hz, 1H), 4.77 - 4.70 (m, 2H), 4.48 (t, J = 6.4 Hz, 2H), 3.94 (s, 2H), 3.60 (s, 2H), 2.19 (s, 6H).

[0423] Table 9. The examples in Table 9 were prepared in a similar manner as was described for Examples 169 and 170 above following Scheme 9.Example 181. 2-|4-chloro-8-|(dimcthylamino)mcthyl|-5-(2.2.2-trinuorocthyl)b]indol-2-yl]-N-methyl-acetamide

[0424] Scheme 10, step 1, Methyl 8-bromo-4-hvdroxy-5H-pyrimido[5,4-b]indole-2- carboxylate:

[0425] To a solution of 3-amino-5-bromo-lH-indole-2-carboxamide (27 g, 106 mmol, 1 equiv.) in MeOH (270 mL) was added dimethyl oxalate (37.6 g, 319 mmol, 3 equiv.) and sodium methoxide (28.7 g, 159.4 mmol, 1.5 equiv.; 30% solution in MeOH). The reaction was stirred at 70°C for 12 hours. Water (1,000 mL) was added to the reaction mixture and the resulting precipitate was filtered and concentrated under reduced pressure to afford the title compound (47.8 g, crude) as a brown solid.

[0426] LCMS: [M+H, M+3] =322.1, 324.1.

[0427] Scheme 10, step 2, Methyl 8-bromo-4-methoxy-5H-pyrimido[5,4-b]indole-2- carboxylate:

[0428] Methyl 8-bromo-4-hydroxy-5H-pyrimido[5,4-b]indole-2-carboxylate (20 g, 62.0 mmol, 1 equiv.) was added to POCh (200 mL) at 20°C. Then the solution was stirred at 110°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the title comound (33 g, crude) as a brown solid.

[0429] Then a solution of methyl 8-bromo-4-chloro-5H-pyrimido[5,4-b]indole-2- carboxylate (33 g, 96.9 mmol, 1 equiv.) in MeOH (350 mL) was treated with NaOMe (26.1 g, 145.3 mmol, 1.5 equiv.; 30% solution in MeOH) and the reaction mixture was stirred at 70°C for 2 hours. The reaction was cooled to RT and diluted with EtOAc (500 mL) and then quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with ACN (1000 mL) and then filtered and dried to afford the title compound (5.8 g, 18% yield) as a brown solid.

[0430] LCMS: [M+H, M+3] = 336.0, 338.1.

[0431] Scheme 10, step 3. methyl 8-bromo-4-methoxy-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indole-2-carboxylate:

[0432] To a solution of methyl 8-bromo-4-methoxy-5H-pyrimido[5,4-b]indole-2- carboxylate (5.8 g, 17.2 mmol, 1 equiv.) and K2CO3 (4.7 g, 34.5 mmol, 2 equiv.) in DMF (58 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.81 g, 20.7 mmol, 1.2 equiv.). The reaction mixture was warmed to RT and stirred for 2 hours. The reaction mixture was cooled to 0°C and then quenched with H2O (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in petroleum ether) to afford the title compound (2.3 g, 32% yield) as a brown solid.

[0433] LCMS: [M+H, M+3] = 418.0, 420.0.

[0434] Scheme 10, step 4, 8-r(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylic acid:

[0435] To a solution of methyl 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-2-carboxylate (2.3 g, 5.5 mmol, 1 equiv.) and potassium ((dimethylamino)methyl)trifluoroborate (3.6 g, 22.0 mmol, 4 equiv.) in 2-methylbutan 2-ol (23 mL) was added a solution of CS2CO3 (3.5 g, 11.0 mmol, 2 equiv.) in H2O (4.6 mL) and [l,r-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (358.4 mg, 550.0 pmol, 0.1 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 90°C for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and and concentrated under reduced pressure. The product was purified by preparative HPLC (column: Waters Xbridge BEH C18 250mm x 70mm x 10pm; mobile phase: 1-40% acetonitrile in water (+10 mM NH4HCO3)) to afford the title compound (2.0 g, 95% yield) as a white solid.

[0436] LCMS: [M+H] = 383.2.

[0437] Scheme 10, step 5. Methyl 8-r(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indole-2-carboxylate:

[0438] 8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-2-carboxylic acid (1.5 g, 3.9 mmol, 1 equiv.) was dissolved in oxalyl chloride (15.0 mL, 171.3 mmol, 43.6 equiv.) and the reaction was stirred at RT for 1 hour. The reaction mixture was concentrated and methanol was added. Removal of the solvent under reduced pressure afforded the title compound (1.1 g, 71% yield) as a yellow solid.

[0439] LCMS: [M+H] = 397.5.

[0440] Scheme 10, step 6. Methyl 8-r(dimethylamino)methyl]-4-hydroxy-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indole-2-carboxylate:

[0441] To a solution of methyl 8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido [5, 4-b] indole-2- carboxylate (1 g, 2.5 mmol, 1 equiv.) in ACN (10 mL) was added TMSC1 (480 pL, 3.7 mmol, 1.5 equiv.) and Nal (567 mg, 3.7 mmol, 1.5 equiv.) at RT. The reaction was stirred at RT for 1 hour. Then water (14 pL, 757 pmol, 0.3 equiv.) was added and the reaction mixture was stirred at 65°C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (5:1 DCM: MeOH) to afford the title compound (800 mg, 83% yield) as a white solid.

[0442] LCMS: [M+H] = 383.1.

[0443] Scheme 10, step 7, Methyl 4-chloro-8-|(dimcthylamino)mcthyl |-5-(2.2.2- trifhioroethyl)pyrimido[5,4-b]indole-2-carboxylate:

[0444] Methyl 8-[(dimethylamino)methyl]-4-hydroxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylate (1 g, 2.6 mmol, 1 equiv.) was dissolved in POCh (20 mL, 214.5 mmol, 82.0 equiv.) and the mixture was stirred at 110°C for 2 hours. The solvent was removed under reduced pressure. The flask was cooled to 0°C and a saturated aqueous solution of NaHCOa was added to adjust the pH to pH = 8. The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were concentrated under reduced pressure. The reaction was purified by preparative TLC (100% THF) to afford the title compound (650 mg, 62% yield) as a yellow solid.

[0445] LCMS: [M+H] = 401.3.

[0446] Scheme 10, step 8. 4-chloro-8-r(dimethylamino)methyl]-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indole-2-carboxylic acid:

[0447] To a solution of methyl 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido [5, 4-b] indole-2- carboxylate (100 mg, 250 pmol, 1 equiv.) in DCE (2 mL) was added hydroxy(trimethyl)stannane (271 mg, 1.5 mmol, 6 equiv.). The mixture was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x I Op m; mobile phase: 1-40% acetonitrile in water (+10mM NH4HCO3)) to afford the title compound (20.6 mg, 20 % yield) as a white solid.

[0448] LCMS: [M+H] = 387.1.

[0449] 1H NMR (400 MHz, DMSO-tfe) 6 = 8.34 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.82(dd, J= 1.2 8.8 Hz 1H), 5.75 (q, J= 8.7 Hz, 2H), 3.87 (s, 2H), 2.38 (s, 6H).

[0450] Scheme 10, step 9. 4-chloro-8-r(dimethylamino)methyl]-N,N-dimethyl-5-(2,2,2- trifluoroethvDpyrimido [5,4-b]indole-2-carboxamide:

[0451] To a solution of 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylic acid (30 mg, 70.9 pmol, 1.0 equiv., HC1) and dimethylamine (28.35 pL, 0.8 equiv.; 2 M solution in THF) in DMF (1 mL) was added DIEA (37 pL, 213 pmol, 3.0 equiv.) and HATU (54 mg, 142 pmol, 2.0 equiv.). The mixture was stirred for 2 hours at RT. The reaction was quenched with (2 mL). The aqueous layer was extracted with ethyl acetate (3 x 1 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 80mm x 30mm x 3pm;mobile phase: 5-35% acetonitrile in water (+0.04% HC1)) to afford the title compound (9 mg, 29% yield) as a white solid.

[0452] LCMS [M+l, M+3] = 414.3, 416.3.

[0453] JH NMR (400 MHz, DMSO-tfe) 8 = 8.58 (s, 1H), 8.18 (d, J= 8.8 Hz, 1H), 8.05 (d, J= 8.4 Hz, 1H), 5.81 (q, J= 8.8 Hz, 2H), 4.49 (s, 2H), 3.07 (s, 3H), 2.89 (s, 3H), 2.74 (s, 6H).

[0454] Table 10. The examples in Table 10 were prepared in a similar manner as was described for Example 181 above following Scheme 10.Example 185. 4-Chloro-8-(2,5-diazaspiror3.4]octan-2-ylmethyl)-5-(2,2,2- tri 0 uorocth y 1 )p y ri m ido [ 5 ,4-b] indole

[0455] Scheme 11, step 1, / e / 7- Butyl 2-[[4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4- b]indol-8-yl1methyl]-2,5-diazaspiro[3.4]octane-5-carboxylate:

[0456] To a solution of 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (200 mg, 599 pmol, 1 equiv.) in acetonitrile (4.0 mL) was added TEA (500 pL, 3.6 mmol, 6.0 equiv.) and tert-butyl 2,5-diazaspiro[3.4]octane-5-carboxylate-oxalic acid (154.0 mg, 299.3 pmol, 0.5 equiv.). The mixture was stirred at RT for 7 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiCE, 10:1 DCM: MeOH) to afford the title compound (46 mg, 13% yield) as a white solid.

[0457] LCMS [M+l, M+3] = 510.2, 512.2.

[0458] Scheme 11, step 2, 4-Chloro-8-(2,5-diazaspiro[3.4]octan-2-ylmethyl)-5-(2,2,2- trifluoroethyDpyrimido [ 5 ,4-b] indole:

[0459] A solution of tert-butyl 2-[[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol- 8-yl]methyl]-2,5-diazaspiro[3.4]octane-5-carboxylate (130 mg, 255 pmol, 1.0 equiv.) in TFA (0.4 mL) and DCM (2.0 mL) was stirred at RT for 1 hour. The reaction mixture was diluted with a saturated aqueous solution of Na2COa (15 mL) and extracted with EtOAc (8 mL). The layers were separated and the organic extract was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150mm x 50mm x 10 pm; mobile phase: 25-55% acetonitrile in water (+10mM NH4HCO3)) to afford the title compound (85 mg, 80% yield) as a white solid.

[0460] LCMS [M+l, M+3] = 410.1, 412.1.

[0461] JH NMR (400 MHz, CHLOROFORM-d) 3 8.93 (s, 1H), 8.30 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 5.34 (q, J= 8.0 Hz, 2H), 3.82 (s, 2H), 3.41 (d, J= 8.0Hz, 2H), 3.09 (d, J = 8.0 Hz, 2H), 2.93 (t, J= 6.8 Hz, 2H), 2.01 (t, J= 6.8Hz, 2H), 1.78 - 1.73 (m, 2H).Example 186. 4-chloro-8-(piperazin-l-ylmethyl)-5-(2,2,2-trifluoroethyl)pyrimidor5,4- bl indole

[0462] Scheme 12, step 1, Ze / 7-butyl 4-[[4-chloro-5-(2,2,2-trifhioroethyl)pyrimido[5,4- b]indol-8-yllmethyl]piperazine-l-carboxylate:

[0463] To a mixture of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carbaldehyde (55.0 mg, 175 pmol, 1.0 equiv.) and tert-butyl piperazine- 1 -carboxylate (65.3 mg, 351 pmol, 2.0 equiv.) in DCE (1 mL) was added AcOH (10.0 pL, 175.3 pmol, 1.0 equiv.) and the mixture was stirred for 15 minutes. Then NaBH(OAc)3 (37.1 mg, 175.3 pmol, 1.0 equiv.) was added and the reaction was stirred at RT for 1 hour. The reaction was quenched by the addition H2O (10 mL), and then the mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiCE, 1: 1 ethyl acetate: petroleum ether) to afford the title compound (38.0 mg, 45% yield) as a white solid.

[0464] LCMS: [M+l, M+3] = 484.4, 486.4.

[0465] Scheme 12, step 2, 4-chloro-8-(piperazin-l-ylmethyl)-5-(2,2,2- trifluoroethyDpyrimido [ 5 ,4-b] indole:

[0466] A solution of HC1 in dioxane (0.2 mL, 4M) was added to a flask containing tertbutyl 4- [ [4-chloro-5-(2,2,2-trifluoroethyl)pyrimido [5 ,4-b] indol-8-yl] methyl] piperazine- 1 - carboxylate (35.0 mg, 72.3 pmol, 1.0 equiv.) and the reaction was stirred at RT for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna Cl 8 75mm x 30mm x 3pm; mobile phase: 5-35% acetonitrile in water (+0.04%HCl)) to afford the title compound (10.0 mg, 36% yield) as a white solid (hydrochloride salt).

[0467] LCMS: [M+l, M+3] = 384.1, 386.1.

[0468] 1H NMR (400 MHz, DMSO-d6) δ 12.49 - 11.69 (br s, 1H), 9.57 (br s, 2H), 8.99 (s, 1H), 8.65 (s, 1H), 8.14 (q, J = 3.6 Hz, 2H), 5.79 (q, J = 8.8 Hz, 2H), 4.63 (br s, 2H), 3.72 - 3.12 (m, 8H).

[0469] Table 11. The examples in Table 11 were prepared in a similar manner as was described for Examples 185 or 186 in schemes 11 and 12.Example 199. 4-chloro-8-F(5-methyl-2,5-diazaspiroF3.4]octan-2-yl)methyl]-5-(2,2,2- trifluoroethyl)p yrimido F 5 ,4-bl indole

[0470] 4-Chloro- 8- F ( 5 -methyl-2,5-diazaspiro F 3.4] octan-2-yl)methyl1 -5-(2,2,2- trifluoroethyllpyrimido F 5 ,4-b] indole:

[0471] To a solution of 4-chloro-8-(2,5-diazaspiro[3.4]octan-2-ylmethyl)-5-(2,2,2- trifluoroethyl)pyrimido [5, 4-b] indole (35.0 mg, 85.4 pmol, 1.0 equiv.) in DCE (1.0 mL) was added formaldehyde (3.2 pL, 42.7 pmol, 0.5 equiv.; 37% solution in water) and HOAc (4.9 pL, 85.4 pmol, 1.0 equiv.). The mixture was stirred at RT for 1 hour. An additional portion of NaBH(OAc)3 (36.2 mg, 170.8 pmol, 2.0 equiv.) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100mm x 30mm x 10pm; mobile phase: 30-60% acetonitrile in water (+10mM NH4HCO3)) to afford the title compound (8.0 mg, 22% yield) as a white solid.

[0472] LCMS [M+l, M+3] = 424.1, 426.1.

[0473] JH NMR (400 MHz, CHLOROFORM-d) 3 8.93 (s, 1H), 8.31 (s, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 5.34 (br d, J= 8.0 Hz, 2H), 3.83 (s, 2H), 3.34 (s, 2H), 3.16 (s, 2H), 2.77 - 2.61 (m, 2H), 2.48 (s, 3H), 2.22 - 2.05 (m, 2H), 1.77 - 1.73 (m, 2H).

[0474] Table 12. The examples in Table 12 were prepared in a similar manner as was described for Example 199 above.Example 203. l-[4-chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yll-N,N- dimethyl-methan amine

[0475] Scheme 13, step L 5-bromo-2-[(4-methoxyphenyl)methylamino]-4-methyl- benzonitrile:

[0476] To a mixture of 5-bromo-2-fluoro-4-methyl-benzonitrile (15.0 g, 70.0 mmol, 1.0 equiv.) and para-methoxybenzylamine (18.1 mL, 140.1 mmol, 2.0 equiv.) in DMSO (150 mL) was added K2CO3 (29.0 g, 210.2 mmol, 3.0 equiv.). The mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to RT and quenched with water (300 mL). The mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (12.2 g, 53% yield) as a white solid.

[0477] JH NMR (400 MHz, DMSO-tfc) 87.74 (s, 1H), 7.35 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 2.60 - 2.55 (m, 2H), 2.28 (s, 3H).

[0478] Scheme 13, step 2, 2-amino-5-bromo-4-methyl-benzonitrile:

[0479] A mixture of 5-bromo-2-[(4-methoxyphenyl)methylamino]-4-methyl-benzonitrile (12.0 g, 36.2 mmol, 1.0 equiv.) in DCM (60 mL) and TFA (30 mL) was stirred at RT for 30 minutes. The reaction mixture was concentrated and then quenched by the addition of a saturated aqueous solution of NaHCOa (90 mL) at RT. The mixture was extracted with DCM. The extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to afford the title compound (7.0 g, 90% yield) as a yellow solid.

[0480] ’ H NMR (400 MHz, DMSO-tfc) 67.58 (s, 1H), 6.74 (s, 1H), 6.14 (br s, 2H), 2.23 (s, 3H).

[0481] Scheme 13, step 3. ethyl 2-(4-bromo-2-cyano-5-methyl-anilino)acetate:

[0482] To a mixture of 2-amino-5-bromo-4-methyl-benzonitrile (4.0 g, 18.9 mmol, 1.0 equiv.) and ethyl 2-oxoacetate (11.6 g, 56.8 mmol, 3.0 equiv.) in DMF (50 mL) was added TMSC1 (12.3 g, 113.7 mmol, 14.43 mL, 6.0 equiv.), the mixture was stirred for 2 hours at RT. Then NaBH(OAc)a (10.0 g, 47.3 mmol, 2.5 equiv.) was added and the mixture was stirred at RT for 12 hours. The reaction mixture was quenched by addition the addition of saturated aqueous solution of NaHCOa (150 mL) at RT, and then extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 250mm x 150mm x 15pm; mobile phase: 50-85% acetonitrile in water (+0.05% HC1)) to afford the title compound (2.2 g, 39% yield) as a yellow solid.

[0483] LCMS: [M+1, M+3] = 296.9, 298.8.

[0484] 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.73 (s, 1H), 6.43 (t, J = 6.0 Hz, 1H), 4.18 - 4.10 (m, 2H), 4.05 (d, J = 6.0 Hz, 2H), 2.29 (s, 3H), 1.24 - 1.17 (m, 3H).

[0485] Scheme 13, step 4.1-(tert-Butyl) 2-ethyl 3-amino-5-bromo-6-methyl-1H-indole- 1,2-dicarboxylate:

[0486] To a mixture of ethyl 2-(4-bromo-2-cyano-5-methyl-anilino)acetate (2.2 g, 7.4 mmol, 1.0 equiv.) in DCM (20 mL) was added TEA (5.1 mL, 37.0 mmol, 5.0 equiv.), Boc2O (9.7 g, 44.4 mmol, 6.0 equiv.) and DMAP (90 mg, 740 μmol, 0.1 equiv.). The mixture was stirred at RT for 12 hours. The reaction mixture was quenched by the addition of a saturated, aqueous solution of NaHCO3(60 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-7% ethyl acetate in petroleum ether) to afford the title compound (2.6 g, 83% yield) as a yellow solid.

[0487] LCMS: [M-55, M-53] = 397.2, 399.2.

[0488] 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.50 (d, J = 15.6 Hz, 1H), 4.38 (d, J = 16.4 Hz, 2H), 4.23 - 4.03 (m, 2H), 2.40 (s, 3H), 1.43 - 1.40 (m, 3H), 1.38 (s, 9H).

[0489] Scheme 13, step 5.1-(tert-Butyl) 2-ethyl-5-bromo-3- (((dimethylamino)methylene)amino)-6-methyl-1H-indole-1,2-dicarboxylate:

[0490] To a mixture of 1-(tert-butyl) 2-ethyl 3-amino-5-bromo-6-methyl-1H-indole-1,2- dicarboxylate (2.6 g, 6.5 mmol, 1.0 equiv.) in DMF (25 mL) was added 1,1-dimethoxy-N,N- dimethyl-methanamine (1.1 mL, 8.5 mmol, 1.3 equiv.). The mixture was stirred at 100°C for 4 hours. The reaction mixture was cooled to RT, diluted with water, and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (2.9 g, 98% yield) as a yellow oil.

[0491] LCMS: [M+1, M+3] = 452.2, 454.2.

[0492] Scheme 13, step 6.8-bromo-7-methyl-5H-pyrimido[5,4-b]indol-4-ol:

[0493] A mixture of 1-(tert-butyl) 2-ethyl-5-bromo-3- (((dimethylamino)methylene)amino)-6-methyl-1H-indole-1,2-dicarboxylate (2.9 g, 6.4 mmol, 1.0 equiv.) in MeOH (10 mL) and NH3·H2O (20 mL) was stirred at 70°C for 48 hours. The mixture was cooled to RT and the solid was filtered off and dried under reduce pressure to afford the title compound (900 mg, 48% yield) as a gray solid.

[0494] LCMS: [M+1, M+3] = 278.0, 279.9.

[0495] Scheme 13, step 7.8-bromo-4-chloro-7-methyl-5H-pyrimido[5,4-b]indole:

[0496] A mixture of 8-bromo-7-methyl-5H-pyrimido[5,4-b]indol-4-ol (900.0 mg, 3.2 mmol, 1.0 equiv.) in POCl3(9 mL) was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (700 mg, 73% yield) as a yellow solid.

[0497] LCMS: [M+1, M+3] = 296.1, 298.2.

[0498] 12.47 (s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 7.67 (s, 1H), 2.57 (s, 3H).

[0499] Scheme 13, step 8.8-bromo-4-chloro-7-methyl-5-(2,2,2-trifluoroethyl)- pyrimido[5,4-b]indole:

[0500] To a solution of 8-bromo-4-chloro-7-methyl-5H-pyrimido[5,4-b]indole (200 mg, 674 μmol, 1.0 equiv.) in DMF (2 mL) was added K2CO3 (373 mg, 2.7 mmol, 4.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (313 mg, 1.3 mmol, 2.0 equiv.) and the mixture was stirred at RT for 20 hours. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL) and then the mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 1:1 ethyl acetate: petroleum ether) to afford the title compound (100.0 mg, 38% yield) as a yellow solid.

[0501] LCMS: [M+1, M+3] = 378.1, 380.1.

[0502] Scheme 13, step 9.1-[4-chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine:

[0503] To a mixture of 8-bromo-4-chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (100 mg, 264 μmol, 1.0 equiv.) and potassium ((dimethylamino)methyl)trifluoroborate (174 mg, 1.0 mmol, 4.0 equiv.) in 2-methylbutan-2- ol (0.8 mL) was added a solution of Cs2CO3(172 mg, 528 μmol, 2.0 equiv.) in H2O (0.2 mL) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17.2 mg, 26.4 μmol, 0.1 equiv.) under an atmosphere of nitrogen. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to RT, diluted with H2O (10 mL), and then extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C1880mm x 30mm x 3µm; mobile phase: 10- 40% acetonitrile in water (+0.04% HCl)) to afford the title compound (11.1 mg, 11% yield; hydrochloride salt) as a yellow solid.

[0504] LCMS: [M+1, M+3] = 357.1, 359.1.

[0505] 1H NMR (400 MHz, DMSO-d6) δ 10.04 (br s, 1H), 8.96 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 5.73 (q, J = 8.8 Hz, 2H), 4.53 (d, J = 5.6 Hz, 2H), 2.81 (d, J = 4.8 Hz, 6H), 2.69 (s, 3H). Example 204.2-[4-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]pyrazol-1-yl]- N,N-dimethyl-ethanamine

[0506] Scheme 14, step 1.2-[4-[4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol- 8-yl]pyrazol-1-yl]-N,N-dimethyl-ethanamine:

[0507] To a solution of 8-iodo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (180 mg, 442 μmol, 1.0 equiv.) and N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazol-1-yl]ethanamine (176 mg, 663 μmol, 1.5 equiv.) in DMF (2.0 mL) and H2O (0.4 mL) was added K2CO3(183.3 mg, 1.3 mmol, 3.0 equiv.) and Pd(dppf)Cl2·CH2Cl2 (36.1 mg, 44.2 μmol, 0.1 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 110°C for 1 hour. The mixture was cooled to RT and poured into H2O (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 DCM: methanol) to afford the title compound (170 mg, 90% yield) as a black solid.

[0508] LCMS [M+1] = 419.1.

[0509] 1H NMR (400 MHz, METHANOL-d4) δ 8.66 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.92 (dd, J = 1.2, 8.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 5.39 (q, J = 8.8 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H), 4.26 (s, 3H), 2.90 (t, J = 6.8 Hz, 2H), 2.34 (s, 6H).

[0510] Scheme 14, step 2.2-[4-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8- yl]pyrazol-1-yl]-N,N-dimethyl-ethanamine:

[0511] 2-[4-[4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]pyrazol-1-yl]- N,N-dimethyl-ethanamine (0.1 g, 239 μmol, 1.0 equiv.) and dichlorophosphorylbenzene (1.0 mL) were combined at RT and the mixture was stirred at 140°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified bypreparative HPLC (column: Phenomenex luna C18150mm x 25mm x 10µm; mobile phase: 15-45% acetonitrile in water (+0.2% formic acid)) to afford the title compound (33.8 mg, 33% yield) as a white solid.

[0512] LCMS [M+1, M+3] = 423.3, 425.2.

[0513] 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.10 - 8.03 (m, 3H), 5.75 (q, J = 8.8 Hz, 2H), 4.23 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 6.4 Hz, 2H), 2.20 (s, 6H). Example 205.4-chloro-8-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole

[0514] Scheme 14, step 1. tert-Butyl 7-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate:

[0515] To a solution of 4-chloro-8-iodo-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (50.0 mg, 121.4 μmol, 1.0 equiv.) and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (39.2 mg, 109.3 μmol, 0.9 equiv.) in DMF (0.5 mL) and H2O (0.1 mL) was added Pd(PPh3)2Cl2(8.5 mg, 12.1 μmol, 0.1 equiv.) and K2CO3 (50 mg, 364 μmol, 3.0 equiv.). The mixture was stirred at 50°C for 30 minutes. The mixture was cooled to RT and poured into H2O (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 3:1 petroleum ether: ethyl acetate) to afford the title compound (50.0 mg, 80% yield) as a white solid.

[0516] LCMS [M+1, M+3] = 517.3, 519.4.

[0517] 4-chloro-8-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole:

[0518] tert-Butyl 7-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-3,4- dihydro-1H-isoquinoline-2-carboxylate (45.0 mg, 87.0 μmol, 1.0 equiv.) was treated with HCl (2.0 mL; 4M solution in dioxane) and the mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was trituratedwith acetonitrile and the mixture was filtered and the filter cake was concentrated under reduced pressure to afford the title compound (30.0 mg, 83% yield; hydrochloride salt) as a white solid.

[0519] LCMS [M+1, M+3] = 417.0, 419.0.

[0520] 1H NMR (400 MHz, DMSO-d6) δ = 9.43 (br s, 2H), 8.98 (s, 1H), 8.57 (s, 1H), 8.17 (s, 2H), 7.79 - 7.73 (m, 2H), 7.37 (br d, J = 8.4 Hz, 1H), 5.86 - 5.73 (m, 2H), 4.36 (br s, 2H), 3.42 (br d, J = 3.6 Hz, 2H), 3.07 (br t, J = 6.0 Hz, 2H). Example 206.4-chloro-8-(6-methylpyridazin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole

[0521] Scheme 14, step 1.4-chloro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole:

[0522] To a solution of 4-chloro-8-iodo-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (200 mg, 486 μmol, 1.0 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (148 mg, 583 μmol, 1.2 equiv.) in dioxane (2.0 mL) was added KOAc (143 mg, 1.4 mmol, 3.0 equiv.) and Pd(dppf)Cl2·CH2Cl2 (39.6 mg, 48.6 μmol, 0.1 equiv.). The mixture was stirred at 100°C for 16 hours under an atmosphere of nitrogen. The mixture was cooled to RT and poured into H2O (4 ml). The aqueous phase was extracted with EtOAc (3 x 4 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (SiO2, 2:1 petroleum ether: ethyl acetate) to afford the title compound (80.0 mg, 40% yield) as a yellow solid.

[0523] LCMS [M+1, M+3] = 412.1, 414.1.

[0524] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.95 (s, 2H), 8.19 (dd, J = 0.8, 8.8 Hz, 1H), 7.57 (d, J = 8.0Hz, 1H), 5.37 (q, J = 8.0 Hz, 2H), 1.28 - 1.25 (m, 12H).

[0525] Scheme 14, step 2.4-chloro-8-(6-methylpyridazin-3-yl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido[5,4-b]indole:

[0526] To a mixture of 3-bromo-6-methylpyridazine (42 mg, 243 μmol, 2.0 equiv.), K2CO3 (50 mg, 364 μmol, 3.0 equiv.), 4-chloro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole (50.0 mg, 121.4 μmol, 1.0 equiv.) in dioxane (0.5 mL) and H2O (0.1 mL) was added Pd(dppf)Cl2·CH2Cl2 (9.9 mg, 12.1 μmol, 0.1 equiv.). The mixture was degassed with nitrogen and then stirred at 90°C for 4 hours under an atmosphere of nitrogen. The reaction mixture was cooled to RT and filtered. The residue was triturated with acetonitrile and filtered to afford the title compound (20.0 mg, 44% yield) as a gray solid.

[0527] LCMS [M+1, M+3] = 378.1, 380.1.

[0528] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.2 Hz, 1H), 9.01 (s, 1H), 8.66 (dd, J = 1.6, 8.8 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 5.82 (q, J = 8.8 Hz, 2H), 2.69 (s, 3H).

[0529] Table 13. The examples in Table 13 were prepared in a similar manner as was described for Examples 204, 205, or 206 following Scheme 14.Example 221, N-| |4-chloro-8-|(dimcthylamino)mcthyl |-5-(2.2.2-trinuorocthyl )pyrimido|5.4- b]indol-2-yl] methyl] -2-methoxy-4-methylsulfonyl-aniline

[0530] Step 1, l-r4-methoxy-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimidor5,4-b]indol-8-yl1- N.N-dimcthyl-mcthanaminc:

[0531] A mixture of l-[2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol- 8-yl]-N,N-dimethyl-methanamine (2.0 g, 5.3 mmol, 1.0 equiv.), 4, 4,5, 5-tetramethyl-2- vinyl- 1,3, 2-dioxaborolane (3.3 g, 21.4 mmol, 4 equiv.), K2CO3 (742 mg, 5.3 mmol, 1.0 equiv.) in dioxane (10.0 mL) and H2O (1.0 mL) was degassed with nitrogen. Then Pd(PPh3)4 (620 mg, 537 pmol, 0.1 equiv.) was added and the mixture was degassed with nitrogen again. The mixture was stirred at 100°C for 2 hours under an atmosphere of nitrogen. The reaction mixture was cooled to RT and quenched with water. The mixture was diluted with EtOAc and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-30% ethyl acetate in petroleum ether) to afford the title compound (1.0 g, 36% yield) as a yellow solid.

[0532] LCMS [M+l] = 365.4.

[0533] Step 2, l-[4-chloro-5-(2,2,2-trifhioroethyl)-2-vinyl-pyrimido[5,4-b]indol-8-yl1-N,N-dimethyl-methanamine:

[0534] A solution of l-[4-methoxy-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimido[5,4-b]indol- 8-yl]-N,N-dimethyl-methanamine (200 mg, 549 pmol, 1 equiv.) in dichlorophosphorylbenzene (2 mL) was stirred at 120°C for 1 hour. The reaction mixture was cooled to RT and quenched with a saturated aqueous solution of NaHCO ,. The mixture was then diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude title compound (200 mg, 69 % yield) was obtained as a yellow oil, which was used in the next step without further purification.

[0535] LCMS [M+l, M+3] = 369.5, 371.5.

[0536] Step 3. 4-chloro-8-|(dimcthylamino)mcthyl |-5-(2.2.2-trinuorocthyl )pyrimido|5.4- blindole-2-carbaldehyde:

[0537] To a solution of l-[4-chloro-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimido[5,4-b]indol- 8-yl]-N,N-dimethyl-methanamine (450 mg, 1.2 mmol, 1.0 equiv.) in dioxane (5.0 mL) and H2O (2.5 mL) was added K^OsCL-EhO (22.5 mg, 61 pmol, 0.05 equiv.), NaICU (3.1 g, 14.6 mmol, 12 equiv.), and 2,6-dimethylpyridine (1.14 mL, 9.7 mmol, 8 equiv.). The mixture was stirred at 20°C for 1 hour. The reaction was diluted with ethyl acetate, filtered, and concentrated under reduced pressure to afford the title compound (450.0 mg, 99% yield) as a yellow solid, which was used in the next step without further purification.

[0538] LCMS [M+l, M+3] = 371.3, 373.3.

[0539] Step 4, N- chloro-8-r(dimethylamino)methyl]-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-2-yl]methyl]-2-methoxy-4-methylsulfonyl-aniline:

[0540] To a solution of 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carbaldehyde (200.0 mg, 539.4 pmol, 1 equiv.) and 2- methoxy-4-methylsulfonyl-aniline (76 mg, 378 pmol, 0.7 equiv.) in DCE (0.5 mL) was added AcOH (62 pL, 1.0 mmol, 2 equiv.) and NaBH(OAc)3 (286 mg, 1.35 mmol, 2.5 equiv.). The mixture was stirred at RT for 2 hours. The mixture was diluted with water and the mixture was extracted with ethyl acetate. The extracts dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column 1: Phenomenex luna C18 80mm x 30mm x 3 pm; mobile phase: 15-45% acetonitrile in water (+0.04% HC1) and then a second purification on column 2: Waters Xbridge BEH C18 100mm x 30mm x 10pm; mobile phase: 30-60% acetonitrile in water (+10mM NH4HCO3)) to afford the title compound (10.4 mg, 50% yield) as a white solid.

[0541] LCMS [M+l, M+3] = 556.0, 558.0.

[0542] JH NMR (400 MHz, DMSO-tfc) <5 = 8.16 (s, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.77 (dd, J = 1.6, 8.8 Hz, 1H), 7.29 (dd, J = 2.0, 8.4 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.65 (t, J = 6.0 Hz, 1H), 5.70 (q, J = 8.8 Hz, 2H), 4.74 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H), 3.60 (s, 2H), 3.07 (s, 3H), 2.19 (s, 6H).Example 222, N- chloro-8-r(dimethylamino)methyl]-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-2-yl]methyl]-l-methyl-pyrazol-4-amine

[0543] The title compound was prepared in similar manner to that described for example 221.

[0544] LCMS [M+l, M+3] = 452.0, 454.0.

[0545] JH NMR (400 MHz, DMSO-tfc) d = 8.20 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.75 (dd, J = 1.6, 8.8 Hz, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 5.69 (q, J = 8.8 Hz, 2H), 5.08 (t, J = 6.8 Hz, 1H), 4.37 (d, J = 6.4 Hz, 2H), 3.65 (s, 3H), 3.59 (s, 2H), 2.19 (s, 6H).Example 223. 4-chloro-8-|(dimcthylamino)mcthyl |-N-|2-( l -mcthylpyrazol-4-yl ) ethyll-5-(2,2,2-trifluoroethyl)pyrimidor5,4-b]indol-2-amine

[0546] Step 1, 8-r(dimethylamino)methyl]-2-[2Tl-methylpyrazol-4-yl)ethylamino]-5- (2.2.2-trinuorocthyl ) 4-ol:

[0547] A mixture of l-[2-Chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl] -N,N-dimethyl-methanamine (200 mg, 537 pmol, 1.0 equiv.) and 2-(l-methyl- lH-pyrazol-4-yl)ethan-l-amine (560 mg, 4.4 mmol, 8.3 equiv.) was stirred at 120°C for 2 hours. The reaction was cooled to RT and quenched with H2O (10 mL). The mixture was filtered and the filter cake was washed with H2O (30 mL) and dried under vacuum to afford the title compound (200 mg, 59% yield) as a brown oil. This material was used in the next step without further purification.

[0548] LCMS: [M+l] = 448.2.

[0549] Step 2, 4-chloro-8-r(dimethylamino)methyl]-N-r2-(l-methylpyrazol-4-yl) ethyl]- 5-(2,2,2-trifluoroethyl)p yrimido [ 5 ,4-b] indol-2- amine:

[0550] POCh (1.5 mL) was addd to a flask containing 8-[(dimethylamino)methyl]-2-[2- (l-methylpyrazol-4-yl)ethylamino] -5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (90.0 mg, 201 pmol, 1.0 equiv.) and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100mm x 40mm x 3pm; mobile phase: 15-45% acetonitrile in water (+0.04%HCl) to afford the title compound (15.1 mg, 15% yield; hydrochloride salt) as a green solid.

[0551] LCMS: [M+l, M+3] = 466.2, 468.

[0552] JH NMR (400 MHz, DMSO-tfc) 3 8.31 (s, 1H), 7.96 - 7.91 (m, 1H), 7.89 - 7.84 (m, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 5.57 (q, J = 8.8 Hz, 2H), 4.44 (br d, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.51 (br2.75 - 2.69 (m, 8H).Example 224, N-benzyl-4-chloro-8-r(dimethylamino)methyl]-N-methyl-5-(2,2,2- trifluoroethyllp yrimido [ 5 ,4-b] indol-2-amine

[0553] Step 1, 2-[benzyl(methyl)amino]-8-r(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-4-ol:

[0554] N-methyl-l-phenyl-methanamine (2.0 mL, 15.5 mmol, 28.8 equiv.) and l-[2- chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N,N-dimethyl- methanamine (200.0 mg, 536.5 pmol, 1 equiv.) were combined in a flask and the mixture was stirred at 120°C for 4 hours. The reaction mixture was cooled to RT and quenched with H2O (5mL). The mixture was extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (200 mg, 84% yield) as a white solid.

[0555] LCMS: [M+H] = 444.4.

[0556] Step 2, N-benzyl-4-chloro-8-r(dimethylamino)methyl]-N-methyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine:

[0557] POCh (2 mL) was added to a flask containing 2-[benzyl(methyl)amino]-8- [(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (200 mg, 451 pmol, 1.0 equiv.) and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to RT and the pH was adjusted to pH = 9 by the addition of a saturated aqueous solution of NaHCOa. The aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with water, dried over NaaSCU, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150mm x 50mm x 10pm; mobile phase: 60-95% acetonitrile in water (+10mM NH4HCO3)) to afford the title compound (25.0 mg, 12% yield) as a white solid.

[0558] LCMS: [M+H, M+3] = 462.2, 464.1.

[0559] ^NMR (400 MHz, DMSO-tfc) 6 8.00 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.37 - 7.19 (m, 5H), 5.52 (q, J= 8.4 Hz, 2H), 4.95 (s, 2H), 3.53 (s, 2H), 3.17 (s, 3H), 2.17 (s, 6H).

[0560] Table 14. The examples in Table 14 were prepared in a similar manner as was described for Example 223 or Example 224 above.Example 229. 4-chloro-8-r(dimethylamino)methyl]-N-(l-methylpyrazol-4-yl)-5-(2,2,2- trifluoroethyl)p yrimido [ 5 ,4-b I i ndol -2-am i nc

[0561] Step 1, 8-r(dimethylamino)methyl]-4-methoxy-N-(l-methylpyrazol-4-yl)-5- (2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-2-amine:

[0562] To a mixture of l-[2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine (200 mg, 537 pmol, 1 equiv.), 1 -methyip yrazol-4- amine (156 mg, 1.61 mmol, 3 equiv.) and CS2CO3 (350 mg, 1.07 mmol, 2 equiv.) in 2- methylbutan-2-ol (2 mL) was added [2-(2-aminophenyl)phenyl]palladium(II)-dicyclohexyl- [2-(2,4,6-triisopropylphenyl)phenyl]phosphane methanesulfonate (45 mg, 53.7 pmol, 0.1 equiv.) at RT under an atmosphere of nitrogen. The mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to RT and quenched with H2O (1 mL). The mixture wasextracted with EtOAc (3 x 1 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduce pressure. The residue was purified by preparative TLC (SiCL, 10:1 ethyl acetate: methanol) to afford the title compound (145 mg, 62% yield) as a yellow solid.

[0563] LCMS: [M+H] = 434.3.

[0564] Step 2, 4 -chloro-8-r(dimethylamino)methyl]-N-(l-methylpyrazol-4-yl)-5-(2,2,2- trifhioroethyl)pyrimido[5,4-b]indol-2-amine:

[0565] POCh (2.0 mL, 21.5 mmol, 71.5 equiv.) was added to a flask containing 8- [(dimethylamino)methyl]-4-methoxy-N-(l-methylpyrazol-4-yl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine (130 mg, 300 pmol, 1 equiv.) and the mixture was stirred at 110°C for 1 hour. The mixture was cooled to RT and concentrated under reduce pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100mm x 40mm x 3pm; mobile phase: 10-40% acetonitrile in water (+0.04% HC1)) to afford the title compound (24.8 mg, 19% yield; hydrochloride salt) as a white solid.

[0566] LCMS: [M+l, M+3] = 438.2, 440.1.

[0567] JH NMR (400 MHz, DMSO-tfe) 8 9.77 (s, 1H), 8.52 (br s, 1H), 8.04 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 5.61 (q, J = 8.8 Hz, 2H), 4.48 (d, J = 1.6 Hz, 2H), 3.88 (s, 3H), 2.76 (s, 6H).

[0568] Table 15. The examples in Table 15 were prepared in a similar manner as was described for Example 229 above.Example 233. 2-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimidor5,4-b]indol-8-yl)-N,N- dimethylethan- 1 - amine

[0569] Step 1, 4-mcthoxy-5-(2.2.2-ti%luorocthyl )-8-vinyl-5H-pyrimido|5.4-b I indole:

[0570] To a solution of 8-iodo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (930 mg, 2.2 mmol, 1.0 equiv.) in dioxane (10.0 mL) and H2O (2.0 mL) was added K2CO3 (631 mg, 4.5 mmol, 2.0 equiv.), Pd(dppf)Ch-CH2C12 (187 mg, 228 pmol, 0.1 equiv.), and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (7.0 g, 45.6 mmol, 7.7 mL, 20.0 equiv.). The mixture was stirred at 100°C for 1 hour under an atmosphere of nitrogen. The mixture was cooled to RT and poured into H2O (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-15% ethyl acetate in petroleum ether) to afford the title compound (520 mg, 74% yield) as a white solid.

[0571] LCMS [M+l] = 308.2.

[0572] JH NMR (400 MHz, CHLOROFORM-d) 3 8.73 (s, 1H), 8.37 (s, 1H), 7.76 (dd, J = 1.4, 8.6 Hz, 1H), 7.48 (d, J= 8.6 Hz, 1H), 6.91 (dd, J= 10.8, 17.6 Hz, 1H), 5.85 (d, J = 17.6 Hz, 1H), 5.31 (d, J= 10.8 Hz, 1H), 5.15 (q, J= 8.4 Hz, 2H), 4.24 (s, 3H).

[0573] Step 2, 2-(4-methoxy-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol-8- yl)ethan-l-ol:

[0574] To a solution of 4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-5H-pyrimido[5,4- b]indole (110 mg, 358 pmol, 1.0 equiv.) in THF (1.0 mL) was added 9-BBN (2.1 mL, 3.0 equiv.; 0.5 M solution in THF). The mixture was then stirred at RT for 16 hours. The mixture was then cooled to 0°C and an aqueous IM solution of NaOH (220.0 pL, 6.2 eq) and H2O2 (241 pL, 2.5 mmol, 7.0 equiv.; 30% solution in water) were added. The mixture was stirred at RT for 30 minutes. The mixture was quenched with a saturated aqueous solution of Na2SOa (10 mL) at 0°C. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (50-100% ethyl acetate in petroleum ether) to afford the title compound (510 mg) as a white solid.

[0575] LCMS [M+l] = 326.1.

[0576] ’ H NMR (400 MHz, CHLOROFORM-d) 3 8.71 (s, 1H), 8.22 (s, 1H), 7.58 - 7.54 (m, 1H), 7.49 - 7.45 (m, 1H), 5.14 (q, J = 8.4 Hz, 2H), 4.24 (s, 3H), 3.98 (t, J= 6.6 Hz, 2H), 3.09 (t, 7= 6.4 Hz, 3H).

[0577] Step 3. 2-(4-methoxy-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol-8- yl) acetaldehyde:

[0578] To a solution of 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol- 8-yl)ethan-l-ol (400 mg, 1.2 mmol, 1.0 equiv.) in acetonitrile (8.0 mL) was added 2- iodylbenzoic acid (999 mg, 3.5 mmol, 2.9 equiv.) at RT. The mixture was stirred at 80°C for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in petroleum ether) to afford the title compound (120 mg, 30% yield) as a white solid.

[0579] LCMS [M+l] = 310.1.

[0580] 1H NMR (400 MHz, CHLOROFORM-d) 3 9.86 (t, J = 2.0 Hz, 1H), 8.75 (s, 1H),8.27 (br s, 1H), 7.57 - 7.49 (m, 2H), 5.17 (q, J= 8.4 Hz, 2H), 4.26 (s, 3H), 3.92 (d, J= 2.0 Hz, 3H).

[0581] Step 4, 2-(4-methoxy-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylethan- 1 - amine:

[0582] To a solution of 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol- 8-yl)acetaldehyde (100 mg, 309 pmol, 1.0 equiv.) in THF (1.5 mF) was added N- methylmethanamine (310 pF, 2.0 equiv.; 2M in THF) and AcOH (35 pF, 619 pmol, 2.0 equiv.). The mixture was stirred at RT for 1 hour before NaBHaCN (23 mg, 371 pmol, 1.2 equiv.) was added. The mixture was stirred at RT for 1 hour. The mixture was poured into H2O (30 mF) and extracted with ethyl acetate (3 x 30 mF). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TEC (S 1O2, 5: 1 ethyl acetate: MeOH) to afford the title compound (40.0 mg, 37% yield) as a white solid.

[0583] ECMS [M+l] = 353.1.

[0584] ’ H NMR (400 MHz, CHEOROFORM-7) 3 8.72 (s, 1H), 8.16 (s, 1H), 7.61 - 7.54 (m, 1H), 7.51 - 7.45 (m, 1H), 5.14 (q, J= 8.2 Hz, 2H), 4.24 (s, 3H), 3.23 - 3.13 (m, 2H), 2.93 (br s, 2H), 2.57 (br s, 6H).

[0585] Step 5. 2-(4-chloro-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylethan- 1 - amine:

[0586] A solution of 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8- yl)-N,N-dimethylethan-l -amine (40.0 mg, 113.5 pmol, 1.0 equiv.) in dichlorophosphorylbenzene (1.5 mF) was stirred at 160°C for 2 hours. The mixture was cooled to RT and quenched with a saturated aqueous solution of NaHCOa (50 mF). The mixture was extracted with EtOAc (3 x 20 mF). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPEC (column: Welch ultimate C18 150mm x 25mm x 7pm; mobile phase: 10-40% acetonitrile in water (+0.2% formic acid)) to afford the title compound (5.3 mg, 13% yield) as a white solid.

[0587] ECMS [M+l, M+3] = 357.0, 359.0.

[0588] 1H NMR (400 MHz, CHEOROFORM-7) 3 8.93 (s, 1H), 8.53 (br s, 1H), 8.24 (s,1H), 7.66 (d, 7 = 8.6 Hz, 1H), 7.53 (d, 7 = 8.6 Hz, 1H), 5.34 (q, 7 = 8.0 Hz, 2H), 3.12 - 3.05 (m, 2H), 2.85 - 2.76 (m, 2H), 2.45 (s, 6H).Example 234, N-| |4-chloro-8-|(dimcthylamino)mcthyl |-5-(2.2.2-trifluorocthyl )pyrimido|5.4- b1indol-2-yl1methyl1-l-methyl-pyrazol-4-amine

[0589] The title compound was prepared in similar manner to that described for example 233.

[0590] LCMS [M+l, M+3] = 412.0, 414.0.

[0591] JH NMR (400 MHz, CHLOROEORM-d) 3 8.92 (s, 1H), 8.22 (s, 1H), 7.62 (br d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 5.33 (q, J = 8.0 Hz, 2H), 3.08 - 3.01 (m, 2H), 2.91 - 2.69 (m, 10H), 2.50 (s, 3H).Example 235. 4-chloro-8-(l-methyl-4-piperidyl)-5-(2,2,2-trifluoroethyl)-pyrimido[5,4- b] indole

[0592] Step 1, 8-iodo-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-4-ol:

[0593] To a solution of 4-chloro-8-iodo-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole(1.1 g, 2.67 mmol, 1 equiv.) in dioxane (15 mL) was added an aqueous solution of NaOH (8.02 mL, 3 equiv.; IM). The mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled to RT and poured into water (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuum to afford the title compound (1.0 g) as a white solid. This material was used in the next step without further purification.

[0594] LCMS [M+l] = 394.0.

[0595] ’ H NMR (400 MHz, DMSO-tfe) 3 8.34 (d, J= 1.6 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 5.64 (q, J = 9.2 Hz, 2H).

[0596] Step 2, 8-(l-methyl-l,2,3,6-tetrahvdropyridin-4-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido [ 5 ,4-b] indol-4-ol:

[0597] To a solution of 8-iodo-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (150 mg, 382 pmol, 1 equiv.) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine (102 mg, 458 pmol, 1.2 equiv.) in dioxane (1.5 mL) and H2O (0.1 mL) was added NaoCOa (121 mg, 1.14 mmol, 3 equiv.) and Pd(dppf)Ch (28 mg, 38.2 pmol, 0.1 equiv. The mixture was stirred at 100°C for 1.5 hours. The reaction mixture was cooled to RT and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150mm x 25mm x 10pm; mobile phase: 1-31% acetonitrile in water (+formic acid modifier)) to afford the title compound (86 mg, 62% yield) as a white solid.

[0598] LCMS [M+l] = 363.3.

[0599] JH NMR (400 MHz, METHANOL-^) 6 8.18 (s, 1H), 8.10 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 6.27 (s, 1H), 5.54 (q, J= 8.8 Hz, 2H), 2.94 - 2.83 (m, 2H), 2.82 - 2.74 (m, 2H), 2.54 - 2.42 (m, 3H), 1.34 - 1.23 (m, 2H).

[0600] Step 3. 8-(l-methylpiperidin-4-yl)-5-(2, 2, 2-trifluoroethyl)-5H-pyrimido [5,4- b]indol-4-ol:

[0601] To a solution of 8-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indol-4-ol (83.0 mg, 229.0 pmol, 1.0 equiv.) in MeOH (1 mL) was added PtCL (260 mg, 1.1 mmol, 5.0 equiv.) under an atmosphere of nitrogen. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under an atmosphere of hydrogen (15 psi) at RT for 2 hours. The reaction mixture was filtered and concentrated to afford the title compound (65.0 mg, crude) as a brown solid.

[0602] LCMS [M+l] = 365.2.

[0603] 1H NMR (400 MHz, CHLOROFORM-d) 5 8.05 - 8.03 (m, 1H), 8.02 (s, 1H), 7.59- 7.39 (m, 2H), 5.41 - 5.33 (m, 2H), 3.07 - 2.97 (m, 1H), 2.73 (s, 1H), 2.46 - 2.43 (m, 1H), 2.39 - 2.32 (m, 2H), 1.98 - 1.87 (m, 3H), 1.30 - 1.24 (m, 4H).

[0604] Step 4, 4 -chloro-8-(l-methyl-4-piperidyl)-5-(2,2,2-trifhioroethyl)pyrimido[5,4- blindole:

[0605] A solution of 8-(l-methyl-4-piperidyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-4-ol (60 mg, 165 pmol, 1 equiv.) in POCI3 (0.5 mL) was stirred at 110 °C for 16 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 150mm x 25mmx I Opm; mobile phase: 0-27% acetonitrile in water (+formic acid modifier)) to afford the title compound (10.4 mg, 17% yield) as a yellow solid.

[0606] LCMS [M+l, M+3] = 383.0, 384.9.

[0607] JH NMR (400 MHz, CHLOROFORM-d) 5 8.92 (s, 1H), 8.26 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 5.40 - 5.27 (m, 2H), 3.07 (d, J= 11.2 Hz, 2H), 2.82 - 2.66 (m, 1H), 2.39 (s, 3H), 2.24 - 2.11 (m, 2H), 1.97 (s, 4H).Examples 236 and 237, 4-chloro-8-r(3R)-l-methyl-3-piperidyl]-5-(2,2,2- trifluoroethvDpyrimido [5, 4-b] indole and 4-chloro-8-|(3.S')- l -mcthyl-3-pipcridyl |-5-(2.2.2- trifluoroethyl)p yrimido [ 5 ,4-b] indole

[0608] Step 1, tert-Butyl 5-r4-hydroxy-5-(2,2,2-trifhioroethyl)pyrimido[5,4-b]indol-8- yl]-3,6-dihydro-2H-pyridine-l-carboxylate:

[0609] To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine- 1 -carboxylate (189 mg, 611 pmol, 1.2 equiv.) and 8-iodo-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indol-4-ol (200 mg, 509 pmol, 1.0 equiv.) in dioxane (2.0 mL) and H2O (0.4 mL) was added Na2COa (161.7 mg, 1.5 mmol, 3.0 equiv.) and Pd(dppf)Ch (37.2 mg, 50.9 pmol, 0.1 equiv.) under an atmosphere of nitrogen. The mixture was stirred at 100°C for 1 hour. The mixture was cooled to RT and poured into water (5 mL). The mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 63% yield) as a yellow solid.

[0610] LCMS [M+l] = 449.1.

[0611] ’ H NMR (400 MHz, DMSO-ri6) d 12.62 (s, 1H), 8.09 (d, J= 2.4 Hz, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 5.64 (q, J= 8.8 Hz, 2H), 4.32 (s, 2H), 3.50 (t, J= 4.8 Hz, 2H), 2.34 - 2.26 (s, 2H), 1.44 (s, 9H).

[0612] Step 2, fert-Butyl 3-(4-hydroxy-5-(2,2,2-trifhioroethyl)-5H-pyrimido[5,4-b]indol- 8-yl)piperidine- 1 -carboxylate:

[0613] 10% Pd on C (831 mg, 781 μmol, 1.0 equiv.) was added to the reaction flask under argon and methanol (2.0 mL) was added to submerge the catalyst. Then a solution of tert-butyl 5-[4-hydroxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-3,6-dihydro-2H- pyridine-1-carboxylate (350 mg, 781 μmol, 1.0 equiv.) in methanol (4.0 mL) was added. The suspension was degassed under vacuum and purged with hydrogen gas three times. The mixture was stirred at 40°C for 12 hours under an atmosphere of hydrogen. The reaction mixture was filtered and concentrated to afford the title compound (300 mg, 75% yield) as a yellow solid.

[0614] LCMS [M+1] = 451.1.

[0615] 1H NMR (400 MHz, METHANOL-d4) δ 8.09 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 5.53 (q, J = 8.8 Hz, 2H), 4.22 - 4.13 (m, 2H), 2.92 - 2.85 (m, 3H), 2.10 (d, J = 10.4 Hz, 1H), 1.85 (d, J = 11.2 Hz, 2H), 1.68 - 1.58 (m, 1H), 1.48 (s, 9H).

[0616] Step 3.8-(Piperidin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-4-ol:

[0617] HCl (3.0 mL, 18.0 equiv.; 4M solution in dioxane) was added to a flask containing tert-butyl 3-(4-hydroxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)piperidine-1- carboxylate (300 mg, 666 μmol, 1.0 equiv.). The mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated under reduced pressure to afford the title compound (230 mg, 80% yield; hydrochloride salt) as a white solid.

[0618] LCMS [M+1] = 351.2.

[0619] 1H NMR (400 MHz, METHANOL-d4) δ 8.15 (s, 1H), 7.97 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.59 - 5.53 (m, 2H), 3.17 - 3.06 (m, 2H), 2.88 - 2.82 (m, 1H), 2.73 - 2.60 (m, 2H), 2.05 (d, J = 10.8 Hz, 1H), 1.86 - 1.65 (m, 4H).

[0620] Step 4.8-[(3R)-1-methyl-3-piperidyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-4-ol and 8-[ -1-methyl-3-piperidyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol:

[0621] To a solution of 8-(piperidin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indol-4-ol (230 mg, 657 μmol, 1.0 equiv.) in DCM (11.5 mL) and methanol (9.2 mL) was added formaldehyde (145 μL, 5.2 mmol, 8.0 equiv.; 37% solution in water) at RT. After 1 hour, NaBH(OAc)3(1.1 g, 5.6 mmol, 8.0 equiv.) was added and the mixture was stirred at RT for 2 hours. A saturated aqueous solution of NaHCO3 was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm x 10µm);mobile phase: 30% methanol in CO2 (+0.1% NH3·H2O)) to afford 8-[(3R)-1-methyl-3- piperidyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (85.0 mg, 35% yield).

[0622] LCMS [M+1] = 365.1.

[0623] 1H NMR (400 MHz, METHANOL-d4) δ 8.08 (s, 1H), 8.02 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 1.6, 8.8 Hz, 1H), 5.52 (q, J = 8.8 Hz, 2H), 3.11 - 2.98 (m, 3H), 2.36 (s, 3H), 2.20 (t, J = 11.2 Hz, 1H), 2.12 (dt, J = 2.4, 12.0 Hz, 1H), 2.04 - 2.00 (m, 1H), 1.93 - 1.87 (m, 1H), 1.86 - 1.75 (m, 1H), 1.66 - 1.56 (m, 1H).

[0624] and 8-[(3S)-1-methyl-3-piperidyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4- ol (88.0 mg, 36% yield).

[0625] LCMS [M+1] = 365.1.

[0626] 1H NMR (400 MHz, METHANOL-d4) δ 8.08 (s, 1H), 8.03 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 1.6, 8.8 Hz, 1H), 5.52 (q, J = 8.8 Hz, 2H), 3.14 - 2.98 (m, 3H), 2.39 (s, 3H), 2.27 - 2.13 (m, 2H), 2.06 - 2.01 (m, 1H), 1.95 - 1.76 (m, 2H), 1.68 - 1.57 (m, 1H).

[0627] Step 5.4-chloro-8-[(3R)-1-methyl-3-piperidyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole:

[0628] POCl3(1.0 mL) was added to a flask containing 8-[(3R)-1-methyl-3-piperidyl]-5- (2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (50.0 mg, 137 μmol, 1.0 equiv.) and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18150mm x 25mm x 10µm; mobile phase: 12-42% acetonitrile in water (+ formic acid modifier)) to afford the title compound (22.5 mg, 42% yield; formic acid salt) as a white solid.

[0629] LCMS [M+1, M+3] = 383.0, 385.0.

[0630] 1H NMR (400 MHz, METHANOL-d4) δ 8.88 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 7.90 - 7.87 (m, 1H), 7.80 (dd, J = 1.6, 8.8 Hz, 1H), 5.63 (q, J = 8.4 Hz, 2H), 3.62 - 3.53 (m, 2H), 3.27 - 3.26 (m, 1H), 3.18 - 3.12 (m, 1H), 3.03 - 2.97 (m, 1H), 2.89 (s, 3H), 2.14 (d, J = 11.6 Hz, 2H), 2.05 - 1.84 (m, 2H).

[0631] Step 5.4-chloro-8-[(3S)-1-methyl-3-piperidyl]-5-(2,2,2-trifluoroethyl)- pyrimido[5,4-b]indole:

[0632] POCl3(1.0 mL) was added to a flask containing 8-[(3S)-1-methyl-3-piperidyl]-5- (2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (50.0 mg, 137.2 μmol, 1.0 equiv.) and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18150mm x 25mm x 10µm; mobile phase: 12-42% acetonitrilein water (+ formic acid modifier)) to afford the title compound (18.8 mg, 35% yield; formic acid salt) as a white solid.

[0633] LCMS [M+1, M+3] = 383.0, 385.0.

[0634] 1H NMR (400 MHz, METHANOL-d4) δ 8.89 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.90 - 7.87 (m, 1H), 7.81 - 7.79 (m, 1H), 5.63 (q, J = 8.4 Hz, 2H), 3.62 - 3.52 (m, 2H), 3.29 - 3.25 (m, 1H), 3.17 - 3.11 (m, 1H), 2.99 (dt, J = 2.4, 12.4 Hz, 1H), 2.88 (s, 3H), 2.14 (d, J = 11.4 Hz, 2H), 2.04 - 1.84 (m, 2H). Examples 238 and 239. (R)-4-chloro-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole and (S)-4-chloro-8-(1-(4-methylpiperazin-1- yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole

[0635] Step 1.1-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8- yl)ethan-1-one:

[0636] To a mixture of 8-iodo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (500 mg, 1.2 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)stannane (830 μL, 2.4 mmol, 2.0 equiv.) in toluene (5.0 mL) was added Pd(PPh3)4(141.9 mg, 122.8 μmol, 0.1 equiv.) at RT under an atmosphere of nitrogen. The reaction mixture was stirred 80°C for 2 hours. The mixture was cooled to RT and poured into a saturated aqueous solution of KF (15 ml). Then mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 79% yield) as a yellow solid.

[0637] LCMS: [M+1] = 324.1.

[0638] 1H NMR (400 MHz, METHANOL-d4) δ 9.13 (s, 1H), 9.03 (s, 1H), 8.47 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 5.58 (q, J = 8.4 Hz, 2H), 4.45 (s, 3H), 2.76 (s, 3H).

[0639] Step 2.4-methoxy-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido[5,4-b]indole:

[0640] To a solution of 1 -methylpiperazine (137 pL, 1.2 mmol, 2.0 equiv.) in titanium (IV) isopropoxide (2.0 mL) was added l-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indol-8-yl)ethan- 1-one (200 mg, 619 pmol, 1.0 equiv.) at RT. The mixture was stirred at 90°C for 1 hour before the addition of NaBthCN (311 mg, 4.9 mmol, 8.0 equiv.). The mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to RT and the mixture was diluted with water and ethyl acetate. The filtrate was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (10:1 EtOAc: MeOH) to afford the title compound (170 mg, 65% yield) as a yellow oil.

[0641] LCMS: [M+l] = 408.3.

[0642] The racemic title copmound was separated by SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm x 10pm); mobile phase: 35% methanol in CO2 (+0.1% NH3 H2O)) to afford (R)-4-methoxy-8-(l-(4-methylpiperazin-l-yl)ethyl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole (80.0 mg, 45% yield):

[0643] JH NMR (400 MHz, CHLOROFORM-d) 3 8.72 (s, 1H), 8.26 (s, 1H), 7.67 (dd, J = 1.6, 8.8 Hz, 1H), 7.47 (d, J= 8.8 Hz, 1H), 5.20 - 5.08 (m, 2H), 4.24 (s, 3H), 3.61 (d, J = 6.8 Hz, 1H), 2.73 - 2.31 (m, 8H), 2.26 (s, 3H), 1.47 (d, J= 6.8 Hz, 3H). and (5)-4-methoxy-8-(l- (4-methylpiperazin-l-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole (60.0 mg, 34 % yield):

[0644] 1H NMR (400 MHz, CHLOROFORM-d) 3 8.73 (s, 1H), 8.30 (s, 1H), 7.66 - 7.59(m, 1H), 7.54 (d, J= 8.0 Hz, 1H), 5.18 (q, J= 8.4 Hz, 2H), 4.25 (s, 3H), 3.94 - 3.72 (m, 1H), 3.47 - 2.85 (m, 8H), 2.72 (d, J= 18.4 Hz, 3H), 1.26 (s, 3H).

[0645] Step 3. (R)-4-chloro-8-(l-(4-methylpiperazin- l-yl)ethyl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido[5,4-b]indole:

[0646] Phenylphosphonic dichloride (0.8 mL) was added to a flask containing (R)-4- methoxy-8-(l-(4-methylpiperazin-l-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (80.0 mg, 196.3 pmol, 1.0 equiv.) and the mixture was stirred at 140°C for 2 hours. The mixture was cooled to RT and poured into a saturated aqueous solution of NaHCOa. The pH was adjusted to 7 by the addition of solid NaHCOa. The aqueous phase was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over NaaSCL, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25mm x 10 um; mobile phase: 10-40% acetonitrile in water (+formic acid modifier)) to afford the title compound (6.8 mg, 8% yield) as a colorless oil.

[0647] LCMS: [M+l, M+3] = 412.0, 414.0.

[0648] JH NMR (400 MHz, CHLOROFORM-ri) 3 8.93 (s, 1H), 8.36 (s, 1H), 7.75 (dd, J = 1.2, 8.8 Hz, 1H), 7.54 (d, J= 8.8 Hz, 1H), 5.35 (q, J= 8.4 Hz, 2H), 3.72 - 3.68 (m, 1H), 2.86 (s, 5H), 2.66 (d, J = 5.6 Hz, 3H), 2.53 (s, 3H), 1.47 (d, J= 6.8 Hz, 3H).

[0649] Step 3. (S)-4-chloro-8-(l-(4-methylpiperazin- l-yl)ethyl)-5-(2,2,2-trifluoroethyl)- 5H-pyrimido[5,4-b]indole:

[0650] Phenylphosphonic dichloride (0.8 mL) was added to a flask containing (.S’)-4- methoxy-8-(l-(4-methylpiperazin-l-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole (60.0 mg, 147.2 pmol, 1.0 equiv.) and the mixture was stirred at 140°C for 2 hours. The mixture was cooled to RT and poured into a saturated aqueous solution of NaHCOa. The pH was adjusted to pH = 7 by the addition of solid NaHCOa. The aqueous phase was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150mm x 25mm x 10 pm; mobile phase: 10-40% acetonitrile in water (+formic acid modifier)) to afford the title compound (6.6 mg, 10% yield) as a colorless oil.

[0651] LCMS: [M+l, M+3] = 412.3, 414.3.

[0652] 1H NMR (400 MHz, CHLOROFORM-ri) 3 8.94 (s, 1H), 8.35 (s, 1H), 7.73 (d, J =8.4 Hz, 1H), 7.54 (d, J= 8.4 Hz, 1H), 5.34 (q, J= 8.0 Hz, 2H), 3.70 (d, J = 4.8 Hz, 1H), 3.13 - 2.51 (m, 11H), 1.45 (d, J= 6.0 Hz, 3H).

[0653] Example 240, 2-[4-chloro-8-r(dimethylamino)methyl]pyrimido [5,4-b]indol-5- yl] acetonitrile

[0654] Step L (4-chloro-5H-pyrimido [5,4-b]indol-8-yl) methanol:

[0655] To a solution of methyl 4-chloro-5H-pyrimido[5,4-b]indole-8-carboxylate (1.3 g, 4.97 mmol, 1.0 equiv.) in THF (13.0 mL) was added LiAlH4 (377 mg, 9.9 mmol, 2.0 equiv.) at 0°C under an atmosphere of nitrogen. The mixture was stirred at RT for 2 hours. The reaction mixture was cooled to 0°C and quenched by the sequential addition of of H2O (1.3mL), 15% aqueous NaOH (1.3 mL), and H2O (3.9 mL). After being stirred at RT for 10 minutes, the solid was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (10:1 DCM: methanol) to afford the title compound (800 mg, 69% yield) as a yellow solid.

[0656] LCMS: [M+l, M+3] = 234.1, 236.1.

[0657] JH NMR (400 MHz, METHANOL-^) d 8.79 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.67 - 7.63 (m, 1H), 4.79 (s, 2H).

[0658] Step 2, 4-chloro-5H-pyrimido [5,4-b]indole-8-carbaldehyde:

[0659] A mixture of (4-chloro-5H-pyrimido[5,4-b]indol-8-yl)methanol (200.0 mg, 0.86 mmol, 1.0 equiv.) and MnCL (744.1 mg, 8.5 mmol, 10 equiv.) in DCE (6.0 mL) was degassed with nitrogen and then the mixture was stirred at 70 °C for 1 hour under an atmosphere of nitrogen. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (120 mg, 61% yield) as a yellow solid.

[0660] LCMS: [M+l, M+3] = 232.1, 234.1.

[0661] ‘ H NMR (400 MHz, DMSO-d6) 5 12.96 - 12.86 (m, 1H), 10.15 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H).

[0662] Step 3. 2-(4-chloro-8-formyl-pyrimido[5,4-b]indol-5-yl)acetonitrile:

[0663] 4 -chloro-5H-pyrimido[5,4-b]indole-8-carbaldehyde (100 mg, 432 pmol, 1.0 equiv.), 2-iodoacetonitrile (79 mg, 475 pmol, 1.1 equiv.) and K2CO3 (179 mg, 1.3 mmol, 3.0 equiv.) were combined in DMF (1.0 mL) and the mixture was stirred at 50°C for 3 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 10 ml). The organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (60 mg, 51% yield) as a white solid.

[0664] LCMS: [M+l, M+3] = 271.1, 273.1.

[0665] ‘ H NMR (400 MHz, DMSO-d6) <5 10.28 - 10.12 (m, 1H), 9.05 (s, 1H), 8.94 (s, 1H), 8.36 (d, J = 9.2. Hz, 1H), 8.25 (d, J= 9.2 Hz, 1H), 6.07 (s, 2H).

[0666] Step 4, 2-[4-chloro-8-r(dimethylamino)methyl]pyrimido [5,4-b]indol-5- yl] acetonitrile:

[0667] A solution of 2-(4-chloro-8-formyl-pyrimido[5,4-b]indol-5-yl)acetonitrile (40.0 mg, 148 pmol, 1.0 equiv.), dimethylamine (81 pL, 1.1 equiv.; 2.0 M in THF) and AcOH (17 pL, 296 pmol, 2.0 equiv.) in DCE (2.0 mL) was stirred at RT for 30 minutes. Then NaBH(OAc)3 (78.3 mg, 369 pmol, 2.5 equiv.) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150mm x 25mm x 10pm;mobile phase: 0-27% acetonitrile in water (+formic acid modifier)) to afford the title compound (13.7 mg, 30% yield) as a yellow solid.

[0668] LCMS: [M+l, M+3] = 300.1, 302.0.

[0669] JH NMR (400 MHz, DMSO-d6) 5 8.94 (s, 1H), 8.21 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 5.99 (s, 2H), 3.63 (s, 2H), 2.20 (s, 6H).Preparation of Y220C TP53 TR-FRET binding probe, BP1, 5-[(3aS,4S,6aR)-2-oxo- l,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yri-N-r2-[2-[2-[2-[[3-methoxy-4-[3-r4- (tetrahydropyran-4-ylamino)-l-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino] phenyl] sulfonylamino] ethoxy] ethoxy] ethoxy] ethyl] pentanamide

[0670] BP1 synthesis, step la, 2-iodo-4-nitro-l-(2,2,2-trifluoroethyl)indole: To a solution of 2-iodo-4-nitro-lH-indole (3.0 g, 10.4 mmol, 1.0 equiv.) in THF (20 mL) was added NaH (2.0 g, 52.0 mmol, 5.0 equiv.; 60.0% dispersion in oil) at 0°C by portions, and stirred at 0°Cfor 30 minutes.2,2,2-trifluoroethyl trifluoromethanesulfonate (9.6 g, 41.0 mmol, 4.0 equiv.) was added to the reaction mixture at 0°C in portions. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (20 mL) and the resulting mixture was partitioned between EtOAc (200 mL) and H2O (200 mL) and the aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (15:1 to 12:1 petroleum ether:EtOAc) to afford the title compound (5.0 g, crude) as yellow solid.

[0671] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (d, J = 8.2 Hz, 1H), 7.80 - 7.63 (m, 2H), 7.33 (t, J = 8.2 Hz, 1H), 4.85 (q, J = 8.2 Hz, 2H).

[0672] BP1 synthesis, step 2a, 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine: To a solution of 2-iodo-4-nitro-1-(2,2,2-trifluoroethyl)indole (1.9 g, 5.1 mmol, 1.0 equiv.) in EtOH (20.0 mL) and H2O (5.0 mL) was added Fe (717 mg, 12.8 mmol, 2.5 equiv.) and NH4Cl (687 mg, 12.8 mmol, 2.5 equiv.). The mixture was stirred at 80 °C for 2 hours. The reaction solution was filtered through a pad of diatomite and the filtrate was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.7 g, 97% yield) as yellow solid.

[0673] LCMS [M+1] = 341.1.

[0674] BP1 synthesis, step 3a, 2-iodo-N-tetrahydropyran-4-yl-1-(2,2,2- trifluoroethyl)indol-4-amine: To a solution of 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine (600 mg, 1.7 mmol, 1.0 equiv.) in DMF (10 mL) was added chloro(trimethyl)silane (559.8 μL, 4.4 mmol, 2.5 equiv.) and tetrahydropyran-4-one (648.1 μL, 7.0 mmol, 4.0 equiv.). The mixture was stirred at 0°C for 2 hours. Borane-tetrahydrofuran complex (1 M, 8.8 mL, 5.0 equiv.) was added to the mixture under N2and the resulting mixture was stirred at 0-20°C for 12 hours. The reaction was poured into a saturated aqueous solution of NH4Cl (1.5 ml) and extracted with EtOAc (3 × 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (600 mg, 80% yield) as white solid.

[0675] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.03 (s, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.90 - 6.70 (m, 2H), 6.34 (d, J = 7.8 Hz, 1H), 4.69 (q, J = 8.4 Hz, 2H), 4.11 - 4.00 (m, 2H), 3.92 - 3.71 (m, 1H), 3.73 - 3.63 (m, 1H), 3.56 (t, J = 10.6 Hz, 2H), 2.97 (s, 2H), 2.89 (s, 1H), 2.68 (d, J = 9.4 Hz, 1H), 2.24 - 2.01 (m, 2H).

[0676] LCMS [M+1] = 425.1.

[0677] BP1 synthesis, step 1b, tert-Butyl N-[2-[2-[2-[2-[(3-methoxy-4-nitro- phenyl)sulfonylamino]ethoxy]ethoxy]-ethoxy]ethyl]carbamate: To a solution of tert-butyl N- [2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-ethyl]carbamate (906 mg, 3.1 mmol, 1.3 equiv.) in DCM (15 mL) was added TEA (1.6 mL, 11.9 mmol, 5.0 equiv.) and 3-methoxy-4-nitro- benzenesulfonyl chloride (600 mg, 2.4 mmol, 1.0 equiv.). The mixture was stirred at 15°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (50 mL) and H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.1 g, 91% yield) as a brown oil.

[0678] 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 4.00 (s, 3H), 3.53 - 3.41 (m, 10H), 3.15 - 2.90 (m, 6H), 2.65 (t, J = 5.7 Hz, 1H), 1.36 (s, 9H).

[0679] LCMS [M+1] = 408.2.

[0680] BP1 synthesis, step 2b, tert-Butyl N-[2-[2-[2-[2-[(4-amino-3-methoxy- phenyl)sulfonylamino]ethoxy]ethoxy]-ethoxy]ethyl]carbamate: To a solution of tert-butyl N- [2-[2-[2-[2-[(3-methoxy-4-nitro-phenyl)sulfonylamino]ethoxy]ethoxy]ethoxy]- ethyl]carbamate (2.0 g, 3.9 mmol, 1.0 equiv.) in EtOH (12.0 mL) and H2O (3.0 mL) was added Fe (1.1 g, 19.7 mmol, 5.0 equiv.) and NH4Cl (1.1 g, 19.7 mmol, 5.0 equiv.). The mixture was stirred at 80°C for 1 hour. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (3 × 20 mL). The filtrate was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (50 mL) and H2O (30 mL). Then the aqueous layer was extracted again with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.5 g, 80% yield) as a brown oil.

[0681] 1H NMR (400 MHz, DMSO-d6) δ 7.20 (t, J = 6.0 Hz, 1H), 7.16 - 7.13 (m, 1H), 7.12 (s, 1H), 6.76 (br t, J = 5.6 Hz, 1H), 6.69 - 6.63 (m, 1H), 6.73 - 6.60 (m, 1H), 5.56 (s, 2H), 3.80 (s, 3H), 3.50 - 3.42 (m, 7H), 3.40 - 3.35 (m, 3H), 3.05 (q, J = 6.0 Hz, 2H), 2.80 (q, J = 6.0 Hz, 2H), 1.36 (s, 9H).

[0682] LCMS [M+1] = 378.3.

[0683] BP1 synthesis, step 3b, tert-Butyl N-[2-[2-[2-[2-[[3-methoxy-4-(3- trimethylsilylprop-2-ynylamino)phenyl]- sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl N-[2-[2-[2-[2-[(4-amino-3-methoxy-phenyl)sulfonylamino]ethoxy]ethoxy]ethoxy]-ethyl]carbamate (1.5 g, 3.1 mmol, 1.0 equiv.) in DCM (15 mL) and acetic acid (3 mL) was added 3- trimethylsilylprop-2-ynal (396 mg, 3.1 mmol, 1.0 equiv.). The mixture was stirred at 35°C for 17 hours and then sodium triacetoxyborohydride (2.6 g, 12.5 mmol, 4.0 equiv.) was added to the mixture. The mixture was stirred at 35°C for 17 hours. The reaction mixture was diluted with EtOAc (50 mL) and H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 50 ml). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 (250mm × 70mm × 15 um); mobile phase: 40-75% ACN in water (+NH4HCO3modifier)) to afford the title compound (480 mg, 26% yield) as a white solid.

[0684] 1H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.23 (m, 2H), 7.16 (d, J = 1.8 Hz, 1H), 6.73 (br t, J = 5.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.11 (t, J = 6.0 Hz, 1H), 4.01 (d, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.54 - 3.40 (m, 8H), 3.36 (br t, J = 5.8 Hz, 4H), 3.31 (s, 2H), 3.05 (q, J = 6.0 Hz, 2H), 2.82 (q, J = 6.0 Hz, 2H), 2.07 (s, 1H), 1.36 (s, 9H).

[0685] LCMS [M+1] = 488.4.

[0686] BP1 synthesis, step 4b, tert-Butyl N-[2-[2-[2-[2-[[3-methoxy-4-(prop-2- ynylamino)phenyl]sulfonylamino]-ethoxy]ethoxy]ethoxy]ethyl]carbamate: To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-(3-trimethylsilylprop-2- ynylamino)phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]-carbamate (580.0 mg, 986.7 μmol, 1.0 equiv.) in MeOH (6.0 mL) was added K2CO3 (272.7 mg, 1.9 mmol, 2.0 equiv.). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (400 mg, 79% yield) as an off-white oil.

[0687] 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.24 (m, 2H), 7.15 (d, J = 1.8 Hz, 1H), 6.74 (t, J = 5.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.13 (t, J = 6.0 Hz, 1H), 3.97 (dd, J = 2.0, 6.2 Hz, 2H), 3.83 (s, 3H), 3.50 - 3.41 (m, 8H), 3.39 - 3.33 (m, 4H), 3.11 - 3.00 (m, 3H), 2.81 (q, J = 6.0 Hz, 2H), 2.07 (s, 3H), 1.36 (s, 9H).

[0688] LCMS [M+1] = 416.3.

[0689] BP1 synthesis, step 5b, tert-Butyl N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4- (tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]-ethyl]carbamate: To a solution oftert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-(prop-2-ynylamino)phenyl]sulfonylamino]ethoxy]- ethoxy]ethoxy]ethyl]carbamate (200 mg, 388 μmol, 1.0 equiv.) in ACN (2.0 mL) was added dichloropalladium-triphenylphosphane (27.2 mg, 38.7 μmol, 0.1 equiv.) and copper(I)iodide (7.4 mg, 38.8 μmol, 0.1 equiv.), 2-iodo-N-tetrahydropyran-4-yl-1-(2,2,2-trifluoroethyl)indol- 4-amine (165 mg, 388 μmol, 1.0 equiv.) and triethylamine (162 µL, 1.1 mmol, 3.0 equiv.) under an atmosphere of nitrogen gas. The mixture was stirred at 70°C for 2 hours. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL) and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (200 mg, 64% yield) as a white solid.

[0690] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.32 - 7.24 (m, 1H), 7.19 (d, J = 1.6 Hz, 2H), 7.08 (s, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.80 - 6.63 (m, 2H), 6.32 (t, J = 6.4 Hz, 1H), 6.21 (d, J = 7.8 Hz, 1H), 5.96 - 5.96 (m, 1H), 5.54 (d, J = 8.4 Hz, 1H), 5.01 - 4.84 (m, 2H), 4.33 (d, J = 6.2 Hz, 1H), 3.93 - 3.83 (m, 4H), 3.51 - 3.39 (m, 9H), 3.38 - 3.34 (m, 1H), 3.38 - 3.29 (m, 7H), 3.04 (q, J = 5.8 Hz, 2H), 2.81 (q, J = 5.8 Hz, 2H), 2.50 (d, J = 1.6 Hz, 72H), 2.04 - 1.97 (m, 1H), 1.91 (br d, J = 13.4 Hz, 1H), 1.95 - 1.85 (m, 1H), , 1.36 (s, 9H).

[0691] LCMS [M+1] = 812.3.

[0692] BP1 synthesis, step 6b, N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]-3- methoxy-4-[3-[4-(tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]benzenesulfonamide: To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-[3- [4-(tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2- ynylamino]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]-ethyl]carbamate (200 mg, 246 μmol, 1.0 equiv.) in DCM (0.6 mL) was added TFA (0.8 mL). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (150 mg, 86% yield) as a brown oil. The crude product was used directly in the next step.

[0693] LCMS [M+1] = 712.4.

[0694] BP1 synthesis, step 7b, TR-FRET binding probe, BP1, 5-[(3aS,4S,6aR)-2-oxo- 1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4- (tetrahydropyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]phenyl]- sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]pentanamide: To a solution of N-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethyl]-3-methoxy-4-[3-[4-(tetrahydropyran-4-ylamino)-1-(2,2,2- trifluoroethyl)indol-2-yl]prop-2-ynylamino]benzenesulfonamide (40.0 mg, 56.2 μmol, 1.0equiv.) in DCM (1 mL) was added TEA (28.4 mg, 281 pmol, 39.1 pL, 5.0 equiv.) and (2,5- dioxopyrrolidin-l-yl) 5-[(3aS,4S,6aR)-2-oxo-l,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol- 4-yl]pentanoate (19.1 mg, 56.2 pmol, 1.0 equiv.). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford a residue that was purified by preparative HPLC (column: Phenomenex Luna C18 200mm x 40mm x lOum; mobile phase: 35-70% ACN in water (+formic acid modifier)) to afford the title compound (11.2 mg, 21% yield) as a white solid.

[0695] JH NMR (400 MHz, DMSO-tfe) 67.80 (t, J = 5.6 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.19 (d, J= 1.8 Hz, 1H), 7.08 (s, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 6.70 (d, J= 8.4 Hz, 1H), 6.40 (s, 1H), 6.36 - 6.28 (m, 2H), 6.22 (d, J= 7.8 Hz, 1H), 5.55 (d, J = 2.2 Hz, 1H), 4.93 (q, J = 9.2 Hz, 2H), 4.41 - 4.22 (m, 3H), 4.18 - 4.07 (m, 1H), 3.95 - 3.79 (m, 5H), 3.52 - 3.36 (m, 14H), 3.23 - 3.13 (m, 2H), 3.11 - 3.02 (m, 1H), 2.90 - 2.74 (m, 3H), 2.57 (d, J = 12.6 Hz, 1H), 2.05 (t, J = 7.4 Hz, 2H), 1.91 (d, J = 12.4 Hz, 2H), 1.57 - 1.39 (m, 5H), 1.70 - 1.38 (m, 2H), 1.36 - 1.20 (m, 2H).

[0696] LCMS [M+l] = 938.3.Biological Assays

[0697] Compound potency (IC50) was assessed in a TR-FRET binding assay measuring the association of the biotinylated- small molecule probe BP1 to the Y220C TP53 mutant DBD. Specifically, a 5 microliter mixture consisting of 32 nM BP1 and 48 nM streptavidin- d2 (Cisbio) in 10 mM KH2PO4 pH 7.2, 150 mM NaCl, 0.01% BSA, 0.01% Tween-20 and 0.1 mM TCEP was added to 384-well plates containing duplicate 10-point dose response titrations of test compounds in 60 nL DMSO (0.6% f.c. DMSO (v / v)). An additional 5 microliter mixture consisting of 10 nM Y220C TP53 DBD (e. coli expressed, His-TEV-P89- T312-FLAG; Uniprot ID P04637-1) and 0.3 nM MAb Anti FLAG M2-Tb cryptate (Perkin Elmer) in 10 mM KH2PO4 pH 7.2, 150 mM NaCl, 0.01% BSA, 0.01% Tween-20 and 0.1 mM TCEP was added to the 384-well plates. Mixtures were incubated at 20°C. The TR- FRET response was monitored after 4 hours and 24 hours of incubation of the BP1 mixture and compound mixture. Plates were read in an EnVision plate reader (Perkin Elmer) with Ex / Em 615 / 665. To determine the potency (IC50) of the test compounds (competitive binding to TP53 Y220C protein in the presence of the biotinylated probe, BP1), TR-FRET ratios were normalized to the average ratio of DMSO control wells (0% inhibition) and to the average minimum ratio (100% inhibition) obtained with 5 micromolar BP1 positive control compound. Test compound dose-responses were fitted using a non-linear regression with 4-parameters fitting, providing IC50 and nHill slope. Results are show in Table 5 below and are expressed as the ranges described here: A: IC50 < 0.100 pM; % inhibition > 90%; B: IC50 = 0.100-1.00 pM; % inhibition = 70-90%; C: IC50 = 1.00-10.0 pM; % inhibition = 50-70%; D: ICso = 10.0-60.0 pM; % inhibition = 10-50%; E: IC50 > 60.0 pM; % inhibition < 10%.

[0698] The TR-FRET assay described above may be used to assess the binding affinity of both reversible and covalent TP53 Y220C ligands, stabilizers, and correctors and can also discrimate between reversible and covalent TP53 Y220C ligands, stabilizers, and correctors. To validate the TR-FRET assay described above we characterized a selection of TP53 Y220C ligands, stabilizers, and correctors previously described in the scientific literature. PK9301 and PK9323, compounds described by Joerger, et. al. (ACS Chem. Biology 2020, 75, 657- 668) that have been shown to bind to TP53 Y220C via X-ray crysallography and stabilize the mutant protein as judged by differential scanning fluorimetry (DSF), have an IC50 = 1.5 pM and 4.1 pM, respectively, in the TR-FRET binding assay described above. PK5196, a compound described by Jeorger, Boeckler, et.al. (J. Am. Chem. Soc. 2012, 134, 6810-6818) that has been shown to bind TP53 Y220C via X-ray crysallography and stabilize the mutant protein as judged by differential scanning fluorimetry (DSF), nuclear magnetic resonance (NMR), and isothermal calorimetry (ITC), has an IC50 = 9.7 pM in the TR-FRET assay described above. PK9301, PK9323, and PK5196 are all reversible TP53 Y220C ligands / stabilizers and as such display time-independent activity in the TR-FRET assay described above. Identical or nearly identical IC50 values are observed at both the 4h and 24h time points. Covalent ligands / modifiers generally have time-dependent activity since covalent modification of the protein leads to a lasting, cumulative effect as the reaction with the target protein progresses. Compounds of Formula I often display time-dependent displacement of the TR-FRET binding probe, BP1, from TP53 Y220C distinguishing them from reversible TP53 Y220C ligands / stabilizers / correctors. We believe in certain instances that covalent modification of mutant TP53 Y220C may lead to more durable stabilization of the mutant protein and result in more robust restoration of wild-type TP53 function relative to reversible ligands. This covalent mechanism of action may be advantageous for small molecule therapies targeted towards medical conditions, such as cancer, associated with or ascribed to the TP53 Y220C mutant protein.Table 5.

[0001] While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0002] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

Listing of Claims:

1. A compound having the Formula I:or a pharmaceutically acceptable salt thereof, whereinR1is selected from optionally substituted alkyl;R2is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRaRb, -ORC, -NHC(O)RC, -C(O)NRdRe, -C(O)Rf, and -SRg;R3is selected from hydrogen, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NRalRbl, -ORcl, -NHC(O)Rcl, - C(O)NRdlRel, -C(O)Rfl, and -SRgl;R4is halo, cyano, optionally substituted alkyl, and optionally substituted alkoxy;X is selected from halo, -S(O)2alkyl, and -S(O)alkyl;Ra, Ral, Rb, Rbl, Rc, and Rclare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted heterocyclyl;Rd, Re, and Rgare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’, -C(O)OR’, -C(O)NR’R”, -S(O)R’, and -S(O)2R’ ; or Rdand Retogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;Rdl, Rel, and Rglare each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(O)R’1, -C(O)OR’1, - C(O)NR’1R”1, -S(O)R’1, and -S(O)2R’1; or Rdland Reltogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;Rfand Rf1are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R’ R’1, R’’, and R’’1are each independently selected from hydrogen and optionally substituted (C1-C4)alkyl; and p is 0, 1, or 2.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, -SO2CH3, and -SOCH3.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is selected from chloro, bromo, fluoro, and -SO2CH3.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is chloro.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyano(C1-C4)alkyl, and - (C1-C4)alkyl(C3-C6)cycloalkyl).

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl and halo(C1-C4)alkyl.

8. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1is selected from -CH2CH3, -CH2CF3, -CH2CF2CH3, -CH2CF2CF3, - CH2CN, and -CH2-cyclopropyl.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is -CH2CF3.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7- membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1- C4)alkyl[4- to 6-membered heterocyclyl], -NRaRb, -ORc, -(C1-C4)alkylORc, -C(O)Rf, - C(O)NRdRe, -(C1-C4)alkylNRdRe, -(C1-C4)alkylNRaC(O)Rb, -(C1-C4)alkylC(O)Rf, -(C1- C4)alkylC(O)NRdRe, and -SRg, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5; Ra, Rb, and Rcare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, - (C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6; Rd, Re, and Rgare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -(C1-C4)alkylOR’, -(C1-C4)alkylNR’R’’, -(C1-C4)alkylC(O)NR’R’’, -(C1- C4)alkylC(O)R’, -(C1-C4)alkylC(O)OR’, -(C1-C4)alkylS(O)R’, -(C1-C4)alkylS(O)2R’, (C1- C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], -C(O)R’, -C(O)OR’, -C(O)NR’R’’, -S(O)R’, and -S(O)2R’, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7; or Rdand Retogether with the nitrogen atom to which they are attached form a 4- to 6- membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7; Rfis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8; Ra, R5, R6, R7, and R8are each independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -OR’, -NR’R’’, -(C1-C4)alkylNR’R’’ -(C1-C4)alkylC(O)NR’R’’, oxo, -(C1-C4)alkylOR’, -C(O)R’, -S(O)R’, and - S(O)2R’; and R’ and R’’ are each independently selected from hydrogen, (C1-C4)alkyl, and (C3- C6)cycloalkyl.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NRaRb, -ORc, -C(O)NRdRe, - (C1-C4)alkylNRdRe, -(C1-C4)alkylNRaC(O)Rb, and -(C1-C4)alkylC(O)NRdRe, wherein for each occurrence of 5- to 7-membered heteroaryl, phenyl, (C3-C6)cycloalkyl, and 4- to 6- membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, (C1-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NRaRb, -ORc, -C(O)NRdRe, -(C1- C4)alkylNRdRe, -(C1-C4)alkylNRaC(O)Rb, and -(C1-C4)alkylC(O)NRdRe, wherein said cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R5.

13. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, and Rcare each independently selected from hydrogen, (C1-C4)alkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], (C3-C6)cycloalkyl, phenyl, -(C1-C4)alkylphenyl, 4- to 6-membered heterocyclyl, and -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl, said groups are each optionally substituted with 1 to 3 groups selected from R6.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each independently selected from halo, (C1-C4)alkyl,halo(C1- C4)alkyl, -(C1-C4)alkylOR’, and S(O)2R’.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3, - CH2NHC(O)CH3, -CH2NHSO2CH3, -CH2C(O)NHCH3, -CH2C(O)N(CH3)2, -CH2C(O)NHCH2CF3, -CH2C(O)NHCH2OCH3, -CH2C(O)NH2, -CH2C(O)N(CH3)(CH2CF3), -16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, chloro, and -OCH2CF3.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R3is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, - (C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylORc1, -(C1-C4)alkylphenyl, 4- to 10-membered heterocyclyl, -(C1-C4)alkyl[4- to 10-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -ORc1, -(C1- C4)alkylORc1, -C(O)Rf1, -C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1-C4)alkylC(O)Rf1, -(C1- C4)alkylC(O)NRd1Re1, and -SRg1, wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, and 4- to 10-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R5a; Ra1, Rb1, and Rc1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, 4- to 6- membered heterocyclyl, -(C1-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a; Rd1, Re1, Rg1, and Rh1, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, -(C1-C4)alkylC(O)OR’1, -(C1-C4)alkylS(O)R’1, -(C1-C4)alkylS(O)2R’1, (C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 8-membered heterocyclyl, -(C1-C4)alkyl[4- to 8- membered heterocyclyl], -C(O)R’1, -C(O)OR’1, -C(O)NR’1R’’1, -S(O)R’1, and -S(O)2R’1, wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R7a; or Rd1and Re1together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclyl or 5- to 7-membered heteroaryl each optionally substituted with 1 to 3 groups selected from R7a; Rf1is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, (C3- C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl,wherein said phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R8a; R5a, R6a, R7a, and R8aare each independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, cyano, -NR’1R’’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkyC(O)OR’1, -(C1- C4)alkylC(O)NR’1R’’1, oxo, -(C1-C4)alkylOR’1, -C(O)NR’1R’’1, -OR’1, C(O)OR’1, -C(O)R’1, -S(O)R’1, -S(O)2R’1, 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R’1; and R’1and R’’1are each independently selected from hydrogen, (C1-C4)alkyl, (C3- C6)cycloalkyl, and 4- to 7-membered heterocyclyl.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkyl[4- to 10-membered heterocyclyl], -(C1- C4)alkyl[5- to 7-membered heteroaryl], 4- to 10-membered heterocyclyl, -(C1-C4)alkylORc1, - NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, -C(O)NRd1Re1, and -(C1-C4)alkylNRg1Rh1, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 10-membered heterocyclyl, and 4- to 9-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R5a.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkylORc1, 4- to 10-membered heterocyclyl, - (C1-C4)alkyl[4- to 10-membered heterocyclyl], -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, - C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, wherein each 4- to 10-membered heterocyclyl are optionally substituted with 1 to 3 groups selected from R5a.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -(C1-C4)alkylORc1, -NRa1Rb1, -NHC(O)Rc1, -C(O)Rf1, - C(O)NRd1Re1, -(C1-C4)alkylNRg1Rh1, -(C1-C4)alkyl[piperazinyl], -(C1-C4)alkyl[piperidinyl], - (C1-C4)alkyl[morpholinyl], -(C1-C4)alkyl[pyrrolindyl], -(C1-C4)alkyl[diazepanyl], -(C1- C4)alkyl[azetindinyl], piperazinyl, and tetrahydropyridinyl, wherein said piperidinyl, morpholinyl, pyrrolindyl, diazepanyl, tetrahydropyridinyl, azetindinyl, and each occurrence of piperazinyl are optionally substituted with 1 to 3 groups selected from R5a.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R5ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -NR’1R’’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkyC(O)OR’1, oxo, -(C1- C4)alkylOR’1, -C(O)NR’1R’’1, -OR’1, C(O)OR’1, -C(O)R’1, and 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R’1.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R5ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, imidazolyl piperazinyl, pyrazolyl, triazolyl, terazolyl, azetidinyl, oxo, -N[(C1-C4)alkyl]2, -(C1- C4)alkylNH2, -(C1-C4)alkylNH[(C1-C4)alkyl], -(C1-C4)alkylN[(C1-C4)alkyl]2, -(C1- C4)alkylC(O)N[(C1-C4)alkyl]2, -(C1-C4)alkylOH, -(C1-C4)alkylO(C1-C4)alkyl, -(C1- C4)alkylC(O)OH, C(O)OH, -OH, C(O)NH2, and -C(O)(C1-C4)alkyl.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Rc1is selected from 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein the 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R6a.

25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Rc1is piperidinyl or pyridinyl, each optionally substituted with 1 to 3 groups selected from R6a.

26. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R6ais (C1-C4)alkyl.

27. The compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Ra1and Rb1are each independently selected from hydrogen, -(C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 6-membered heterocyclyl, wherein for each occurrence of 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, said groups are each optionally substituted with 1 to 3 groups selected from R6a.

28. The compound of any one of Claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Ra1and Rb1are each independently selected from hydrogen and -(C1-C4)alkyl[5- to 7-membered heteroaryl], wherein said 5- to 7-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R6a.

29. The compound of any one of Claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Ra1is hydrogen and Rb1is -(C1-C4)alkyl[pyridinyl], wherein said pyridinyl is optionally substituted with 1 to 3 groups selected from R6a.

30. The compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein Rf1is 4- to 6-membered heterocyclyl optionally substituted with 1 to 3 groups selected from R8a.

31. The compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Rf1is piperazinyl optionally substituted with 1 to 3 groups selected from R8a.

32. The compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R8ais (C1-C4)alkyl.

33. The compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Rd1and Re1are each independently selected from hydrogen, -(C1- C4)alkylNR’1R’’1, (C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 8-membered heterocyclyl, wherein said 5- to 7-membered heteroaryl, and 4- to 8-membered heterocyclyl, are each optionally substituted with 1 to 3 groups selected from R7a.

34. The compound of any one of Claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Rd1and Re1are each independently selected from hydrogen, -(C1- C4)alkylN[(C1-C4)alkyl]2, (C1-C4)alkyl[pyridinyl], and piperidinyl, wherein said pyridinyl and piperidinyl, are each optionally substituted with 1 to 3 groups selected from R7a.

35. The compound of any one of Claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Rg1and Rh1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR’1, -(C1-C4)alkylNR’1R’’1, -(C1-C4)alkylC(O)NR’1R’’1, - (C1-C4)alkylC(O)R’1, (C1-C4)alkylphenyl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 8-membered heterocyclyl, wherein said phenyl, 5- to 7-membered heteroaryl, and 4- to 8- membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R7a.

36. The compound of any one of Claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Rg1and Rh1are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkyl[pyridinyl], -(C1-C4)alkylO(C1-C4)alkyl, (C1-C4)alkylphenyl, - (C1-C4)alkylN[(C1-C4)alkyl]2, pyridinyl, piperidinyl, pyrrolidinyl, -(C1-C4)alkylC(O)N[(C1- C4)alkyl]2, halo(C1-C4)alkyl, -(C1-C4)alkylC(O)(morpholinyl), wherein said phenyl, pyridinyl, piperidinyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R7a.

37. The compound of any one of Claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R7ais selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, (C1-C4)alkoxy, and cyano.

38. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R3is selected from –CH2NHCH3, –CH2N(CH3)2, –(CH2)2N(CH3)2, - CH2N(CH3)(CH2)2OCH3, -CH2N(CH3)(CH2)2N(CH3)2, -CH2NH(CH2CH3), - CH2N(CH3)(CH2)3N(CH3)2, -CH2NH(CH2)2N(CH2CH3)2, CH2NHC(CH3)3,-39. The compound of Claim 1, wherein the compound is selected fromor a pharmaceutically acceptable salt thereof.

40. A compound according to any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

41. A method of treating a condition responsive to the activation of wild- type tumor suppressor protein TP53 function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof, or the composition of Claim 40.

42. The method of Claim 41, wherein the condition is a cancer.

43. The method of Claim 41 or 42, wherein the condition is a cancer harboring a Y220C mutation.

44. The method of any one of Claims 41 to 43, wherein the cancer is a solid tumor or a heme malignancy.

45. The method of any one of Claims 41 to 44, wherein the cancer is selected from lung cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, glioma, glioblastoma, endometrial cancer, esophageal cancer, gastric cancer, prostate cancer, head and neck cancer, bladder cancer, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), sarcoma, and melanoma.

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