Compounds and compositions for targeting TP53-Y220C mutants

Abstract

Compounds of Formula (I) and pharmaceutically acceptable salts and compositions thereof are provided, which are useful in the treatment of various conditions associated with p53 activation.

Description

[0001] Related Applications

[0002] This application claims 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

[0003] The transcription factor TP53 acts as a tumor suppressor gene and is inactivated by mutation in about 50% of all tumors. TP53 regulates multiple intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence. The Y220C mutation is a common TP53 missense mutant associated with over 100,000 new cancer cases globally each year, primarily breast and ovarian cancers. The Y220C mutation causes a major structural change in the TP53 protein and is known to form a new protein cavity estimated to accommodate small molecule drug candidates. Critically, the mutation-induced cleft is far from the TP53 surface involved in DNA recognition or protein-protein interactions, enabling the development of targeted chemical agents that stabilize the DNA binding domain without interfering with its natural substrate binding. Stabilization can restore TP53 function, thereby reactivating the TP53 tumor suppressor pathway and shrinking or killing tumors. SUMMARY

[0004] Provided herein are compounds having Formula I:

[0005]

[0006] and pharmaceutically acceptable salts and compositions thereof, wherein R 1 , R 2 , R 3 , R 4 , X, and p are as described herein. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof are used 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 the function of wild-type tumor suppressor protein TP53 (WT TP53). In one aspect, it is believed that the described compounds are covalent modifiers of TP53 Y220C that cause stabilization of the mutant protein and can restore wild-type function to the dysfunctional mutant protein. See, for example, the Examples section below.

[0007] Also included are pharmaceutical compositions comprising the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof, and methods of their preparation. DETAILED DESCRIPTION

[0008] 1. General description of compounds

[0009] In a first embodiment, provided herein is a compound of Formula I:

[0010]

[0011] R 1 is selected from optionally substituted alkyl;

[0012] R 2 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NR a R b , -OR c , -NHC(O)R c , -C(O)NR d R e , -C(O)R f , and -SR g ;

[0013] R 3 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NR a1 R b1 , -OR c1 , -NHC(O)R c1 , -C(O)NR d1 R e1 , -C(O)R f1 , and -SR g1 ;

[0014] R 4 is halogen, cyano, optionally substituted alkyl, and optionally substituted alkoxy;

[0015] X is selected from halogen, -S(O)2alkyl, and -S(O)alkyl;

[0016] R a , R a1 , R b , R b1 , R c , and R c1 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted heterocyclyl;

[0017] R d , R e , and R geach independently selected from the group consisting of 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 R d and R e together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

[0018] R d1 , R e1 and R g1 each independently selected from the group consisting of 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' 1 R" 1 , -S(O)R' 1 and -S(O)2R' 1 ; or R d1 and R e1 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

[0019] R f and R f1 each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

[0020] R', R' 1 , R" and R" 1 each independently selected from the group consisting of hydrogen and optionally substituted (Ci-C4)alkyl; and

[0021] p is 0, 1, or 2.

[0022] 2. Definitions

[0023] When used to describe a chemical group that can have multiple points of attachment, the hyphen (-) indicates the point of attachment of the group to the variable it defines. For example, -NR a R b indicates that the point of attachment of the group is on the nitrogen atom.

[0024] The terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0025] The term "alkyl," used alone or as part of a larger moiety, e.g., "haloalkyl," refers to a straight or branched chain monovalent hydrocarbon group.

[0026] "Alkoxy" refers to an alkyl group linked through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propyloxy, and butyloxy.

[0027] The term "haloalkyl" includes mono-haloalkyl, poly-haloalkyl, and per-haloalkyl groups, wherein the halo is independently selected from fluorine, chlorine, bromine, and iodine.

[0028] "Haloalkoxy" is a haloalkyl group connected to another moiety via an oxygen atom, e.g., -OCHF2or -OCF3.

[0029] The term "oxo" denotes the group =O.

[0030] The term "heteroaryl," used alone or as part of a larger moiety, refers to a 5- to 12-membered aromatic group containing 1-4 heteroatoms selected from N, O, and S. The heteroaryl group can be monocyclic or bicyclic. Monocyclic heteroaryl groups include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Bicyclic heteroaryl compounds include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, imidazopyridinyl, benzoxazolyl, benzoxadiazolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be appreciated that optional substituents on the heteroaryl group, when specifically designated, can be present at any substitutable position and include, for example, the position to which the heteroaryl group is attached.

[0031] The term "heterocyclyl" refers to 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., bridged, fused, or spiro bicyclic) or tricyclic. The heterocyclyl ring can be attached to its side group at any heteroatom or carbon atom, thereby forming a stable structure. Examples of such saturated or partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidinonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclyl" also includes unsaturated heterocyclyl groups fused, for example, with another unsaturated heterocyclyl or aryl or heteroaryl ring, such as, for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that, when specifically designated, optional substituents on the heterocyclyl group can be present at any substitutable position and include, for example, the position at which the heterocyclyl group is attached (e.g., in the case of an optionally substituted heterocyclyl group or an optionally substituted heterocyclyl group).

[0032] The term "spiro" refers to two rings sharing one ring atom (e.g., carbon).

[0033] The term "fused" refers to two rings sharing two adjacent ring atoms with each other.

[0034] The term "bridged" refers to two rings sharing three ring atoms with each other.

[0035] 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 3 to 10 carbon ring atoms, unless otherwise specified. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be appreciated that, when specified, optional substituents on the cycloalkyl or cycloaliphatic group can be present at any substitutable position and include, for example, the position at which the cycloalkyl group is attached.

[0036] The term "optionally substituted" indicates that one or more hydrogens on the designated moiety can be replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent on every substitutable position of the group, as valency permits. Optional substituents include, but are not limited to, one or more groups selected from cyano (–CN), halogen, imino (=NH), nitro (–NO2), oxo (=O), –C(O)R i , –C(O)OR i , –C(O)NRii R iii , -C(O)SR i , -C(NR i )NR ii R iii , -C(S)R i , -C(S)OR i , -C(S)NR ii R iii , -OR i , -OC(O)R i , -OC(O)OR i , -OC(O)NR ii R iii , -OC(O)SR i , -OC(NR i )NR ii R iii , -OC(S)R i , -OC(S)OR i , -OC(S)NR ii R iii , -OP(O)(OR ii )OR iii , -OS(O)R i , -OS(O)2R i , -OS(O)NR ii R iii , -OS(O)2NR ii R iii , -NR ii R iii , -NR i C(O)R iv , -NR i C(O)OR iv , -NR i C(O)NR ii R iii , -NR a C(O)SR iv , -NR i C(NR iv )NR ii R iii , -NR i C(S)R iv , -NR i C(S)OR iv , -NR i C(S)NR ii R iii , -NR i S(O)R iv , -NR iS(O)2R iv , -NR i S(O)NR ii R iii , -NR i S(O)2NR ii R iv , -SR i , -S(O)R i , -S(O)2R i , -S(O)NR ii R iv , -S(O)2NR ii R iv , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a , wherein each R i , R ii , R iii , and R iv is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a , or R ii and R iii , together with the N atom to which they are attached, form a heterocyclyl optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a , wherein each Q a is independently selected from the group consisting of cyano, halogen, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, -C(O)R v , -C(O)OR v , -C(O)NR vi R vii , -C(O)SR v , -C(NR v )NR vi R vii , -C(S)R v , -C(S)OR v , -C(S)NR vi R vii , -OR v , -OC(O)R v , -OC(O)OR v , -OC(O)NR vi Rvii -OC(O)SR v -OC(NR v )NR vi R vii -OC(S)R v -OC(S)OR v -OC(S)NR vi R vii -OP(O)(OR v )OR vi -OS(O)R v -OS(O)2R v -OS(O)NR vi R vii -OS(O)2NR v R vii -NR vi R vii -NR v C(O)R viii -NR e C(O)OR vi -NR v C(O)NR vi R vii -NR v C(O)SR vi -NR v C(NR viii )NR vi R vii -NR v C(S)R viii -NR v C(S)OR vi -NR v C(S)NR vi R vii -NR v S(O)R viii -NR v S(O)2R viii -NR v S(O)NR vi R vii -NR v S(O)2NR vi R vii -SR v -S(O)R v -S(O)2R v -S(O)NR vi R vii and -S(O)2NR vi R vii ; wherein Rv , R vi , R vii , and R viii each independently is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; or (iii) R vi and R viii together with the N atom to which they are attached form heterocyclyl.

[0037] In certain aspects, when specified, one or more hydrogen atoms on the disclosed compounds can be replaced with deuterium. Such deuterium-substituted compounds can have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent “non-deuterated” compound.

[0038] One or more compounds described herein can exist in various tautomeric forms, and are part of the present disclosure. The term “tautomer” or “tautomeric” refers to two or more compounds / substituents that are interconvertible by the migration of at least one formal charge and at least one change in the constitution of a molecule. All isomeric forms of such compounds are expressly included. Thus, when a compound herein is represented by a structural formula or specified by a chemical name, all tautomeric forms in which the compound can exist are encompassed by the structural formula.

[0039] Compounds having one or more chiral centers can exist as different stereoisomers. Stereoisomers are compounds that differ only in the way their atoms are arranged in space. Stereoisomers include all diastereomers, enantiomers, and epimers, as well as racemates and mixtures thereof. “Geometric isomers” refer to isomers differing in the orientation of substituents around a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic ring system. The atoms on either side of a carbon-carbon double bond (excluding H) can be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are on the same side) configuration. “Cis” refers to substituents on the same side of a ring, while “trans” refers to substituents on opposite sides of a ring.

[0040] When the stereochemical configuration of a chiral center in a compound having one or more chiral centers is described by its chemical name (e.g., the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by a “wedge” bond), the indicated configuration is enriched greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% relative to the opposite configuration. The “enrichment of the indicated configuration relative to the opposite configuration” is a molar percentage determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of compounds having the same or opposite stereochemical configuration in the mixture.

[0041] When a geometric isomer is named or described by name or structure, the indicated isomer is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% enriched relative to the opposite isomer. The “enrichment of the indicated isomer relative to the opposite isomer” is a molar percentage determined by dividing the number of compounds having the indicated geometric configuration by the total number of all compounds having the same or opposite geometric configuration in the mixture.

[0042] When a disclosed compound is named or described by structure without indicating stereochemistry, it is understood that the name or structure encompasses one possible stereoisomer or geometric isomer without the other isomer, or a mixture of the encompassed stereoisomer or geometric isomer.

[0043] The terms “subject” and “patient” can be used interchangeably and refer to a mammal in need of treatment, such as domestic 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.

[0044] The terms “inhibit,” “impair,” or “inhibitory” include a reduction in the baseline activity of a biological activity or process.

[0045] The terms “treat,” “treatment,” “treated,” and “treating” as used herein 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 can be effected after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment can be effected in the absence of symptoms. For example, treatment can be of 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 predisposing factors), i.e., prophylactic or preventative treatment. Treatment can also continue after symptoms have resolved, for example to delay their recurrence.

[0046] 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 can 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.

[0047] For use in medicine, the salts of the compounds described herein refer to "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, nitric, and sulfuric acids, and salts of organic acids such as acetic, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids. Compounds of the application having an acidic group such as a carboxylic acid can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include, for example, ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth metal salts such as magnesium and calcium salts. Compounds having a quaternary ammonium group also contain a counterion such as chloride, bromide, iodide, acetate, perchlorate, and the like. Other examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, benzoate, and salts with amino acids such as glutamic acid.

[0048] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is capable of eliciting a desired or beneficial biological or medical response in a subject, for example, a dose of between 0.01-100 mg / kg body weight / day.

[0049] 3. Compounds

[0050] 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.

[0051] In a third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of chloro, bromo, fluoro, -SO2CH3, and -SOCH3, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, as part of the third embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 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 the 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.

[0052] In a fourth embodiment, R 1 is selected from the group consisting of (Ci-C4)alkyl, halo(Ci-C4)alkyl, cyano(Ci-C4)alkyl, and -(Ci-C4)alkyl(C3-C6)cycloalkyl), wherein the remaining variables are as described above for Formula I or the second or third embodiments. Alternatively, as part of the fourth embodiment, R 1(C1-C4)alkyl and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment or the third embodiment. In another alternative, as part of the fourth embodiment, R 1 -CH2CH3, -CH2CF3, -CH2CF2CH3, -CH2CF2CF3, -CH2CN, and -CH2-cyclopropyl, wherein the remaining variables are as described above for Formula I or the second embodiment or the third embodiment. In another alternative, as part of the fourth embodiment, R 1 -CH2CH3, -CH2CF3, -CH2CF2CH3, and -CH2CF2CF3, wherein the remaining variables are as described above for Formula I or the second embodiment or the third embodiment. In another alternative, as part of the fourth embodiment, R 1 -CH2CF3, wherein the remaining variables are as described above for Formula I or the second embodiment or the third embodiment.

[0053] In a fifth embodiment, R 2 halogen, (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], -NR a R b , -OR c , -(C1-C4)alkylOR c , -C(O)R f , -C(O)NR d R e , -(C1-C4)alkylNR d R e , -(C1-C4)alkylC(O)R f , -(C1-C4)alkylC(O)NR d R e , and -SR g , wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, the groups are each optionally substituted with 1 to 3 groups selected from R 5 , and R 2selected from the group consisting of hydrogen, halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(Ci-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(Ci-C4)alkyl[4- to 6-membered heterocyclyl], -NR a R b , -OR c , -(Ci-C4)alkylOR c , -C(O)R f , -C(O)NR d R e , -(Ci-C4)alkylNR d R e , -(Ci-C4)alkylNR a C(O)R b , -(Ci-C4)alkylC(O)R f , -(Ci-C4)alkylC(O)NR d R e , and -SR g , wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, each of said groups is optionally substituted with 1 to 3 groups selected from R 5 ;

[0054] R a , R b , and R c are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(Ci-C4)alkylphenyl, 4- to 6-membered heterocyclyl, -(Ci-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, each of said groups is optionally substituted with 1 to 3 groups selected from R 6 ;

[0055] R d , R e , and R geach independently is selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkylOR', -(Ci-C4)alkylNR'R", -(Ci-C4)alkylC(O)NR'R", -(Ci-C4)alkylC(O)R', -(Ci-C4)alkylC(O)OR', -(Ci-C4)alkylS(O)R', -(Ci-C4)alkylS(O)2R', (Ci-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, -(Ci-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, the group is each optionally substituted with 1 to 3 groups selected from R 7 ; or R d and R e , together 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 R 7 ; and the remaining variables are as described above for Formula I or any one of the second through fourth embodiments.

[0056] R f is selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein the 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 R 8 ; and the remaining variables are as described above for Formula I or any one of the second through fourth embodiments.

[0057] R a , R 6 , R 7 , and R 8 each independently is selected from the group consisting of (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (C3-C6)cycloalkyl, -OR', -NR'R", -(Ci-C4)alkylNR'R", -(Ci-C4)alkylC(O)NR'R", oxo, -(Ci-C4)alkylOR', -C(O)R', -S(O)R', and -S(O)2R'; and

[0058] R' and R" each independently is selected from the group consisting of hydrogen, (Ci-C4)alkyl, and (C3-C6)cycloalkyl, wherein the remaining variables are as described above for Formula I or any one of the second through fourth embodiments.

[0059] In a sixth embodiment, R2 selected from hydrogen, halogen, (Ci-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NR a R b , -OR c , -C(O)NR d R e , -(Ci-C4)alkylNR d R e , -(Ci-C4)alkylNR a C(O)R b , and -(Ci-C4)alkylC(O)NR d R e , wherein for each occurrence of 5- to 7-membered heteroaryl, phenyl, (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, the groups are each optionally substituted with 1 to 3 groups selected from R 5 , and wherein the remaining variables are as described above for Formula I or any one of the second through fifth embodiments. Alternatively, as part of the sixth embodiment, R 2 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halogen, (Ci-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7- membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NR a R b , -OR c , -C(O)NR d R e , -(Ci-C4)alkylNR d R e , -(Ci-C4)alkylNR a C(O)R b , and -(Ci-C4)alkylC(O)NR d R e , wherein for each occurrence of 5- to 7-membered heteroaryl, phenyl, (C3-C6)cycloalkyl, and 4- to 6-membered heterocyclyl, the groups are each optionally substituted with 1 to 3 groups selected from R 5 , and wherein the remaining variables are as described above for Formula I or any one of the second through fifth embodiments. Alternatively, as part of the sixth embodiment, R 2 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halogen, (Ci-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NR a R b , -OR c , -C(O)NR d R e , -(Ci-C4)alkylNR d Re -(Ci-C4)alkylNR a C(O)R b and -(Ci-C4)alkylC(O)NR d R e wherein the cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R 5 , and the remaining variables are as described above for Formula I or any one of the second through fifth embodiments. Alternatively, as part of the sixth embodiment, R 2 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halogen, (Ci-C4)alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NR a R b , -OR c , -C(O)NR d R e , -(Ci-C4)alkylNR d R e and -(Ci-C4)alkylC(O)NR d R e wherein the cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with 1 to 3 groups selected from R 5 , and the remaining variables are as described above for Formula I or any one of the second through fifth embodiments.

[0060] In the seventh embodiment, R a , R b , and R c in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (Ci-C4)alkyl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(Ci-C4)alkylphenyl, 4- to 6-membered heterocyclyl, and -(Ci-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl, the group is each optionally substituted with 1 to 3 groups selected from R 6 , and the remaining variables are as described above for Formula I or any one of the second through fifth embodiments. Alternatively, as part of the seventh embodiment, R a , R b , and R ceach independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], (C3-C6)cycloalkyl, phenyl, -(Ci-C4)alkylphenyl, 4- to 6- membered heterocyclyl, and -(Ci-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 R 6

[0061] In an eighth embodiment, R 5 and R 6 each independently are selected from the group consisting of (Ci-C4)alkyl and halo(Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second through seventh embodiments. Alternatively, as part of the eighth embodiment, R 5 and R 6 each independently are selected from the group consisting of halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkylOR ’ and S(O)2R’, wherein the remaining variables are as described above for Formula I or any one of the second through seventh embodiments.

[0062] In a ninth embodiment, R 2 is selected from the group consisting of hydrogen, chloro, methyl, cyclopropyl, -OCH2CF3, wherein the remaining variables are as described above for Formula I or any one of the second through eighth embodiments. Alternatively, as part of the ninth embodiment, R 2 is selected from the group consisting of 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,

[0063]

[0064]

[0065] ​wherein the remaining variables are as described above for formula I or any one of the second through eighth embodiments. Alternatively, as part of the ninth embodiment, R 2 is selected from hydrogen, chloro, and -OCH2CF3, wherein the remaining variables are as described above for formula I or any one of the second through eighth embodiments. In another alternative, as part of the ninth embodiment, R 2 is hydrogen, wherein the remaining variables are as described above for formula I or any one of the second through eighth embodiments.

[0066] In a tenth embodiment, R 3 is selected from halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(Ci-C4)alkylOR c1 , -(Ci-C4)alkylphenyl, 4- to 10-membered heterocyclyl, -(Ci-C4)alkyl[4- to 9-membered heterocyclyl], -NR a1 R b1 , -NHC(O)R c1 , -OR c1 , -(Ci-C4)alkylOR c1 , -C(O)R f1 , -C(O)NR d1 R e1 , -(Ci-C4)alkylNR g1 R h1 , -(Ci-C4)alkylC(O)R f1 , -(Ci-C4)alkylC(O)NR d1 R e1 , and -SR g1 , wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, the groups are each optionally substituted with 1 to 3 groups selected from R 5a ;

[0067] R a1 , R b1 , and R c1each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkylOR', -(Ci-C4)alkylNR' R", -(Ci-C4)alkylC(O)R', -(Ci-C4)alkylC(O)OR', -(Ci-C4)alkylC(O)NR' R", -(Ci-C4)alkylS(O)R', -(Ci-C4)alkylS(O)2R', (Ci-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and -(Ci-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, each of said groups is optionally substituted with 1 to 3 groups selected from R 6a ;

[0068] R d1 , R e1 , R g1 , and R h1 each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkylOR', -(Ci-C4)alkylNR' R", -(Ci-C4)alkylC(O)R', -(Ci-C4)alkylC(O)OR', -(Ci-C4)alkylC(O)NR' R", -(Ci-C4)alkylS(O)R', -(Ci-C4)alkylS(O)2R', (Ci-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, and -(Ci-C4)alkyl[4- to 6-membered heterocyclyl], wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, each of said groups is optionally substituted with 1 to 3 groups selected from R 1 ; 1 R 1 ; 1 R 1 ; 1 R 1 ; 1 R 1 ; 1 R 1 ; 1 R 1 ; 1 R 1 ; 7a wherein for each occurrence of (C3-C6)cycloalkyl, phenyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl, each of said groups is optionally substituted with 1 to 3 groups selected from R d1 and R e1 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or 5- to 7-membered heteroaryl group, each of which is optionally substituted with 1 to 3 groups selected from R 7a ;

[0069] R f1selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 6-membered heterocyclyl, wherein each of phenyl, (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, and 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from R 8a ;

[0070] R 5a , R 6a , R 7a , and R 8a are each independently selected from halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (C3-C6)cycloalkyl, cyano, -NR 1 R 1 , -(Ci-C4)alkylNR 1 R 1 , -(Ci-C4)alkylC(O)NR 1 R 1 , oxo, -(Ci-C4)alkylOR 1 , -C(O)R 1 , -S(O)R 1 , and -S(O)2R 1 ; and

[0071] R 1 and R 1 are each independently selected from hydrogen, (Ci-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 through ninth embodiments. Alternatively, as part of the tenth embodiment, R 3 in Formula I, or a pharmaceutically acceptable salt thereof, is selected from halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C6)cycloalkyl, -(Ci-C4)alkyl(C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], phenyl, -(Ci-C4)alkylOR c1 , -(Ci-C4)alkylphenyl, 4- to 10-membered heterocyclyl, -(Ci-C4)alkyl[4- to 10-membered heterocyclyl], -NR a1 R b1 , -NHC(O)R c1 , -OR c1 , -(Ci-C4)alkylOR c1 , -C(O)R f1 , -C(O)NR d1 R e1 , -(Ci-C4)alkylNRg1 R h1 , -(C1-C4)alkylC(O)R f1 , -(C1-C4)alkylC(O)NR d1 R e1 , and -SR g1 , wherein for each occurrence of (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, phenyl, and 4- to 10-membered heterocyclyl, each of said groups is optionally substituted with 1 to 3 groups selected from R 5a ;

[0072] R a1 , R b1 , and R c1 are 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, each of said groups is optionally substituted with 1 to 3 groups selected from R 6a ;

[0073] R d1 , R e1 , R g1 , and R h1 are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR’ 1 , -(C1-C4)alkylNR’ 1 R” 1 , -(C1-C4)alkylC(O)NR’ 1 R” 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’ 1 R” 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, each of said groups is optionally substituted by 1 to 3 groups selected from R 7a or R d1 and R e1 Together with the nitrogen atom to which they are attached, they form a group each optionally substituted by 1 to 3 groups selected from R 7a a 4- to 8-membered heterocyclic group or a 5- to 7-membered heteroaryl group substituted with

[0074] R f1 is 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 by 1 to 3 groups selected from R 8a The group substitution;

[0075] R 5a 、R 6a 、R 7a and R 8a Each is independently selected from halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyl, 5 to 7 membered heteroaryl, cyano, -NR' 1 R” 1 、-(C1-C4)alkylNR' 1 R” 1 、-(C1-C4)alkyl C(O)OR' 1 、-(C1-C4)alkyl C(O)NR' 1 R” 1 , oxo, -(C1-C4)alkyl OR' 1 、-C(O)NR' 1 R” 1 、-OR' 1 、C(O)OR' 1 、-C(O)R' 1 、-S(O)R' 1 、-S(O)2R' 1 , optionally 1 to 3 selected from R' 1 a 4- to 6-membered heterocyclic group substituted with a group of

[0076] R' 1 and R” 1each independently selected from the group consisting of hydrogen, (Ci-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 through ninth embodiments.

[0077] In an eleventh embodiment, R 3 is selected from the group consisting of -(Ci-C4)alkyl[4- to 9-membered heterocyclyl], -(Ci-C4)alkyl[5- to 7-membered heteroaryl], 4- to 6-membered heterocyclyl, -(Ci-C4)alkylOR c1 , -NR a1 R b1 , -NHC(O)R c1 , -C(O)R f1 , -C(O)NR d1 R e1 , and -(Ci-C4)alkylNR g1 R h1 wherein the (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 R 5a , wherein the remaining variables are as described above for Formula I or any one of the second through tenth embodiments. Alternatively, R 3 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of -(Ci-C4)alkyl[4- to 10-membered heterocyclyl], -(Ci-C4)alkyl[5- to 7-membered heteroaryl], 4- to 10-membered heterocyclyl, -(Ci-C4)alkylOR c1 , -NR a1 R b1 , -NHC(O)R c1 , -C(O)R f1 , -C(O)NR d1 R e1 , and -(Ci-C4)alkylNR g1 R h1 wherein the (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 R 5a , wherein the remaining variables are as described above for Formula I or any one of the second through tenth embodiments. Alternatively, R 3 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of -(Ci-C4)alkylOR c1 , 4- to 10-membered heterocyclyl, -(Ci-C4)alkyl[4- to 10-membered heterocyclyl], -NR a1 R b1 , -NHC(O)R c1 , -C(O)Rf1 -C(O)NR d1 R e1 and -(C1-C4)alkylNR g1 R h1 wherein each 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from R 5a , and wherein the remaining variables are as described above for Formula I or any one of the second through tenth embodiments. Alternatively, R 3 in the compounds of Formula I, or pharmaceutically acceptable salts thereof, is selected from -(C1-C4)alkylOR c1 , 4- to 6-membered heterocyclyl, -(C1-C4)alkyl[4- to 9-membered heterocyclyl], -NR a1 R b1 , -NHC(O)R c1 , -C(O)R f1 , -C(O)NR d1 R e1 and -(C1-C4)alkylNR g1 R h1 , and wherein the 4- to 6-membered heteroaryl and 4- to 9-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R 5a , and wherein the remaining variables are as described above for Formula I or any one of the second through tenth embodiments. Alternatively, R 3 in the compounds of Formula I, or pharmaceutically acceptable salts thereof, is selected from -(C1-C4)alkylOR c1 , -NR a1 R b1 , -NHC(O)R c1 , -C(O)R f1 , -C(O)NR d1 R e1 , -(C1-C4)alkylNR g1 R h1 , -(C1-C4)alkyl[piperazinyl], -(C1-C4)alkyl[piperidinyl], -(C1-C4)alkyl[morpholinyl], -(C1-C4)alkyl[pyrrolidinyl], -(C1-C4)alkyl[diazepanyl], -(C1-C4)alkyl[azetidinyl], piperazinyl, and tetrahydropyridinyl, wherein the piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, tetrahydropyridinyl, azetidinyl, and each occurrence of piperazinyl are optionally substituted with 1 to 3 groups selected from R 5a , and wherein the remaining variables are as described above for Formula I or any one of the second through tenth embodiments.

[0078] In a twelfth embodiment, R 5a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C6)cycloalkyl, -NR 1 R" 1 , -(Ci-C4)alkylNR 1 R" 1 , -(Ci-C4)alkylOR 1 , and -C(O)R 1 , wherein the remainder of the variables are as described above for Formula I or any one of the second through eleventh embodiments. Alternatively, as part of the twelfth embodiment, R 5a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, cyclopropyl, -N[(Ci-C4)alkyl]2, -(Ci-C4)alkylN[(Ci-C4)alkyl]2, -(Ci-C4)alkylOH, -(Ci-C4)alkylO(Ci-C4)alkyl, and -C(O)(Ci-C4)alkyl, wherein the remainder of the variables are as described above for Formula I or any one of the second through eleventh embodiments.

[0079] In a thirteenth embodiment, R c1 is selected from 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl, wherein each of the 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from R 6a , wherein the remainder of the variables are as described above for Formula I or any one of the second through twelfth embodiments. Alternatively, as part of the thirteenth embodiment, R c1 is piperidinyl or pyridinyl, each optionally substituted with 1 to 3 groups selected from R 6a , wherein the remainder of the variables are as described above for Formula I or any one of the second through twelfth embodiments.

[0080] In a fourteenth embodiment, R 6a is (Ci-C4)alkyl, wherein the remainder of the variables are as described above for Formula I or any one of the second through thirteenth embodiments.

[0081] In a fifteenth embodiment, R a1 and R b1each independently selected from the group consisting of hydrogen, -(Ci-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, the groups are each optionally substituted with 1 to 3 groups selected from R 6a , and the remaining variables are as described above for Formula I or any one of the second through fourteenth embodiments. Alternatively, as part of the fifteenth embodiment, R a1 and R b1 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from the group consisting of hydrogen and -(Ci-C4)alkyl[5- to 7-membered heteroaryl], wherein the 5- to 7-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 6a , and the remaining variables are as described above for Formula I or any one of the second through fourteenth embodiments. In another alternative, as part of the fifteenth embodiment, R a1 is hydrogen and R b1 is -(Ci-C4)alkyl[pyridyl], wherein the pyridyl is optionally substituted with 1 to 3 groups selected from R 6a , and the remaining variables are as described above for Formula I or any one of the second through fourteenth embodiments.

[0082] In a sixteenth embodiment, R f1 in 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 R 8a , and the remaining variables are as described above for Formula I or any one of the second through fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, R f1 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is piperazinyl optionally substituted with 1 to 3 groups selected from R 8a , and the remaining variables are as described above for Formula I or any one of the second through fifteenth embodiments.

[0083] In a seventeenth embodiment, R 8a in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (Ci-C4)alkyl, and the remaining variables are as described above for Formula I or any one of the second through sixteenth embodiments.

[0084] In an eighteenth embodiment, R d1 and R e1 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from the group consisting of hydrogen, -(Ci-C4)alkylNR’ 1 R” 1(C1-C4)alkyl[5- to 7-membered heteroaryl] and 4- to 6-membered heterocyclyl, wherein each of said 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from R 7a , and the remaining variables are as described above for formula I or any one of the second through seventeenth embodiments. Alternatively, as part of the eighteenth embodiment, R d1 and R e1 in the compound of formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkylNR 1 R" 1 , (C1-C4)alkyl[5- to 7-membered heteroaryl] and 4- to 8-membered heterocyclyl, wherein each of said 5- to 7-membered heteroaryl and 4- to 8-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from R 7a , and the remaining variables are as described above for formula I or any one of the second through seventeenth embodiments. Alternatively, as part of the eighteenth embodiment, R d1 and R e1 in the compound of formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkyl, (C1-C4)alkyl[pyridyl] and piperidinyl, wherein each of said pyridyl and piperidinyl is optionally substituted with 1 to 3 groups selected from R 7a , and the remaining variables are as described above for formula I or any one of the second through seventeenth embodiments.

[0085] In the nineteenth embodiment, R g1 and R h1 in 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 1 R" 1 , -(C1-C4)alkylC(O)NR 1 R" 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 each of said phenyl, 5- to 7-membered heteroaryl and 4- to 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from R 7a , and the remaining variables are as described above for formula I or any one of the second through eighteenth embodiments. Alternatively, as part of the nineteenth embodiment, R g1 and R h1each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkylOR 1 , -(Ci-C4)alkylNR 1 R 1 , -(Ci-C4)alkylC(O)NR 1 R 1 , -(Ci-C4)alkylC(O)R 1 , (Ci-C4)alkylphenyl, -(Ci-C4)alkyl[5- to 7-membered heteroaryl], and 4- to 8-membered heterocyclyl, wherein the phenyl, 5- to 7-membered heteroaryl, and 4- to 8-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from R 7a , and wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. Alternatively, as part of the nineteenth embodiment, R g1 and R h1 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkyl[pyridyl], -(Ci-C4)alkylO(Ci-C4)alkyl, (Ci-C4)alkylphenyl, -(Ci-C4)alkylN[(Ci-C4)alkyl]2, pyridyl, piperidyl, pyrrolidinyl, -(Ci-C4)alkylC(O)N[(Ci-C4)alkyl]2, halo(Ci-C4)alkyl, -(Ci-C4)alkylC(O)(morpholinyl), wherein the phenyl, pyridyl, piperidyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R 7a , and wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. Alternatively, as part of the nineteenth embodiment, R g1 and R h1 in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, -(Ci-C4)alkyl[pyridyl], -(Ci-C4)alkylO(Ci-C4)alkyl, (Ci-C4)alkylphenyl, -(Ci-C4)alkylN[(Ci-C4)alkyl]2, piperidyl, pyrrolidinyl, -(Ci-C4)alkylC(O)N[(Ci-C4)alkyl]2, halo(Ci-C4)alkyl, -(Ci-C4)alkylC(O)(morpholinyl), wherein the phenyl, pyridyl, piperidyl, pyrrolidinyl, and morpholinyl are each optionally substituted with 1 to 3 groups selected from R 7asubstituted with 1 to 3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, (Ci-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. In another alternative, as part of the nineteenth embodiment, R 7a substituted with 1 to 3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, (Ci-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. In another alternative, as part of the nineteenth embodiment, R

[0086] In a twentieth embodiment, R 3 substituted with 1 to 3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, (Ci-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. In another alternative, as part of the nineteenth embodiment, R -CH2N(CH3)(CH2)2OCH3, -CH2N(CH3)(CH2)2N(CH3)2, -CH2N(CH3)(CH2)3N(CH3)2, -CH2N(CH3)CH2C(O)N(CH3)2, -C(O)NH CH2N(CH3)2,

[0087] substituted with 1 to 3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, (Ci-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. In another alternative, as part of the nineteenth embodiment, R 3 substituted with 1 to 3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, (Ci-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. In another alternative, as part of the nineteenth embodiment, R

[0088]

[0089]

[0090]

[0091] substituted with 1 to 3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, (Ci-C4)alkoxy, and cyano, wherein the remaining variables are as described above for Formula I or any one of the second through eighteenth embodiments. In another alternative, as part of the nineteenth embodiment, R

[0092] Compounds of Formula I are further disclosed in the Examples and are included in the present disclosure. The pharmaceutically acceptable salts thereof, as well as the neutral forms, are included.

[0093] 4. Uses, formulations, and administration

[0094] The compounds and compositions described herein are generally useful for modulating the activity of TP53. In some aspects, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein are covalent modifiers of Y220C. In some aspects, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein stabilize TP53. In some aspects, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein restore the function of wild-type tumor suppressor protein p53 (WT TP53).

[0095] In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating a disorder associated with TP53 function. In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating a disorder responsive to activation of TP5 function. In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating a disorder responsive to restoration of TP53 function, for example, a disorder in which protein function is lost due to a mutation (e.g., a Y220C mutation).

[0096] In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating cancer. In some aspects, the compounds and pharmaceutical compositions described herein are useful for treating a cancer that expresses a TP53 mutant (e.g., a cancer harboring a Y220C mutation).

[0097] Particular cancers that can be treated with the compounds, salts, and compositions of the present application include, but are not limited to, solid tumors, hematological malignancies, ovarian cancer, esophageal cancer, colorectal cancer, head and neck cancer, laryngeal cancer, lung cancer, leukemia (e.g., acute myeloid leukemia (AML)), sarcoma, testicular cancer, melanoma, cervical cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, endometrial cancer, esophageal cancer, gastric cancer, prostate cancer, bladder cancer, myelodysplastic syndrome (MDS), sarcoma, and melanoma.

[0098] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of the disorder. Further provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of the disorder.

[0099] In certain aspects, the pharmaceutical compositions described herein are formulated to be administered to a patient in need of such compositions. The pharmaceutical compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenterally" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. The pharmaceutical compositions of the present disclosure in sterile injectable forms can be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0100] In some aspects, the pharmaceutical compositions are administered orally.

[0101] The specific dose and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in a combination will also depend on the particular compound in the pharmaceutical combination.

[0102] Examples

[0103] Chemical Synthesis

[0104] The following representative examples are intended to help illustrate the present disclosure and are not intended to be limiting to the scope of the present invention.

[0105] Scheme 1.

[0106]

[0107] 4-chloropyrimidoindoles such as S10 can be prepared via a nine step process starting with the appropriate fluorocyanobenzoate or fluorocyanonicotinate represented by S1. Nucleophilic aromatic substitution of S1 with glycine ester gives intermediate S2 which can be converted to 3-aminoindole derivative S3. Condensation of S3 with dimethylformamide dimethyl acetal followed by treatment with ammonia gives hydroxypyrimidoindole intermediate S5. S5 can be converted to chloride intermediate S6 using phosphorus oxychloride. Alkylation of S6 with the appropriate electrophile gives S7. Reduction of S7 gives benzyl alcohol intermediate S8 which is converted to benzyl chloride intermediate S9 using thionyl chloride. Alkylation of S9 with the appropriate amine gives the target compound such as S10.

[0108] Scheme 2.

[0109]

[0110] 4-chloropyrimidoindoles such as S17 can be prepared from intermediates such as S15 via a two-step procedure. Oxidation of S15 gives intermediate S16 which can be converted to the target compound such as S17 via reductive amination.

[0111] Scheme 3.

[0112]

[0113] 4-chloropyrimidoindoles such as S17 can be prepared from intermediates such as S15 via a two-step procedure. Oxidation of S15 gives intermediate S16 which can be converted to the target compound such as S17 via reductive amination.

[0114] Scheme 4.

[0115]

[0116] 4-chloropyrimidoindoles such as S22 can be prepared from intermediates such as S18 via a four-step procedure. Treatment of S18 with trimethyltin hydroxide gives an acidic intermediate such as S19 which can be converted to the amine intermediate S21 via a two-step procedure involving a Curtin's rearrangement and acid mediated removal of the Boc protecting group. Derivatization of S21 via reductive amination or amide coupling gives the target compounds represented by S22.

[0117] Scheme 5.

[0118]

[0119] Chloropyrimidoindoles such as S32 can be prepared via a nine-step procedure starting with an appropriate cyano fluoroiodobenzene such as S23. Nucleophilic aromatic substitution of S23 with glycine ethyl ester gives S24 which can be converted to the 3-amino-indole intermediate S25 via treatment with BOC2O and DMAP. Similar to Scheme 1, S25 can be converted to the intermediate S29 via a four-step procedure. Treatment of S29 with sodium methoxide gives the methoxypyrimidoindole intermediate such as S30. Palladium catalyzed amination provides the iodide intermediate S31 which can be converted to the target compound such as S32 via treatment with phosphorus oxychloride.

[0120] Scheme 6.

[0121]

[0122] Dichloropyrimidoindoles such as S40 can be prepared via a seven step sequence starting from an appropriate bromocyanofluorobenzene such as S33. Treatment of S33 with an aminoacetamide followed by base mediated cyclization gives a 3-amino-indole intermediate such as S35. Treatment of S35 with triphosgene gives a dihydroxypyrimidoindole intermediate such as S36 which can be converted to the desired target compound such as S40 by a four step sequence similar to that described in Scheme 1.

[0123] Scheme 7.

[0124]

[0125] Chloropyrimidoindoles such as S46 can be prepared by a five step sequence starting from intermediate S41. Alkylation of S41 with an electrophile gives intermediate S42. Selective displacement of the chloride with sodium methoxide gives intermediate S43. S43 can be converted to S45 by Suzuki coupling with a boronic acid or ester to give intermediate S45 which can then be converted to the target compound S46 by treatment with phenylphosphine dichloride.

[0126] Scheme 8.

[0127]

[0128] Chloropyrimidoindoles such as S55 can be prepared from intermediate S47 by an eight step sequence. The diamide S48 can be prepared by coupling of Boc-glycine with 3-aminoindole S47. Base mediated cyclization of S48 gives the hydroxypyrimidinol intermediate S49 which can be converted to the chloropyrimidine S50 by reaction with POCl3. After protection of the free amine in S50 with a Boc group, the indole can be alkylated with an electrophile to give intermediate S52. Suzuki coupling of S52 with ((dimethylamino)methyl)potassium trifluoroborate followed by treatment with POCl3gives intermediate S54 which can be converted to the target compound such as S55 by amide coupling with a carboxylic acid or reaction with an acid chloride.

[0129] Scheme 9.

[0130]

[0131] Chloropyrimidoindoles such as S64 can be prepared from intermediate S56 via an eight step sequence. Reaction of 3-amino-2-carboxamide indole intermediate S56 with diethyl malonate gives intermediate S57, which can be converted to chloropyrimidine intermediate S58 using POCl3. Alkylation of S58 using an electrophile gives intermediate S59. Displacement of the chloride with sodium methoxide gives S60, which can be converted to 7-diaminomethylpyrimidoindole intermediate S61 by Suzuki coupling with ((dimethylamino)methyl)potassium trifluoroborate. Treatment of S61 with POCl3gives intermediate S62. Hydrolysis of ester S62 with trimethyltin hydroxide gives carboxylic acid intermediate S63, which can be coupled with an amine nucleophile to give target compounds such as S64.

[0132] Scheme 10.

[0133]

[0134] Chloropyrimidoindoles such as S73 can be prepared from intermediate S65 via a nine step sequence. Reaction of 3-amino-2-carboxamide indole intermediate S65 with diethyl oxalate gives intermediate S66, which can be converted to methoxypyrimidine intermediate S67 by sequential treatment with POCl3and sodium methoxide. Alkylation of S67 using an electrophile gives intermediate S68, which can be converted to 7-diaminomethylpyrimidoindole intermediate S69 by Suzuki coupling with ((dimethylamino)methyl)potassium trifluoroborate. Treatment of S69 with oxalyl chloride and methanol gives methyl ester intermediate S70, which can be selectively demethylated with trimethylchlorosilane and sodium iodide to give hydroxypyrimidoindole intermediate S71. Treatment of S71 with POCl3and trimethyltin hydroxide gives carboxylic acid intermediate S73, which can be converted to target compounds such as S74 by amide coupling.

[0135] Scheme 11.

[0136]

[0137] Chloropyrimidoindoles such as S77 can be prepared from intermediate S75 via a two step sequence. Alkylation of an amine with intermediate S75 gives intermediate S76, which can be converted to target compounds such as S77 by treatment with hydrochloric acid.

[0138] Scheme 12.

[0139]

[0140] Chloropyrimidoindoles S80 can be prepared from intermediate S78 via a two-step sequence. Reductive amination of intermediate S75 gives intermediate S79, which can be converted to the target compound, such as S80, by treatment with hydrochloric acid.

[0141] Scheme 13.

[0142]

[0143] Chloropyrimidoindoles such as S90 can be prepared from intermediate S81 via a nine-step sequence. S81 undergoes S N Ar reaction, followed by deprotection with TFA, to give aniline intermediate S83. Reductive amination of S83 with ethyl glyoxylate gives S84. Treatment of S84 with Boc anhydride and 4-dimethylaminopyridine initiates a cyclization to generate indole intermediate S85. Treatment of S85 with DMF-DMA and ammonia in succession gives hydroxypyrimidine alcohol intermediate S87. Treatment of S87 with POCl3gives chloropyrimidoindole intermediate S88. Alkylation of S88 with an electrophile, followed by Suzuki coupling with potassium (dimethylamino)methyl)trifluoroborate gives the target compound such as S90.

[0144] Scheme 14.

[0145]

[0146] Chloropyrimidoindoles such as S94 can be prepared from intermediates such as S91 via one of two different two-step sequences. When X = OMe, S91 undergoes palladium-catalyzed cross-coupling with a boronic acid or boronic ester to generate intermediate S92, which can be converted to the target compound, such as S94, by treatment with POCl3. When X = Cl, S91 undergoes palladium-catalyzed borylation, followed by Suzuki coupling with a boronic acid or boronic ester to generate the target compound such as S94.

[0147] Abbreviations:

[0148] ACN = acetonitrile

[0149] AcOH = acetic acid

[0150] BOC2O = di-tert-butyl dicarbonate

[0151] DCM = dichloromethane

[0152] DCE = 1,2-dichloroethane

[0153] DIEA = N,N-diisopropylethylamine

[0154] DMAP = 4-dimethylaminopyridine

[0155] DMF = dimethylformamide

[0156] DMF-DMA = N,N-dimethylformamide dimethyl acetal

[0157] DPPA = diphenylphosphoryl azide

[0158] EtOAc = ethyl acetate

[0159] EtOH = ethanol

[0160] IPA = isopropyl alcohol

[0161] MeOH = methanol

[0162] TEA = triethylamine

[0163] TFA = trifluoroacetic acid

[0164] THF = tetrahydrofuran

[0165] TMSCl = trimethylsilyl chloride

[0166] TMSBr = trimethylsilyl bromide

[0167] Example 1. 1 -(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine Example 1. 1 -(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine

[0168]

[0169] Scheme 1, step 1. Methyl 3-cyano-4-(2-ethoxy-2-oxo-ethyl)aminobenzoate:

[0170] 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 h. 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 give the title compound (3.7 g, 14.1 mmol, 24% yield) as a white solid.

[0171] 1H NMR (400 MHz, Chloroform-d) δ 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, J = 5.2 Hz, 2H), 3.81 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0172] LCMS [M-1] = 261.1.

[0173] Scheme 1, step 2. 1 -(tert-butyl) 2-ethyl 5-methyl 3-amino-1 H-indole-1,2,5-tricarboxylate:

[0174] To a solution of methyl 3-cyano-4-[(2-ethoxy-2-oxo-ethyl)amino]benzoate (2.7 g, 10.3 mmol, 1.0 eq) in DCM (1.0 mL) was added TEA (1.06 g, 10.4 mmol, 1.4 mL, 1.0 eq), BOC2O (2.7 g, 12.4 mmol, 1.2 eq) and DMAP (125.7 mg, 1.0 mmol, 0.1 eq). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extract was washed with brine (20 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (4.5:1 petroleum ether:EtOAc) to give the title compound (4.4 g, crude) as a white solid.

[0175] 1 H NMR (400 MHz, Chloroform-d) δ 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, J = 5.2 Hz, 2H), 3.81 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0176] LCMS [M-55] = 307.2.

[0177] Scheme 1, step 3. 1 -(tert-butyl) 2-ethyl 5-methyl 3-(((dimethylamino)methylene)amino)-1 H- indole-1,2,5-tricarboxylate: Scheme 1, step 4. Methyl 4-oxo-3,5-dihydropyrimido[5,4-b]indole-8-carboxylate:

[0178] 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 the mixture solution was stirred at 100 °C for 4 h. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (3 x 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 give the title compound (4 g, crude) as a white solid.

[0179] 1 H 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 = 7.2 Hz, 3H).

[0180] LCMS [M+1] = 418.4.

[0181] Scheme 1, step 5. Methyl 4-chloro-5H-pyrimido[5,4-b]indole-8-carboxylate:

[0182] 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 NH3H2O (40 mL). The mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and the filter cake was concentrated under vacuum to give the title compound (1.2 g, crude) as a white solid. This material was used in the next step without further purification.

[0183] 1 H 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).

[0184] LCMS [M+1] = 244.2.

[0185] Scheme 1, step 6. Methyl 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole-8- carboxylate:

[0186] 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 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was triturated with ACN at 20 °C for 10 min to give a residue. The residue was triturated with H2O at 20 °C for 2 min to give the title compound (600 mg, 62% yield) as a yellow solid.

[0187] 1 H 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).

[0188] LCMS [M+1, M+3] = 262.2, 264.2.

[0189] Scheme 1, step 7. (4-Chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)methanol:

[0190] To a dry round bottom flask, 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) was added NaH (115 mg, 2.8 mmol, 60% purity, 1.5 equiv) at 0 °C. The reaction mixture was stirred under nitrogen at 20 °C for 0.5 h, 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 h, the reaction mixture was quenched by adding 10 mL H2O at 0 °C. The mixture was extracted with 20 mL EtOAc, 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 give the title compound (330 mg, 50% yield) as a white solid.

[0191] 1 H 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).

[0192] LCMS [M+1] = 344.2.

[0193] Scheme 1, step 8. 4-Chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole:

[0194] In a 100 mL three-necked flask equipped with a stir bar was charged with 4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole-8-carboxylic acid methyl ester (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, then DIBAL-H solution (1 M, 29.1 mL, 2.0 equiv) was added dropwise over 15 min. The resulting solution was stirred at -60 °C under N2for 1 h. The reaction mixture was quenched by the addition of EtOAc (500 mL), then diluted with saturated aqueous potassium sodium tartrate (500 mL) and extracted with EtOAc (2 x 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 give the title compound (3.0 g, 65% yield) as an off-white solid

[0195] 1 H 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).

[0196] LCMS: [M+1] = 316.1.

[0197] Scheme 1, step 9. 1 -(4-Chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine:

[0198] 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 nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. Most of the SOCl2was removed under reduced pressure, then the mixture was quenched by dropwise addition of H2O (20 mL). The mixture was extracted with EtOAc (3 x 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 give the title compound (2.0 g, 76% yield) as an off-white solid.

[0199] 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).

[0200] LCMS: [M+1] = 334.1.

[0201] Example 1. 1 -(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine Example 2. 1 -[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl-N- (3-pyridinylmethyl)methanamine

[0202] 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 eq) in ACN (10.0 mL) was added dimethylamine (2 M, 1.5 mL, 2.0 eq) dropwise, 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 x 10 ml) at 25 °C for 30 minutes to give the title compound (1.1 g, yield 72%) as a white solid. A 100 mg sample was further purified by preparative HPLC (column: Phenomenex Luna (80 x 30 mm x 3 um); mobile phase: 5% - 35% ACN in water (HC1)) to give the HC1 salt of the title compound (50.0 mg) as a white solid. The HC1 salt of the title compound (50.0 mg) was converted to the formate salt by treatment with formic acid (6.3 mg, 132 umol, 1.0 eq). The mixture was stirred at 25 °C for 5 minutes. The white solid was recrystallized from water and dried by lyophilization to give the formate salt of the title compound (35.0 mg, 66% yield) as a white solid.

[0203] 1 H 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).

[0204] LCMS: [M+1] = 343.0.

[0205] Scheme 1, step 9. 1 -[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl- N-(3-pyridinylmethyl)methanamine: Example 65. 1 -[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl-N- (3-pyridinylmethyl)methanamine

[0206]

[0207] Example 65. 1 -[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl-N- (3-pyridinylmethyl)methanamine Scheme 1, step 9. 4-Chloro-8-[(2-methylpyrimidin-5-yl)oxymethyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole:

[0208] To a solution of 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (100 mg, 299 pmol, 1.0 equiv) in ACN (5 mL) was added TEA (83 pL, 599 pmol, 2.0 equiv) and N-methyl-1-(3-pyridinyl)methanamine (73.1 mg, 599 pmol, 2.0 equiv). The mixture was stirred at 50 °C for 6 h and concentrated. The resulting residue was purified by prep-TLC (10:1 DCM:MeOH) to give the title compound (20.0 mg, 15% yield) as a yellow solid.

[0209] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0210] LCMS: [M+1, M+3] = 420.1, 422.2.

[0211] Example 66. 4-Chloro-8-[(4-methylimidazol-1 -yl)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole Scheme 1, step 9. 4-Chloro-8-[(4-methylimidazol-1 -yl)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole:

[0212]

[0213] Example 35. [4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-1 -(4-methylpiperazin-1 - yl)methanone Scheme 2, step 1. 4-Hydroxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8-carboxylic acid:

[0214] 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 room temperature for 2 h. The mixture was poured into water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch diol 150 mm x 25 mm x 5 pm; mobile phase: 5-50% ethanol in heptane) to give the title compound (15.7 mg, 15% yield) as a white solid.

[0215] LCMS: [M+1, M+3] = 408.1, 410.1.

[0216] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0217] ​ ​

[0218]

[0219] ​ ​

[0220] To a solution of 4-methyl-lH-imidazole (29.4 mg, 359 pmol, 0.6 equiv) in THF (2.0 mL) at 0 °C was added NaH (72 mg, 1.80 mmol, 3.0 equiv; 60% dispersion in oil). 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, the mixture was warmed to room temperature and stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with H2O (5.0 mL), 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% isopropyl alcohol in heptane) to give the title compound (17.5 mg, 7.3% yield) as a white solid.

[0221] LCMS [M+1, M+3] = 380.1, 382.1.

[0222] 1H NMR (400 MHz, Chloroform-d) δ = 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).

[0223] Example 67. l-[[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5.4-b]indol-8-yl]methyl]-4- methyl-piperazin-2-one

[0224]

[0225] The title compound was prepared in a similar manner as described in Example 66.

[0226] LCMS: [M+1, M+3] = 412.1, 414.1.

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0228] Table 1. The examples in Table 1 were prepared in a similar manner as described in Example 1, Example 2, or Example 65 using Scheme 1.

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] ​ ​

[0238]

[0239] ​

[0240] 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 eq) in THF (4 mL) and H2O (1 mL) was added LiOH H2O (67.2 mg, 1.6 mmol, 1.1 eq) and the reaction mixture was stirred at 25 °C for 15 h. The pH of the mixture was adjusted to ~1 with aqueous HC1 (1 M, 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.

[0241] LCMS: [M+1] = 312.0.

[0242] Scheme 2, step 2. 4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5.4-b]indole-8- carbonyl chloride:

[0243] A solution of 4-hydroxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carboxylic acid (50.0 mg, 160.7 μmol, 1 eq) in SOCl2(1 mL) was stirred at 60 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (50 mg, 89% yield) as a yellow solid. This material was used in the next step without further purification.

[0244] LCMS: [M+1] = 344.0 (reaction quenched with MeOH and analyzed by LCMS).

[0245] Scheme 2, step 3. [4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-(4- methylpiperazin-1-yl)methanone: Example 43. 1-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrido[5,4-b]indol-8-yl]-N-methyl- methanamine

[0246] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carboxylic acid (80.0 mg, 229.8 pmol, 1 eq) in THF (1.5 mL) was added TEA (128 pL, 919 pmol, 4 eq) and 1-methylpiperazine (23 pL, 207 pmol, 0.9 eq), then the reaction was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD CI 8 150 mm x 40 mm x 10 pm; mobile phase: 25-55% ACN in water (+ NH4HCO3 modifier)) to give the title compound (24.5 mg, 26% yield) as a white solid.

[0247] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0248] LCMS: [M+1, M+3] = 412.1, 414.1.

[0249] Table 2. The examples in Table 2 were prepared using Scheme 2 in a similar manner as described in Example 35.

[0250]

[0251]

[0252]

[0253] Example 43. 1-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrido[5,4-b]indol-8-yl]-N-methyl- methanamine Scheme 3, step 1. 4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8-carbaldehyde:

[0254]

[0255] Scheme 3, step 2. 1-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N-methyl- methanamine:

[0256] To a solution of [4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]methanol (0.2 g, 634 µmol, 1 eq) in DCE (2 mL) was added MnO2 (550.8 mg, 6.34 mmol, 10 eq). The mixture was stirred at 80 °C for 12 h. 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 give the title compound (0.3 g, crude) as a yellow solid. This material was used in the next step without further purification.

[0257] LCMS: [M+H] = 314.0.

[0258] Example 51. N,N-Dimethyl-1-methanesulfonyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-ylmethanamine Example 51. N,N-Dimethyl-1-methanesulfonyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-ylmethanamine

[0259] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carbaldehyde (90.0 mg, 287 µmol, 1 eq) in DCE (1 mL) was added methylamine (2 M, 287 µL, 2 eq) and AcOH (33 µL, 574 µmol, 2 eq) and the mixture was stirred at room temperature for 0.5 h. NaBH(OAc)3 (152 mg, 717 µmol, 2.5 eq) was added to the mixture and the mixture was stirred at 25 °C for 1 h. 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 (150 mm x 40 mm x 10 µm); mobile phase: 15-50% ACN in water (+ NH4HCO3 modifier)) to give the title compound (54.6 mg, 57% yield) as a white solid.

[0260] 1 H NMR (400 MHz, Chloroform-d) δ 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)

[0261] LCMS: [M+H, M+3] = 329.0, 331.1.

[0262] Table 3. The examples in Table 3 were prepared using Scheme 3 in a similar manner as described for Example 43.

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279] Example 52. 1-(4-Bromo-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine Example 52. 1-(4-Bromo-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylmethanamine

[0280]

[0281] To a solution of 1-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine (30.0 mg, 87.5 μmol, 1.0 equiv) in DMA (1.0 mL) was added NaSO2Me (60.0 mg, 587.7 μmol, 6.7 equiv). The mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to rt and purified by preparative HPLC (column: Phenomenex luna C18 80 cm x 40 mm x 3 mm; mobile phase: 15-55% ACN in water (+ formic acid modifier)) to give the title compound (4.2 mg, 12% yield) as a white solid.

[0282] 1H NMR (400 MHz, DMSO-d6) δ 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).

[0283] LCMS [M+1] = 387.0.

[0284] Example 53. 1-[4-Fluoro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl-N,N-dimethyl- methanamine Example 53. 1-[4-Fluoro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl-N,N-dimethyl- methanamine

[0285]

[0286] A mixture of 1-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N,N- dimethyl-methanamine (30.0 mg, 87.5 μmol, 1.0 equiv) and TMSBr (79.5 μL, 612.7 μmol, 7.0 equiv) in ACN (2.0 mL) was degassed and purged with N2 three times, then the mixture was stirred at 40 °C under N2 atmosphere for 16 h. The reaction mixture was quenched by adding saturated aqueous NaHC03solution (5 mL), diluted with H20 (5 mL), and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna (80 mm x 30 mm x 3 μm); mobile phase: 1-40% ACN in water (+TFA modifier)) to give the title compound (8.5 mg, 25% yield) as a white solid.

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0288] LCMS: [M+1, M+3] = 387.1, 389.1.

[0289] Example 54. 4-Fluoro-8-((4-methylpiperazin-1-yl)methyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole Example 54. 4-Fluoro-8-((4-methylpiperazin-1-yl)methyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole

[0290]

[0291] To a solution of 1-[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 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 pm); mobile phase: 30-55% ACN in water (+ NH4HCO3 modifier)) to give the title compound (20.4 mg, 21% yield) as a white solid.

[0292] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0293] LCMS [M+1] = 327.1.

[0294] Example 120. 4-Chloro-8-(2-methyl-2,7-diazaspiro[3.5]non-7-ylmethyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole Step 1. 4-Chloro-8-(2-methyl-2,7-diazaspiro[3.5]non-7-ylmethyl]-5-(2,2,2-trifluoroethyl) pyrimido[5,4-b]indole:

[0295]

[0296] To a mixture of 1,4,7,10,13,16-hexaoxacyclooctadecane (10.6 mg, 40.2 umol, 0.1 eq) and cesium fluoride (183 mg, 1.2 mmol, 3.0 eq), tetramethylammonium chloride (4.4 mg, 40 umol, 0.1 eq) in ACN (4 mL) was added 4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole (160 mg, 402 umol, 1.0 eq) in one portion at 25 °C under N2atmosphere. The mixture was stirred at 60 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge BEH C18 (100 mm x 25 mm x 5 pm); mobile phase: 5-35% ACN in water (+ NH4HC03modifier)) to give the title compound (37.0 mg, 24% yield) as a yellow solid.

[0297] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0298] LCMS [M+1] = 382.4.

[0299] Step 2. 4-Fluoro-8-(2-methyl-2,7-diazaspiro[3.5]non-7-ylmethyl]-5-(2,2,2-trifluoroethyl) pyrimido[5,4-b]indole: Example 121. N-[[4-Fluoro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]-1-methyl-pyrazole-4-carboxamide

[0300]

[0301] Example 55. 4-Chloro-8-((pyridin-4-yloxy)methyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole Example 56. 1-[4-Chloro-2,2,2-trifluoroethoxy]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine

[0302] A mixture of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8-carbaldehyde (250 mg, 797 pmol, 1.0 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) was combined in DCE (3.0 mL) and stirred at room temperature for 30 min. NaBH(OAc)3 (507 mg, 2.3 mmol, 3.0 equiv) was then added and the mixture was stirred at room temperature for 2 h. The pH of the mixture was adjusted to pH = 9 with solid NaHCO3. The reaction mixture was diluted with water (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 (SiO2, 10:1 DCM:MeOH) to give the title compound (130 mg, 37% yield) as a light yellow solid.

[0303] LCMS: [M+1, M+3] = 438.3, 440.3.

[0304] Step 1. 8-[(Dimethylamino)methyl]-5H-pyrimido[5.4-b]indole-2,4-diol: Step 2. 1-(2,4-Dichloro-5H-pyrimido[5,4-b]indol-8-yl)-N,N-dimethyl-methanamine:

[0305] A mixture of 4-chloro-8-[(2-methyl-2,7-diazaspiro[3.5]non-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- hexaoxacyclooctadecane (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, then the mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge BEH CI 100 mm x 30 mm x 10 pm; mobile phase: 25-40% acetonitrile in water (+10 mM NH4HCO3)) to give the title compound (2.0 mg, 1.3% yield) as a white solid.

[0306] LCMS: [M+1] = 442.3.

[0307] 1H NMR (400 MHz, Chloroform-d) δ = 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).

[0308] ​ ​

[0309]

[0310] Example 121 was prepared in a similar manner as described in Examples 54 and 120.

[0311] LCMS: [M+1] = 519.2.

[0312] 1 H NMR (400 MHz, DMSO-d6): δ 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).

[0313] ​ ​

[0314]

[0315] To a solution of pyridin-4-ol (8.5 mg, 89.7 μmol, 0.5 equiv) and K2CO3 (74.4 mg, 539 μmol, 3.0 equiv) in DMF (0.5 mL) was added 4-chloro-8- (chloromethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indole (60.0 mg, 178 μmol, 1.0 equiv) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 μm; mobile phase: 15-45% ACN in water (+ formic acid modifier)) to give the title compound (23.7 mg, 32% yield) as a white solid.

[0316] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0317] LCMS [M+1, M+3] = 393.0, 395.0.

[0318] ​ ​

[0319]

[0320] ​

[0321] To a solution of 8-bromo-5H-pyrimido[5,4-b]indol-2,4-diol (2.0 g, 7.1 mmol, 1.0 equiv) in 2-methylbutan-2-ol (24.0 mL) and H2O (6.0 mL) was added CS2CO3 (4.6 g, 14.2 mmol, 2.0 equiv) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate (614.4 mg, 714.0 μmol, 0.1 equiv) and potassium [(dimethylamino)methyl]trifluoroborate (2.3 g, 14.2 mmol, 2.0 equiv) under nitrogen atmosphere. The mixture was stirred at 80 °C for 12 h. 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 x 100 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 min to give the title compound (1.1 g, 60% yield) as a white solid.

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 11.69-11.04 (m, 3H), 7.83 (s, 1H), 7.53-7.16 (m, 2H), 3.42 (s, 2H), 2.14 (s, 6H).

[0323] ​

[0324] To a solution of 8-[(dimethylamino)methyl]-5H-pyrimido[5,4-b]indol-2,4-diol (1.1 g, 4.2 mmol, 1.0 equiv) was added phosphoryl dichloride benzene (8.0 mL, 57.1 mmol, 13.4 equiv). The mixture was stirred at 140 °C for 3 h. The reaction mixture was quenched by the addition of saturated aqueous NaHC03(50 mL). The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and H20 (100 mL), and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (Si02, 10:1 THF:MeOH) to give the title compound (280.0 mg, crude) as a yellow oil. This material was used without further purification in the next step.

[0325] LCMS [M+1, M+3] = 295.3, 297.3.

[0326] Step 3. l-[4-chloro-2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine: Indol-8-yl]-N,N-dimethyl-methanamine:

[0327] To a solution of 1-(2,4-dichloro-5H-pyrimido[5,4-b]indol-8-yl)-N,N-dimethyl- methanamine (35.0 mg, 118.5 μmol, 1.0 equiv) in DMF (0.5 mL) was added NaH (14.2 mg, 355.7 μmol, 60.0% purity, 3.0 equiv) at 0 °C, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (55.0 mg, 237.1 μmol, 2.0 equiv) at 20 °C for 2 h. LC-MS showed 1 / 3 of starting material remained and one major peak with desired mass was detected. The reaction mixture solution was quenched with 5 mL H20 at 0 °C, extracted with EtOAc (8 mL), and the organic layer was concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 μm; mobile phase: 40-70% ACN in water (+ NH4HC03modifier)) to give the title compound (3.1 mg, 5.8% yield) as a white solid.

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.92 (d, J = 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).

[0329] LCMS [M+1, M+3] = 440.8, 442.

[0330] Example 57. 4-Chloro-N-(4-pyridinylmethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-amine: amine

[0331]

[0332] Scheme 4, Step 1. 4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8-carboxylic acid:

[0333] 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 eq) in DCE (15 mL) was added hydroxy(trimethyl)stannane (6.1 g, 3375 pmol, 8 eq) and the mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by the addition of aqueous FK (10 mL) and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was triturated with HC1 (1 M, 50 mL) to produce a precipitate which was filtered off to give the title compound (600 mg, 43% yield) as a white solid.

[0334] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0335] LCMS: [M+1, M+3] = 330.0, 331.9.

[0336] Example 58, Scheme 4, Step 2. tert-Butyl N-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]carbamate: Example 59, Scheme 4, Step 3. 4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8- amine:

[0337] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole-8- carboxylic acid (200 mg, 607 pmol, 1 eq) in t-butanol (4 mL) was added TEA (253 pL, 182 pmol, 3 eq) and DPPA (250.44 mg, 910.0 pmol, 197.20 pL, 1.5 eq). The mixture was stirred at 90 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH CI 1000 mm x 30 mm x 1 pm; mobile phase: 50-70% ACN in water (+ NH4HCO3 modifier)) to give the title compound (23.5 mg, 21% yield) as a white solid.

[0338] 1 H NMR (400 MHz, DMSO-d6) 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).

[0339] LCMS: [M+1, M+3] = 401.4, 403.4.

[0340] Scheme 4, Step 4A. 4-Chloro-N-(4-pyridinylmethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-amine:

[0341] 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 eq) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna CI 100 mm x 40 mm x 5 pm; mobile phase: 5-35% ACN in water (+ formic acid modifier)) to give the title compound (19.8 mg, 29% yield) as a yellow solid (formate salt).

[0342] 1 H NMR (400 MHz, DMSO-d6) 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).

[0343] LCMS: [M+1, M+3] = 301.0, 302.8.

[0344] Example 60. N-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-1-methyl- piperidine-4-carboxamide Example 60. N-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-1-methyl- piperidine-4-carboxamide

[0345] To a solution of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-amine (80.0 mg, 266.0 μmol, 1 equiv), pyridine-4-carbaldehyde (57 mg, 532 μmol, 2 equiv) and AcOH (30 μL, 532 μmol, 2 equiv) in DCE (1 mL) was added NaBH(OAc)3 (197 mg, 931 μmol, 3.5 equiv). The mixture was stirred at 25 °C for 1 h. The pH was adjusted to ~9 by the addition of saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 μm; mobile phase: 35-55% ACN in water (+ NH4HCO3 modifier)) to give the title compound (40.0 mg, 38% yield) as a yellow solid.

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0347] LCMS: [M+1, M+3] = 391.8, 393.8.

[0348] Scheme 4, Step 4B. N-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-1-methyl- piperidine-4-carboxamide: Example 62. 4-Chloro-8-(4-methylpiperazin-1-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole

[0349]

[0350] Scheme 5, Step 1. (2-Cyano-4-iodophenyl)glycine ethyl ester: Scheme 5, Step 2. 1-(tert-Butyl) 2-ethyl 3-amino-5-iodo-1H-indole-1,2-dicarboxylate:

[0351] To a mixture of 1-methylpiperidine-4-carboxylic acid (41.9 mg, 293 μmol, 1.1 eq) in DMF (1.0 mL) was added HATU (152 mg, 399 μmol, 1.5 eq), DIEA (185 μL, 1.1 mmol, 4.0 eq) and 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-amine (80.0 mg, 266 μmol, 1.0 eq) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble material and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 mm x 40 mm x 10 μm; mobile phase: 15-45% ACN in water (+ NH4HCO3 modifier)) to give the title compound (22.1 mg, 19% yield) as a white solid.

[0352] 1 H NMR (400 MHz, DMSO-d6) δ 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, J = 2.0, 11.2 Hz, 2H), 1.81 - 1.63 (m, 4H).

[0353] LCMS: [M+1, M+3] = 425.8, 427.8.

[0354] Table 4. The examples in Table 4 were prepared in a similar manner as described for Examples 57 or 60.

[0355]

[0356]

[0357]

[0358]

[0359] Scheme 5, Step 3. 1-(tert-Butyl) 2-ethyl 3-(((dimethylamino)methylene)amino)-5-iodo-1H- indole-1,2-dicarboxylate: Scheme 5, Step 4. 8-Iodo-5H-pyrimido[5,4-b]indol-4-ol:

[0360]

[0361] Scheme 5, Step 5. 4-Chloro-8-iodo-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole:

[0362] To a solution of 2-fluoro-5-iodobenzonitrile (2.0 g, 8.1 mmol, 1.0 equiv) in NMP (20.0 mL) was added glycine ethyl ester-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 h. 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 over 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 give the title compound (1.2 g, 45% yield) as a white solid.

[0363] 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 1.8, 8.8 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.21 (br s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0364] LCMS [M+1] = 331.1.

[0365] Scheme 5, Step 6. 8-Iodo-4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole:

[0366] A mixture of (2-cyano-4-iodophenyl) glycine ethyl ester (1.0 g, 3.0 mmol, 1.0 equiv), BOC2O (1.3 mL, 6.0 mmol, 2.0 equiv), DMAP (37.0 mg, 303 µmol, 0.1 equiv) and TEA (422 µL, 3.0 mmol, 1.0 equiv) in DMF (10.0 mL) was degassed and purged with N2 for 3 times, then the mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. 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 over 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 give the title compound (1.2 g, 92% yield) as a colorless oil.

[0367] 1H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.89 (br d, J = 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).

[0368] Scheme 5, Step 7. 4-Methoxy-8-(4-methylpiperazin-1-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole: Scheme 5, Step 8. 4-Chloro-8-(4-methylpiperazin-1-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole:

[0369] To a solution of 1-(tert-butyl) 2-ethyl 3-amino-5-iodo-1H-indole-1,2-dicarboxylate (800 mg, 1.86 mmol, 1.0 equiv) in DMF (8.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (321 μL, 2.42 mmol, 1.3 equiv) at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was cooled to 25 °C and poured into H2O (30 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 30 mL), dried over 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 give the title compound (530 mg, 59% yield) as a yellow oil.

[0370] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0371] LCMS [M+1] = 486.3.

[0372] Example 63. 4-Chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole

[0373] To a solution of 1-(tert-butyl) 2-ethyl 3-amino-5-iodo-1H-indole-1,2-dicarboxylate (800 mg, 1.86 mmol, 1.0 equiv) in DMF (8.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (321 μL, 2.42 mmol, 1.3 equiv) at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was cooled to 25 °C and poured into H2O (30 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 30 mL), dried over 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 give the title compound (530 mg, 59% yield) as a yellow oil.

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0375] Example 63. 4-Chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole

[0376] 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 h under nitrogen atmosphere. 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 h under nitrogen atmosphere. The reaction mixture solution was quenched by adding saturated aqueous NH4Cl (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 prep-HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 pm; mobile phase: 54-84% ACN in water (+ formic acid modifier)) to give the title compound (17.7 mg, yield 11%) as a white solid.

[0377] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0378] LCMS [M+1, M+3] = 411.8, 413.8.

[0379] Example 63. 4-Chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole

[0380] 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 h. 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 over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the title compound (90.0 mg, 91% yield) as a white solid.

[0381] 1 H NMR (400 MHz, Chloroform-d) d 8.75-8.67 (m, 2H), 7.91 (dd, J = 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).

[0382] LCMS [M+1] = 408.0.

[0383] ​ ​

[0384] 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 a nitrogen atmosphere. The mixture was stirred at 90 °C for 1 h. 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 over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (60.0 mg, 80% yield) as a yellow solid.

[0385] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0386] ​ ​

[0387] A solution of 4-methoxy-8-(4-methylpiperazin-l-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrrolo[5,4-b]indole (50.0 mg, 131.7 μmol, 1.0 equiv) in POCl3(1 mL) was stirred at 110 °C for 16 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna CI 8 150 mm x 25 mm x 10 μm; mobile phase: 39-89% ACN in water (+ formic acid modifier)) to give the title compound (21.4 mg, 41% yield) as a yellow solid.

[0388] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0389] LCMS [M+1, M+3] = 384.0, 386.0.

[0390] Table 6. The examples in Table 6 were prepared in a similar manner as described for Example 62 in Scheme 5.

[0391]

[0392]

[0393]

[0394]

[0395]

[0396] ​ ​

[0397] ​

[0398]

[0399] 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 H20 (0.2 mL) was added Na2C03(61.8 mg, 583 pmol, 3 equiv) and Pd(dppf)Cl2(14.2 mg, 19.4 pmol, 0.1 equiv) under nitrogen atmosphere at 20 °C. The mixture was stirred at 100 °C for 1 h. The mixture was cooled to room temperature, 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 Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 pm; mobile phase: 11-41% ACN in water (+ formic acid modifier)) to give the title compound (18.6 mg, 14% yield) as a white solid.

[0400] 1 H NMR (400 MHz, Methanol-d4) 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, J = 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).

[0401] LCMS [M+1, M+3] = 381.0, 383.0.

[0402] ​ Methyl-methylamine

[0403]

[0404] Scheme 6, step 1. 2-(4-bromo-2-cyano-anilino)acetamide:

[0405] A mixture of 5-bromo-2-fluoro-benzonitrile (5 g, 25.0 mmol, 1 eq) and 2-aminoacetamide hydrochloride (3.04 g, 27.5 mmol, 1.1 eq) in DMSO (50 mL) was added K2CO3(10.37 g, 75.0 mmol, 3 eq) at room temperature. The mixture was stirred at 100 °C for 3 h. The mixture was quenched by adding H2O (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with H2O (3 x 50 mL), dried over 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 give the title compound (2.3 g, 36% yield) as a yellow solid.

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (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).

[0407] Scheme 6, step 2. 3-amino-5-bromo-lH-indole-2-carboxamide:

[0408] A mixture of 2-(4-bromo-2-cyano-anilino)acetamide (5 g, 19.7 mmol, 1 eq) and sodium isopropoxide (1.62 g, 19.7 mmol, 1 eq) in IPA (50 mL) was stirred at 95 °C for 1 h. The mixture was concentrated and diluted with H2O (30 mL). The pH of the mixture was adjusted to 4 with 2N 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 Na2CO3and then extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to give the title compound (3.0 g, 53% yield) as a red solid.

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0410] LCMS: [M+1, M+3] = 254.0, 256.0.

[0411] Scheme 6, step 3. 8-bromo-5H-pyrimido[5,4-b]indole-2,4-diol:

[0412] To a solution of 3-amino-5-bromo-lH-indole-2-carboxamide (4 g, 15.7 mmol, 1 eq) in dioxane (100 mL) was added trichloromethyl chloroformate (4.52 g, 22.8 mmol, 1.45 eq) at 25 °C. The mixture was stirred at 110 °C for 2 h. The mixture was quenched by the addition of H2O (40 mL). The resulting precipitate was filtered off and the solid was concentrated under reduced pressure to give the title compound (3 g, crude) as a yellow solid.

[0413] 1 H NMR (400 MHz, DMSO-d6) δ 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, 1H), 7.36 (d, J = 8.8 Hz, 1H).

[0414] Scheme 6, step 4. 8-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole:

[0415] A mixture of 8-bromo-5H-pyrimido[5,4-b]indole-2,4-diol (1.0 g, 3.57 mmol, 1.0 eq) in phosphoryl dichloride benzene (6.96 g, 35.7 mmol, 5.01 mL, 10.0 eq) was degassed and purged with nitrogen gas for 3 times, then the mixture was stirred at 180 °C for 3 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of saturated aqueous NaHC03solution (100 mL) at room temperature. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, 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 give the title compound (600 mg, 52% yield) as a light yellow solid.

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 2.0, 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H).

[0417] Scheme 6, step 5. 8-bromo-2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole:

[0418] 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 h. 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 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over 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 give the title compound (400 mg, 58% yield) as a yellow solid.

[0419] 1 H NMR (400 MHz, DMSO-d6) d = 8.49 (d, J = 1.2 Hz, 1H), 8.10-8.01 (m, 2H), 5.75 (q, J = 8.8 Hz, 2H).

[0420] Scheme 6, step 6. 2-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido [5,4-b]indol-4-ol:

[0421] 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 a solution of Cs2CO3 (816.6 mg, 2.51 mmol, 2 equiv) in H2O (1.3 mL) and [1,1'- bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (81.6 mg, 125.3 μmol, 0.1 equiv) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, 4:1 DCM:MeOH) to give the title compound (120 mg, crude) as a brown solid. This material was used directly in the next step.

[0422] LCMS: [M+1, M+3] = 359.3, 361.2.

[0423] Scheme 6, step 7. l-[2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N,N- dimethyl-methanamine:

[0424] 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 POCl3(2 mL) was stirred at 110 °C for 16 h. The mixture was cooled to rt and poured into saturated aqueous NaHC03(20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 pm; mobile phase: 40-70% ACN in water (+ NH4HC03modifier)) to give the title compound (14.2 mg, 12% yield) as a brown solid.

[0425] 1 H NMR (400 MHz, DMSO-d) d 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).

[0426] LCMS: [M+1, M+3] = 376.8, 378.7.

[0427] Example 148. l-[4-chloro-5-(2,2,2-trifluoroethyl)-2-[4-(trifluoromethyl)phenyl]pyrimido [5,4-b]indol-8-yl]-N,N-dimethyl-methanamine

[0428]

[0429] Step 1. 8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)-2-[4- (trifluoromethyl)-phenyl]pyrimido[5,4-b]indol-4-ol: Step 2. l-[4-chloro-5-(2,2,2-trifluoroethyl)-2-[4-(trifluoromethyl)phenyl]-pyrimido

[0430] 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 H20 (0.1 mL) was added K2C03(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 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (Si02, 10:1 ethyl acetate:methanol) to give the title compound (100 mg, crude) as a white solid.

[0431] LCMS: [M+1] = 469.2.

[0432] [5,4-b]indol-8-yl]-N,N-dimethyl-methanamine: 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-dimethyl-methanamine

[0433] 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 μmol, 1 equiv) in POCl3(1 mL) was stirred at 110 °C for 1 hour. The residue was concentrated under reduced pressure to give a residue. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm x 30 mm x 5 μm; mobile phase: 30-60% acetonitrile in water (+0.2% formic acid)) to give the title compound (18.8 mg, 18% yield) as a white solid.

[0434] LCMS: [M+1, M+3] = 487.2, 489.2.

[0435] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0436] Scheme 7, step 1. 8-bromo-2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole: Scheme 7, step 2. 8-bromo-2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole:

[0437] Step 3. l-[2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N,N-

[0438]

[0439] dimethyl-methanamine:

[0440] 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 room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were combined, 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 give the title compound (28 g, 82% yield) as a yellow solid.

[0441] LCMS: [M+1, M+3] = 398.1, 400.1.

[0442] Scheme 7, step 4. l-[4-methoxy-2-(l-methylpyrazol-4-yl)-5-(2,2,2-trifluoroethyl)-2,3- dihydro-pyrimido[5,4-b]indol-8-yl]-N,N-dimethyl-methanamine:

[0443] To a solution of 8-bromo-2,4-dichloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indole in methanol (50 mL) was added NaOMe (1.13 g, 6.27 mmol, 1 eq; 30% in methanol). The mixture was heated to 60 °C for 30 minutes. The reaction was cooled to room temperature, diluted with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (5.1 g, crude) as a light yellow solid.

[0444] LCMS: [M+1, M+3] = 393.9, 395.9.

[0445] Scheme 7, step 5. 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-dimethyl-methanamine: Example 152. 4-chloro-2-methyl-8-[(4-methylpiperazin-l-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole

[0446] 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 eq) and potassium ((dimethylamino)methyl)trifluoroborate (2.31 g, 14.0 mmol, 1.2 eq) in 2-methylbutan-2-ol (46 mL) was added to Cs2C03(7.60 g, 23.3 mmol, 2 eq) and [1,1’-bis(ditert-butylphosphine)ferrocene]dichloropalladium(ll) (760 mg, 1.17 mmol, 0.1 eq) in H20 (10 mL) under a nitrogen atmosphere at room temperature. The mixture was stirred at 80 °C for 5 hours. The mixture was cooled to room temperature and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na2S04, 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.

[0447] LCMS: [M+1, M+3] = 373.1, 375.1.

[0448] ​ ​

[0449] A mixture of 1-[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 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (167 mg, 805 pmol, 1.5 equiv) in H20 (0.2 mL) and dioxane (2 mL) was charged with Pd(PPh3)4(62.0 mg, 53.7 pmol, 0.1 equiv) and K2CO3(222 mg, 1.61 mmol, 3 equiv) under a nitrogen atmosphere at room temperature. The mixture was stirred at 100 °C for 12 h. The mixture was cooled to room temperature, 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 Na2S04, and concentrated under reduced pressure. The residue was purified by preparative TLC (S1O2, 10:1 ethyl acetate:methanol) to give the title compound (120 mg, 53% yield) as a yellow solid.

[0450] LCMS: [M+1] = 419.3.

[0451] ​ ​

[0452] A mixture of 1-[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) and phosphoryl dichloride (1 mL, 7.14 mmol, 30.0 equiv) was stirred at 140 °C for 2 h. The mixture was cooled to room temperature and poured into saturated aqueous NaHC03(5 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna CI 8 100 mm x 30 mm x 5 pm; mobile phase: 15-45% acetonitrile in water (+0.2% formic acid)) to give the title compound (49.4 mg, 49% yield) as a white solid.

[0453] LCMS: [M+1, M+3] = 423.2, 425.3.

[0454] 1H NMR (400 MHz, DMSO-d6) δ 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).

[0455] Table 7. The examples in Table 7 were prepared in a similar manner as described for Example 149 in Scheme 7.

[0456]

[0457] ​ ​

[0458]

[0459] Step 1. 2-Chloro-4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl- pyrimido[5,4-b]indole:

[0460] 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-1,3,2-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 [1,1’-bis(ditert-butylphosphino)ferrocene]dichloropalladium(II) (330 mg, 507 µmol, 0.1 equiv) under nitrogen atmosphere at room temperature. The mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature and extracted with CH2Cl2(3 x 20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15-50% ethyl acetate in petroleum ether) to give the title compound (540 mg, 31% yield) as a white solid.

[0461] LCMS: [M+1, M+3] = 342.0, 344.0.

[0462] 1H NMR (400 MHz, Chloroform-d) d 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).

[0463] Step 2. 4-Methoxy-2-methyl-5-(2,2,2-trifluoroethyl)-8-vinyl- pyrimido[5,4-b]indole

[0464] 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- 1,3,5,2,4,6-trioxatriphosphaadamantane (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 μmol, 0.2 equiv), tricyclohexylphosphine (89 mg, 316 μmol, 0.2 equiv) and K3PO4 (1.68 g, 7.90 mmol, 5.0 equiv) under nitrogen atmosphere at room temperature. The mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with brine, dried over 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 give the title compound (170 mg, 33% yield) as a green solid.

[0465] LCMS: [M+1] = 322.1.

[0466] Step 3. 4-Methoxy-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-8-carbaldehyde:

[0467] 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 K2Os04*2H20 (4.9 mg, 13.2 pmol, 0.025 equiv), NaI04(566 mg, 2.65 mmol, 5.0 equiv), 2,6-dimethylpyridine (185 pL, 1.59 mmol, 3.0 equiv) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. 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 Na2S04, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (150 mg, 88% yield) as a white solid.

[0468] LCMS: [M+1] = 324.2.

[0469] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0470] Step 4. 4-Methoxy-2-methyl-8-[(4-methylpiperazin-1-yl)methyl]-5- (2,2,2-trifluoroethyl)pyrimido[5,4-b]indole: Step 5. 4-Chloro-2-methyl-8-[(4-methylpiperazin-1-yl)methyl]-5- (2,2,2-trifluoroethyl)pyrimido[5,4-b]indole:

[0471] To a mixture of 4-methoxy-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-8-carboxaldehyde (100 mg, 309 pmol, 1.0 equiv) and 1-methylpiperazine (69 pL, 619 pmol, 2.0 equiv) in DCE (1.0 mL) at room temperature was added AcOH (17.7 pL, 309 pmol, 1.0 equiv). Then NaBH(OAc)3(196.6 mg, 928.0 pmol, 3.0 equiv) was added and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added dropwise to the reaction mixture and the pH was adjusted to pH = 8 with saturated aqueous NaHC03solution. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated to give the title compound (100 mg, 79% yield) as a yellow solid.

[0472] LCMS: [M+1] = 408.2.

[0473] LCMS: [M+1] = 408.2.1 H NMR (400 MHz, Chloroform-d) d 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).

[0474] Example 153. 1-[4-Chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N-methyl-methanamine Step 1. 2-Chloro-4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl- pyrimido[5,4-b]indole:

[0475] POCI3(1.0 mL) was added in one portion 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 pmol, 1.0 equiv) at room temperature under a nitrogen atmosphere. The mixture was stirred at 120 °C for 18 h. The mixture was cooled to room temperature and quenched by the addition of saturated aqueous NaHC03solution (1 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 mm x 30 mm x 3 pm; mobile phase: 20-45% acetonitrile in water (+ 0.04% HC1)) to give the title compound (10.5 mg) as a white solid.

[0476] LCMS: [M+1, M+3] = 412.2, 414.2.

[0477] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0478] Step 2. 4-Chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole- 8-carbaldehyde: Step 3. 1-[4-Chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol- 8-yl]-N-methyl-methanamine:

[0479]

[0480] Example 154. 4-Chloro-8-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)-2- methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole

[0481] Dichlorophosphoryloxybenzene (10 mL) was added to a flask containing 4-methoxy-2-methyl-5-(2,2,2-trifluoroethyl)-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 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHC03solution, extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (800 mg, crude) as a brown solid.

[0482] LCMS: [M+1] = 326.0.

[0483] Step 1. 3-Chloro-[[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-carboxylic acid tert-butyl ester:

[0484] 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 H20 (4.0 mL) was added K2Os04.2H20 (22.6 mg, 61.4 μmol, 0.025 equiv), NaI04(2.63 g, 12.28 mmol, 5.0 equiv), 2,6-dimethylpyridine (859 μL, 7.37 mmol, 3.0 equiv) under nitrogen atmosphere at room temperature. The reaction was stirred at room temperature for 1 h. 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 Na2S04, filtered, and concentrated under reduced pressure to afford 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.

[0485] LCMS: [M+1] = 326.0.

[0486] Step 2. 4-Chloro-8-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)-2-methyl-5- (2,2,2-trifluoroethyl)pyrimido[5,4-b]indole: Example 155. 4-Chloro-8-(3,6-diazabicyclo[3.1.1]hept-3-ylmethyl)-2- methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole

[0487] To a mixture of 4-chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-8-carboxaldehyde (40.0 mg, 122 pmol, 1.0 equiv) and methylamine (122.0 pL, 244 pmol, 2.0 equiv; 2 M in THF) in DCM (0.4 mL) was added AcOH (21 pL, 366 pmol, 3.0 equiv). The mixture was stirred at room temperature for 30 min, then NaBH(OAc)3 (78 mg, 366 pmol, 3 equiv) was added and the reaction was stirred at room temperature for 2 h. 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 C18 80 mm x 30 mm x 3 pm; mobile phase: 5-40% acetonitrile in water (0.04% HC1)) to give the title compound (12.2 mg, 29% yield; HC1 salt) as a white solid.

[0488] LCMS: [M+1, M+3] = 343.2, 345.2.

[0489] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0490] Example 156. N-((4-Chloro-8-((dimethylamino)methyl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indol-2-yl)methyl)formamide Scheme 8, Step 1. N-[2-[(5-Bromo-2-carbamoyl-1H-indol-3-yl)amino]-2- oxo-ethyl]carbamic acid tert-butyl ester:

[0491]

[0492] Scheme 8, Step 2. N-[(8-Bromo-4-hydroxy-5H-pyrimido[5,4-b]indol-2- yl)methyl]carbamic acid tert-butyl ester: Scheme 8, Step 3. (8-Bromo-4-chloro-5H-pyrimido[5,4-b]indol-2-yl)methanamine hydrochloride:

[0493] To a mixture of 4-chloro-2-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-8-carboxaldehyde (80 mg, 244 pmol, 1 equiv) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (104 mg, 488 pmol, 2 equiv) in DMF (1 mL) was added TMSC1 (186 pL, 1.46 mmol, 6 equiv). The mixture was stirred at room temperature for 20 minutes, then NaBH(OAc)3 (155 mg, 732 pmol, 3 equiv) was added. The reaction was then stirred at room temperature for 2 hours. The mixture was quenched with H2O (1 mL) and extracted with EtOAc (3 x 1 mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The residue was purified by preparative TLC (Si02, 1 : 1 ethyl acetate: petroleum ether) to give the title compound (80 mg, 61% yield) as a yellow oil.

[0494] LCMS: [M+1, M+3] = 524.3, 526.3.

[0495] ​ ​

[0496] 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 pmol, 1 equiv) in HC1 / dioxane (1 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (80 mg, 89% yield; hydrochloride) as a white solid.

[0497] LCMS: [M+1, M+3] = 424.2, 426.2.

[0498] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0499] ​ ​

[0500]

[0501] Example 155 was prepared in a similar manner as described in example 154.

[0502] LCMS: [M+1, M+3] = 410.1, 412.1.

[0503] 1 H 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).

[0504] ​ ​

[0505] (5-bromo-lH-indol-2-yl)methyl)-l-methyl-lH-pyrazole-4-carboxamide

[0506]

[0507] ​ ​

[0508] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (6.1 g, 35.2 mmol, 1.5 eq) in DMF (40.0 mL) was added TEA (9.5 g, 94.0 mmol, 13.1 mL, 4.0 eq), EDCI (9.0 g, 47.0 mmol, 2.0 eq) and 1-oxypyridin-l-ium-2-olate (5.2 g, 47.0 mmol, 2.0 eq). Then 3-amino-5-bromo-lH-indole-2-carboxamide (5.9 g, 23.5 mmol, 1.0 eq) was added and the mixture was stirred at 30 °C for 2 h. 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 with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate at room temperature for 20 min to give the title compound (6.1 g, 58% yield) as a brown solid.

[0509] LCMS: [M+1, M+3] = 411.2, 413.2.

[0510] 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).

[0511] ​ ​

[0512] To a solution of tert-butyl N-[2-[(5-bromo-2-carbamoyl-lH-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 room temperature for 16 h. The reaction mixture was quenched with water (80 mL). The suspension was then 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 Na2S04, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate at room temperature for 20 min to give the title compound (3.2 g, 76% yield) as a brown solid.

[0513] LCMS: [M+1, M+3] = 393.1, 395.1.

[0514] 1 H 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).

[0515] ​

[0516] A solution of tert-butyl N-[(8-bromo-4-hydroxy-5H-pyrimido[5,4-b]indol-2- yl)methyl]aminocarboxylate (4.0 g, 10.1 mmol, 1.0 equiv) in POCl3(20.0 mL) was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in THF at room temperature and quenched by the addition of aqueous NaHC03solution. When the pH was measured as 7, the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (3.1 g) as a black solid.

[0517] LCMS: [M+1, M+3] = 311.0, 312.9.

[0518] Scheme 8, step 4. N-[(8-bromo-4-chloro-5H-pyrrolo[5,4-b]indol-2-yl)methyl]amino carboxylic acid tert-butyl ester: Scheme 8, step 5. N-[[8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-2- yl]methyl]amino carboxylic acid tert-butyl ester:

[0519] 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 H20 (20 mL) was added NaHC03(1.8 g, 21.8 mmol, 2.0 equiv) and Boc20 (1.2 g, 5.4 mmol, 0.5 equiv). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H20 (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-75% ethyl acetate in petroleum ether) to give the title compound (2.9 g, 55% yield) as a brown solid.

[0520] LCMS: [M+1, M+3] = 411.2, 413.2.

[0521] 1 H 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).

[0522] Scheme 8, step 6. N-[[8-(dimethylamino)methyl]-4-hydroxy-5-(2,2,2-trifluoroethyl)pyrrolo[5,4- b]indol-2-yl]methyl]amino carboxylic acid tert-butyl ester Scheme 8, step 7. [4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol- 2-yl]methylamine hydrochloride:

[0523] To a 100 mL three necked flask was added a solution of N-[(8-bromo-4-chloro-5H- pyrimido[5,4-b]indol-2-yl)methyl]carbamic acid tert-butyl ester (2.1 g, 5.1 mmol, 1.0 eq) 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 eq) was added to the mixture in five portions at 0 °C under nitrogen atmosphere and stirred at 0 °C for 1 h. A solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.8 g, 7.6 mmol, 1.5 eq) in DMF (2.0 mL) was added dropwise to the mixture and the resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched by the addition of NH4Cl saturated aqueous solution (50 mL). The mixture was extracted with ethyl acetate (3 x 30 mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50:1 to 10:1 petroleum ether: ethyl acetate) to give the title compound (1.9 g, yield 76%) as a white solid.

[0524] LCMS: [M+1, M+3] = 493.2, 495.2.

[0525] 1 H 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).

[0526] Scheme 8, step 8. N-((4-chloro-8-((dimethylamino)methyl)-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4- b]indol-2-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide: Example 167. N-[[4-chloro-8-(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4- b]indol-2-yl]methyl]-1-methyl-pyrazole-4-carboxamide

[0527] To a mixture of tert-butyl N-[[8-bromo-4-chloro-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]aminocarboxylate (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]- phosphine; methanesulfonate; [2-[2-(methylamino)phenyl]phenyl]palladium(II) (104.5 mg, 121.5 μmol, 0.1 equiv) in one portion under nitrogen atmosphere; the mixture was stirred at 80 °C for 16 h. 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 give the title compound (350 mg, 64% yield) as a white solid.

[0528] LCMS: [M+1] = 454.4

[0529] 1 H 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).

[0530] Step 1. N-[[4-chloro-5-(2,2,2-trifluoroethyl)-8-vinyl-pyrrolo[5,4-b]indol-2-yl]methyl]amino carboxylic acid tert-butyl ester: Step 2. N-[[4-chloro-8-formyl-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-2-yl]methyl]amino carboxylic acid tert-butyl ester.

[0531] A mixture of tert-butyl N-[[8-[(dimethylamino)methyl]-4-hydroxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]aminocarboxylate (40.0 mg, 88.2 μmol, 1 equiv) in POCl3(0.3 mL) was degassed with nitrogen, then the mixture was stirred at 60 °C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature, then poured into H2O (5 mL). The mixture was stirred for 2 min, then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 mm x 30 mm x 3 μm; mobile phase: 5-30% acetonitrile in water (0.04% HC1)) to give the title compound (20.0 mg, 55% yield) as a white solid.

[0532] LCMS: [M+1] = 372.1, 374.0.

[0533] 1 H 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).

[0534] Step 3. N-[[4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol- 2-yl]methyl]amino carboxylic acid tert-butyl ester: Step 4. [4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-2- yl]methylamine hydrochloride:

[0535] [4-Chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methylamine (200 mg, 538 pmol, 1.0 equiv) and 1-methylpyrazole-4- carboxylic acid chloride (156 mg, 1.1 mmol, 2.0 equiv) were mixed in pyridine (2 mL), then the mixture was stirred at room temperature for 30 min under nitrogen atmosphere. The reaction mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic extract was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge C18 150mm x 50mm x 10pm; mobile phase: 15-45% acetonitrile in water (10 mM NH4HCO3)) to give the title compound (25.4 mg, 9.2% yield) as a white solid.

[0536] LCMS: [M+1, M+3] = 480.1, 482.2.

[0537] 1 H 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).

[0538] Table 8. The examples in Table 8 were prepared in a similar manner as described in Example 156, according to Scheme 8.

[0539]

[0540]

[0541]

[0542]

[0543] Step 5. N-[[4-chloro-8-[(4-methylpiperazin-1-yl)methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol- 2-yl]methyl]-1-methyl-pyrazole-4-carboxamide: Example 168. N-[[4-chloro-8-[[3-(dimethylamino)azetidin-1-yl]methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4- b]indol-2-yl]methyl]-1-methyl-pyrazole-4-carboxamide

[0544]

[0545] Example 169. 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-2- yl]-N-methyl-acetamide Scheme 9, step 1. 3-[(5-bromo-2-carbamoyl-1H-indol-3-yl)amino]-3-oxo-propionic acid ethyl ester:

[0546] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.1 g, 7.2 mmol, 1.2 mL, 1.2 equiv), tert-butyl N-[[8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methyl]aminocarboxylate (3.0 g, 6.0 mmol, 1.0 equiv), Cs2CO3(2.1 g, 6.6 mmol, 1.1 equiv), [1,1’-bis(ditert-butylphosphino)ferrocene]dichloropalladium(II) (396 mg, 608 μmol, 0.1 equiv) in 2-methylbutan-2-ol (120 mL) and H2O (30 mL) was degassed with nitrogen, then the mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature, then poured into H2O (50 mL), 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% ethyl acetate in petroleum ether) to give the title compound (2.8 g, crude) as a white solid.

[0547] LCMS [M+1, M+3] = 441.2, 443.2.

[0548] 1 H NMR (400 MHz, Chloroform-d) δ = 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).

[0549] Scheme 9, step 2. 2-(8-bromo-4-chloro-5H-pyrrolo[5,4-b]indol-2-yl)acetic acid ethyl ester: ​

[0550] To a solution of tert-butyl N-[[4-chloro-5-(2,2,2-trifluoroethyl)-8- vinyl- pyrimido[5,4-b]indol-2-yl]methyl]aminocarboxylate (2.2 g, 4.9 mmol, 1.0 equiv) in 1,4-dioxane (80 mL) and water (40 mL) was added K2Os04.H20 (45.9 mg, 124.7 μmol, 0.025 equiv), NaI04(4.2 g, 19.9 mmol, 4.0 equiv) and 2,6-dimethylpyridine (1.1 mL, 9.9 mmol, 2.0 equiv), the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H20 (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-50% ethyl acetate in petroleum ether) to give the title compound (2.5 g, crude) as a white solid.

[0551] LCMS [M+1-56, M+3-56] = 387.0, 389.0.

[0552] 1 H 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).

[0553] ​ ​

[0554] To a solution of tert-butyl N-[[4-chloro-8-formyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]methyl]aminocarboxylate (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 room temperature for 1 h. 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 give the title compound (1.1 g, 92% yield) as a white solid.

[0555] LCMS [M+1, M+3] = 527.4, 529.3.

[0556] 1 H 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).

[0557] ​ ​

[0558] 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]aminocarboxylate (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 room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.1 g, crude) as a white solid.

[0559] LCMS [M+1, M+3] = 427.4, 429.4.

[0560] 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).

[0561] ​ ​

[0562] 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 min. The reaction mixture was concentrated under reduced pressure to give 1-methylpyrazole-4-carbonyl chloride (3.5 g, crude) as a white solid. This material was used in the next stage of the procedure without further purification.

[0563] 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 room temperature for 30 min, then 1-methylpyrazole-4-carbonyl chloride (156.0 mg, 1.0 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 10.5 h. 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 CI 100 mm x 30 mm x 10 μm; mobile phase: 20-35% acetonitrile in water (+10 mM NH4HCO3)) to give the title compound (300 mg, 50% yield) as a white solid.

[0564] LCMS [M+1, M+3] = 535.2, 537.2.

[0565] 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).

[0566] ​ ​

[0567]

[0568] Example 168 was prepared in a similar manner as described in example 167.

[0569] LCMS: [M+1, M+3] = 535.2, 537.2.

[0570] 1 H 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).

[0571] ​ ​

[0572] ​

[0573]

[0574] ​

[0575] Combine 3-amino-5-bromo-lH-indole-2-carboxamide (10.0 g, 39.3 mmol, 1.0 equiv) and diethyl malonate (74.6 mL, 492 mmol, 12.5 equiv) and heat at 200 °C for 30 min under solvent-free conditions. Then add EtOH (300 mL) and continue refluxing for 2 h. Cool the mixture to room temperature and filter the suspension through filter paper to give the title compound (12.5 g, 84% yield) as a brown solid.

[0576] LCMS [M+1, M+3] = 368.2, 370.2.

[0577] ​

[0578] To a solution of 3-[(5-bromo-2-carbamoyl-lH-indol-3-yl)amino]-3-oxo- propanoic acid ethyl ester (16.2 g, 44.0 mmol, 1.0 equiv) in dioxane (160 mL) add POCl3(61.5 mL, 660.0 mmol, 15.0 equiv). Stir the mixture at 90 °C for 12 h. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Then treat the residue with water and adjust the pH to pH = 8. Filter the suspension through filter paper to give the title compound (16.0 g, 89% yield) as a brown solid.

[0579] LCMS [M+1, M+3] = 368.1, 370.1.

[0580] Scheme 9, step 3. 2-[8-bromo-4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]ethanol: ethyl ester:

[0581] To a solution of 2-(8-bromo-4-chloro-5H-pyrimido[5,4-b]indol-2-yl)acetic acid ethyl ester (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) add K2CO3(13.5 g, 97.6 mmol, 3.0 equiv). Stir the mixture at room temperature for 12 h. Dilute the reaction mixture with water (200 mL) and filter the suspension through filter paper. Triturate the filter cake with ethyl acetate for 30 min to give the title compound (12.0 g, 69% yield) as a brown solid.

[0582] LCMS [M+1, M+3] = 450.1, 452.1.

[0583] Scheme 9, step 4. 2-[8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)-pyrimido[5,4- b]indol-2-yl]acetic acid methyl ester: Scheme 9, step 5. 2-[8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetic acid methyl ester:

[0584] To a solution of methyl 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 min. 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 Na2S04, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (12.0 g, 65% yield) as a brown solid.

[0585] LCMS [M+1, M+3] = 432.1, 434.1.

[0586] Scheme 9, step 6. 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetic acid methyl ester: Scheme 9, step 7. 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]acetic acid:

[0587] To a solution of methyl 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 min. 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 Na2S04, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (12.0 g, 65% yield) as a brown solid.

[0588] LCMS [M+1] = 411.1.

[0589] 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: Example 17 0. 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]-N-methyl-acetamide

[0590] 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, then the mixture was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction mixture was diluted with saturated aqueous NaHC03solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the title compound (6.00 g, 81% yield) as a brown solid.

[0591] LCMS [M+1, M+3] = 415.3, 417.3.

[0592] 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: Example 18 1. 2-[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-yl]-N-

[0593] 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 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with H20 (3 x 50 mL). The combined aqueous layers were lyophilized to afford a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm x 30 mm x 5 μm; mobile phase: 5-30% acetonitrile in water (+0.2% formic acid)) to afford the title compound (200 mg, 10% yield) as a white solid.

[0594] LCMS [M+1, M+3] = 401.2, 403.1.

[0595] 1 H 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).

[0596] methyl-acetamide Scheme 10, step 1. 8-bromo-4-hydroxy-5H-pyrimido[5,4-b]indole-2-carboxylic acid methyl ester:

[0597] 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 pmol, 1.0 equiv) in acetonitrile (0.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (77.0 mg, 274.4 pmol, 1.1 equiv), N-methylimidazole (61.6 pL, 773.4 pmol, 3.1 equiv) and methylamine hydrochloride (20.2 mg, 299 pmol, 1.2 equiv). The mixture was stirred at room temperature for 1 h. 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 15 mL of brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 pm; mobile phase: 15-45% acetonitrile in water (+10 mM NH4HC03)) to give the title compound (15.8 mg, 15% yield) as a white solid.

[0598] LCMS: [M+1, M+3] = 413.9, 415.9.

[0599] 1H NMR (400 MHz, DMSO-d6) d = 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).

[0600] Scheme 10, step 2. 8-bromo-4-methoxy-5H-pyrimido[5,4-b]indole-2-carboxylic acid methyl ester: Scheme 10, step 3. 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-2-carboxylic acid methyl ester:

[0601]

[0602] Scheme 10, step 4. 8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylic acid: Scheme 10, step 5. 8-[(dimethylamino)methyl]-4-methoxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylic acid methyl ester:

[0603] 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 eq) and oxetane-3-amine (13.1 mg, 179.6 μmol, 1.2 eq) in THF (1.0 mL) was added DIEA (78.2 μL, 449.1 μmol, 3.0 eq) and T4P (216 mg, 299 μmol, 2.0 eq; 50% EtOAc solution). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into H2O (3 mL) and extracted with EtOAc (3×5 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 C18 150 mm x 50 mm x 10 μm; mobile phase: 20-60% acetonitrile in water (+10 mM NH 4 HCO 3 )) to give the title compound (11.4 mg, yield 16%) as a white solid.

[0604] LCMS:[M+1,M+3]=456.1,458.1.

[0605] 1 H NMR (400MHz, DMSO-d6) δ8.96(d,J=6.4Hz,1H),8.16(s,1H),7.98(d,J=8.8Hz,1H),7.77(d,J=8.8Hz,1H),5.71(q,J= 8.8Hz, 2H), 4.83 (q, J = 6.8Hz, 1H), 4.77-4.70 (m, 2H), 4.48 (t, J = 6.4Hz, 2H), 3.94 (s, 2H), 3.60 (s, 2H), 2.19 (s, 6H).

[0606] Table 9. The examples in Table 9 were prepared according to Scheme 9 in a manner similar to that described for Examples 169 and 170 above.

[0607]

[0608]

[0609]

[0610] Scheme 10, step 6. 8-[(dimethylamino)methyl]-4-hydroxy-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylic acid methyl ester: Scheme 10, step 7. 4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxylic acid methyl ester:

[0611] ​

[0612]

[0613] ​

[0614] To a solution of 3-amino-5-bromo-lH-indole-2-carboxamide (27 g, 106 mmol, 1 eq) in MeOH (270 mL) was added dimethyl oxalate (37.6 g, 319 mmol, 3 eq) and sodium methoxide (28.7 g, 159.4 mmol, 1.5 eq; 30% in MeOH). The reaction was stirred at 70 °C for 12 h. Water (1000 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.

[0615] LCMS: [M+H, M+3] = 322.1, 324.1.

[0616] ​

[0617] Methyl 8-bromo-4-hydroxy-5H-pyrimido[5,4-b]indole-2-carboxylate (20 g, 62.0 mmol, 1 eq) was added to POCl3(200 mL) at 20 °C. The solution was then stirred at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (33 g, crude) as a brown solid.

[0618] The solution of methyl 8-bromo-4-chloro-5H-pyrimido[5,4-b]indole-2-carboxylate (33 g, 96.9 mmol, 1 eq) in MeOH (350 mL) was then treated with NaOMe (26.1 g, 145.3 mmol, 1.5 eq; 30% in MeOH) and the reaction mixture was stirred at 70 °C for 2 h. The reaction was cooled to room temperature 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), then filtered and dried to afford the title compound (5.8 g, 18% yield) as a brown solid.

[0619] LCMS: [M+H, M+3] = 336.0, 338.1.

[0620] ​ ​

[0621] To a solution of 8-bromo-4-methoxy-5H-pyrimido[5,4-b]indole-2-carboxylic acid methyl ester (5.8 g, 17.2 mmol, 1 eq) and K2CO3(4.7 g, 34.5 mmol, 2 eq) in DMF (58 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.81 g, 20.7 mmol, 1.2 eq). The reaction mixture was heated to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 °C 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 give the title compound (2.3 g, 32% yield) as a brown solid.

[0622] LCMS: [M+H, M+3] = 418.0, 420.0.

[0623] ​ ​

[0624] To a solution of 8-bromo-4-methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-2-carboxylic acid methyl ester (2.3 g, 5.5 mmol, 1 eq) and potassium ((dimethylamino)methyl)trifluoroborate (3.6 g, 22.0 mmol, 4 eq) in 2-methylbutanol (23 mL) was added a solution of Cs2CO3(3.5 g, 11.0 mmol, 2 eq) in H2O (4.6 mL) and [1,1’- bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (358.4 mg, 550.0 μmol, 0.1 eq) at room temperature under nitrogen. The mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by preparative HPLC (column: Waters Xbridge BEH C18 250 mm x 70 mm x 10 μm; mobile phase: 1-40% acetonitrile in water (+10 mM NH4HCO3)) to give the title compound (2.0 g, 95% yield) as a white solid.

[0625] LCMS: [M+H] = 383.2.

[0626] ​ ​

[0627] Dissolve 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 eq) in oxalyl chloride (15.0 mL, 171.3 mmol, 43.6 eq) and stir the reaction at room temperature for 1 hour. Concentrate the reaction mixture and add methanol. Remove the solvent under reduced pressure to give the title compound (1.1 g, 71% yield) as a yellow solid.

[0628] LCMS: [M+H] = 397.5.

[0629] ​ ​

[0630] 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 eq) in ACN (10 mL) at room temperature, add TMSCl (480 μL, 3.7 mmol, 1.5 eq) and NaI (567 mg, 3.7 mmol, 1.5 eq). Stir the reaction at room temperature for 1 hour. Then add water (14 μL, 757 μmol, 0.3 eq) and stir the reaction mixture at 65 °C for 3 hours. Dilute the reaction mixture with water (10 mL) and extract with EtOAc (3 x 10 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by preparative TLC (5:1 DCM:MeOH) to give the title compound (800 mg, 83% yield) as a white solid.

[0631] LCMS: [M+H] = 383.1.

[0632] ​ ​

[0633] Dissolve methyl 8-[(dimethylamino)methyl]-4-hydroxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-2-carboxylate (1 g, 2.6 mmol, 1 eq) in POCl3 (20 mL, 214.5 mmol, 82.0 eq) and stir the mixture at 110 °C for 2 hours. Remove the solvent under reduced pressure. Cool the flask to 0 °C and add saturated aqueous NaHCO3 to adjust the pH to pH = 8. Extract the mixture with EtOAc (3 x 20 mL) and concentrate the combined organic layers under reduced pressure. Purify the reaction by preparative TLC (100% THF) to give the title compound (650 mg, 62% yield) as a yellow solid.

[0634] LCMS: [M+H] = 401.3.

[0635] Scheme 10, step 8. 4-Chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole Indole-2-carboxylic acid:

[0636] 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, 1.0 equiv) in DCE (2 mL) was added hydroxy(trimethyl)stannane (271 mg, 1.5 mmol, 6.0 equiv). The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 pm; mobile phase: 1-40% acetonitrile in water (+10 mM NH4HCO3)) to give the title compound (20.6 mg, 20% yield) as a white solid.

[0637] LCMS: [M+H] = 387.1.

[0638] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0639] Scheme 10, step 9. 4-Chloro-8-[(dimethylamino)methyl]-N,N-dimethyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole-2-carboxamide: Example 185. 4-Chloro-8-(2,5-diazaspiro[3.4]octan-2-ylmethyl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole

[0640] 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 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 at room temperature for 2 h. 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 Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 80 mm x 30 mm x 3 pm; mobile phase: 5-35% acetonitrile in water (+0.04% HC1)) to give the title compound (9 mg, 29% yield) as a white solid.

[0641] LCMS [M+1, M+3] = 414.3, 416.3.

[0642] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0643] Table 10. The examples in Table 10 were prepared in a similar manner as described above for Example 181, following Scheme 10.

[0644]

[0645] 4-Chloro-8-[(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)methyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indole: Example 203. 1-[4-Chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-N,

[0646]

[0647] N-dimethyl-methanamine Scheme 13, step 1. 5-Bromo-2-[(4-methoxyphenyl)methylamino]-4-methyl- benzonitrile:

[0648] To a solution of 4-chloro-8-(chloromethyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (200 mg, 599 pmol, 1 eq) in acetonitrile (4.0 mL) was added TEA (500 pL, 3.6 mmol, 6.0 eq) and tert-butyl 2,5-diazaspiro[3.4]octane-5-carboxylate-oxalic acid (154.0 mg, 299.3 pmol, 0.5 eq). The mixture was stirred at room temperature 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 Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (Si02, 10: 1 DCM:MeOH) to give the title compound (46 mg, 13% yield) as a white solid.

[0649] LCMS [M+1, M+3] = 510.2, 512.2.

[0650] Scheme 13, step 2. 2-Amino-5-bromo-4-methyl-benzonitrile: Scheme 13, step 3. Ethyl 2-(4-bromo-2-cyano-5-methylanilino)acetate:

[0651] 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 room temperature for 1 h. The reaction mixture was diluted with saturated aqueous Na2CO3solution (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 150 mm x 50 mm x 10 pm; mobile phase: 25-55% acetonitrile in water (+10 mM NH4HCO3)) to give the title compound (85 mg, 80% yield) as a white solid.

[0652] LCMS [M+1, M+3] = 410.1, 412.1.

[0653] 1 H NMR (400 MHz, Chloroform-d) δ 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 = 8.0 Hz, 2H), 3.09 (d, J = 8.0 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.01 (t, J = 6.8 Hz, 2H), 1.78 - 1.73 (m, 2H).

[0654] Scheme 13, step 4. 1-(tert-Butyl) 2-ethyl 3-amino-5-bromo-6-methyl-1H-indole-1,2- dicarboxylate:

[0655]

[0656] Scheme 13, step 5. 1-(tert-Butyl) 2-ethyl-5-bromo-3-(((dimethylamino) methylene)amino)-6-methyl-1H-indole-1,2-dicarboxylate: Scheme 13, step 6. 8-Bromo-7-methyl-5H-pyrimido[5,4-b]indol-4-ol:

[0657] To a mixture of 4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole-8-carboxaldehyde (55.0 mg, 175 pmol, 1.0 equiv) and piperazine-1- carboxylic acid tert-butyl ester (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 min. Then NaBH(OAc)3 (37.1 mg, 175.3 pmol, 1.0 equiv) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched by the addition of 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 Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (S1O2, 1 : 1 ethyl acetate: petroleum ether) to give the title compound (38.0 mg, 45% yield) as a white solid.

[0658] LCMS: [M+1, M+3] = 484.4, 486.4.

[0659] Scheme 13, step 7. 8-Bromo-4-chloro-7-methyl-5H-pyrimido[5,4-b]indole: ​

[0660] A solution of HC1 in dioxane (0.2 mL, 4 M) was added to a flask containing 4-[[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]methyl]piperazine-1- carboxylic acid tert-butyl ester (35.0 mg, 72.3 pmol, 1.0 equiv) and the reaction was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 mm x 30 mm x 3 pm; mobile phase: 5-35% acetonitrile in water (+0.04% HC1)) to give the title compound (10.0 mg, 36% yield) as a white solid (HC1 salt).

[0661] LCMS: [M+1, M+3] = 384.1, 386.1.

[0662] Table 11. The examples in Table 11 were prepared in a similar manner to that described for Examples 185 or 186 in Schemes 11 and 12.

[0663]

[0664]

[0665]

[0666]

[0667] ​ ​

[0668] ​

[0669]

[0670] ​ ​

[0671] To a solution of 4-chloro-8-(2,5-diazaspiro[3.4]oct-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% aqueous solution) and HOAc (4.9 pL, 85.4 pmol, 1.0 equiv). The mixture was stirred at room temperature for 1 h. Another portion of NaBH(OAc)3 (36.2 mg, 170.8 pmol, 2.0 equiv) was added, and the mixture was stirred at room temperature for 2 h. 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 CI 100 mm x 30 mm x 10 pm; mobile phase: 30-60% acetonitrile in water (+10 mM NH4HCO3)) to give the title compound (8.0 mg, 22% yield) as a white solid.

[0672] LCMS [M+1, M+3] = 424.1, 426.1.

[0673] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0674] Table 12. The examples in Table 12 were prepared in a similar manner as described above for Example 199.

[0675]

[0676]

[0677] ​ ​

[0678]

[0679] ​

[0680] To a mixture of 5-bromo-2-fluoro-4-methyl-benzonitrile (15.0 g, 70.0 mmol, 1.0 eq) and p-methoxybenzylamine (18.1 mL, 140.1 mmol, 2.0 eq) in DMSO (150 mL) was added K2CO3(29.0 g, 210.2 mmol, 3.0 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature 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 give the title compound (12.2 g, 53% yield) as a white solid.

[0681] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (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).

[0682] ​

[0683] A mixture of 5-bromo-2-[(4-methoxyphenyl)methylamino]-4-methyl-benzonitrile (12.0 g, 36.2 mmol, 1.0 eq) in DCM (60 mL) and TFA (30 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated and then quenched with saturated aqueous NaHCO3solution (90 mL) at room temperature. The mixture was extracted with DCM. The extract was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give the title compound (7.0 g, 90% yield) as a yellow solid.

[0684] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 6.74 (s, 1H), 6.14 (br s, 2H), 2.23 (s, 3H).

[0685] ​

[0686] To a mixture of 2-amino-5-bromo-4-methylbenzonitrile (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 TMSCl (12.3 g, 113.7 mmol, 14.43 mL, 6.0 equiv) and the mixture was stirred at room temperature for 2 h. Then NaBH(OAc)3 (10.0 g, 47.3 mmol, 2.5 equiv) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by the addition of saturated aqueous NaHC03 (150 mL) at room temperature, then extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 mm x 150 mm x 15 μm; mobile phase: 50-85% acetonitrile in water (+0.05% HC1)) to give the title compound (2.2 g, 39% yield) as a yellow solid.

[0687] LCMS: [M+1, M+3] = 296.9, 298.8.

[0688] 1 H 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).

[0689] ​

[0690] To a mixture of 2-(4-bromo-2-cyano-5-methyl-anilino)ethyl 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), Boc20 (9.7 g, 44.4 mmol, 6.0 equiv) and DMAP (90 mg, 740 μmol, 0.1 equiv). The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by the addition of saturated aqueous NaHC03solution (60 mL). The mixture was extracted with EtOAc (3 x 30 mL), the combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-7% ethyl acetate in petroleum ether) to give the title compound (2.6 g, 83% yield) as a yellow solid.

[0691] LCMS: [M-55, M-53] = 397.2, 399.2.

[0692] 1 H 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).

[0693] ​ ​

[0694] 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 h. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give the title compound (2.9 g, 98% yield) as a yellow oil.

[0695] LCMS: [M+1, M+3] = 452.2, 454.2.

[0696] ​

[0697] 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 NH3H2O (20 mL) was stirred at 70 °C for 48 h. The mixture was cooled to rt, the solid was filtered off and dried under reduced pressure to give the title compound (900 mg, 48% yield) as a grey solid.

[0698] LCMS: [M+1, M+3] = 278.0, 279.9.

[0699] ​

[0700] 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 h. The reaction mixture was concentrated under reduced pressure to give the title compound (700 mg, 73% yield) as a yellow solid.

[0701] LCMS: [M+1, M+3] = 296.1, 298.2.

[0702] 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 7.67 (s, 1H), 2.57 (s, 3H).

[0703] Scheme 13, step 8. 8-Bromo-4-chloro-7-methyl-5-(2,2,2-trifluoroethyl)- pyrimido[5,4-b]indole:

[0704] 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 h. The reaction mixture was quenched with sat. aq. NH4Cl (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 TLC (SiO2, 1:1 ethyl acetate: petroleum ether) to give the title compound (100.0 mg, 38% yield) as a yellow solid.

[0705] LCMS: [M+1, M+3] = 378.1, 380.1.

[0706] Scheme 13, step 9. l-[4-Chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine: Scheme 13, step 9. l-[4-Chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine:

[0707] To a mixture of 8-bromo-4-chloro-7-methyl-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole (100 mg, 264 pmol, 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 pmol, 2.0 equiv) in H2O (0.2 mL) and [1,1’- bis(ditert-butylphosphino)ferrocene]dichloropalladium(ll) (17.2 mg, 26.4 pmol, 0.1 equiv) under a nitrogen atmosphere. The mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to rt, diluted with H2O (10 mL), and 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 C18 80 mm x 30 mm x 3 pm; mobile phase: 10-40% acetonitrile in water (+0.04% HC1)) to give the title compound (11.1 mg, 11% yield; HC1 salt) as a yellow solid.

[0708] LCMS: [M+1, M+3] = 357.1, 359.1.

[0709] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0710] Example 20. 2-[4-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]pyrazol- 1-yl]-N,N-dimethyl-ethanamine Scheme 14, step 1. 2-[4-[4-Methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8- yl]pyrazol-l-yl]-N,N-dimethyl-ethanamine:

[0711]

[0712] Scheme 14, step 1. 2-[4-[4-Methoxy-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8- yl]pyrazol-l-yl]-N,N-dimethyl-ethanamine: 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:

[0713] 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) under nitrogen atmosphere at room temperature. The mixture was stirred at 110 °C for 1 h. The mixture was cooled to room temperature 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 over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 DCM:methanol) to give the title compound (170 mg, 90% yield) as a black solid.

[0714] LCMS [M+1] = 419.1.

[0715] 1 H 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).

[0716] Example 20. 2-[4-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]pyrazol- 1-yl]-N,N-dimethyl-ethanamine Scheme 14, step 1. 7-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-3,4- dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester:

[0717] 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) under nitrogen atmosphere at room temperature. The mixture was stirred at 110 °C for 1 h. The mixture was cooled to room temperature 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 over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 DCM:methanol) to give the title compound (170 mg, 90% yield) as a black solid.

[0718] LCMS [M+1, M+3] = 423.3, 425.2.

[0719] 1 H 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).

[0720] 4-Chloro-8-(l,2,3,4-tetrahydroisoquinolin-7-yl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indole: Example 20. 2-[4-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]pyrazol- 1-yl]-N,N-dimethyl-ethanamine

[0721]

[0722] Scheme 14, step 1. 4-Chloro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrimido[5,4-b]indole: Scheme 14, step 2. 4-Chloro-8-(6-methylpyridazin-3-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole:

[0723] To 4-chloro-8-iodo-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indole (50.0 mg, 121.4 pmol, 1.0 equiv) and 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro-lH- isoquinoline-2-carboxylic acid tert-butyl ester (39.2 mg, 109.3 pmol, 0.9 equiv) in DMF (0.5 mL) and H2O (0.1 mL) was added Pd(PPh3)2Cl2 (8.5 mg, 12.1 pmol, 0.1 equiv) and K2CO3 (50 mg, 364 pmol, 3.0 equiv). The mixture was stirred at 50 °C for 30 min. 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 over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TCL (SiO2, 3: 1 petroleum ether: ethyl acetate) to give the title compound (50.0 mg, 80% yield) as a white solid.

[0724] LCMS [M+1, M+3] = 517.3, 519.4.

[0725] Example 20. 2-[4-[4-Chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]pyrazol- 1-yl]-N,N-dimethyl-ethanamine

[0726] tert-Butyl 7-[4-chloro-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-8-yl]-3,4- dihydro-lH-isoquinoline-2-carboxylate (45.0 mg, 87.0 μmol, 1.0 equiv) was treated with HC1 (2.0 mL; 4 M in dioxane) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with acetonitrile, the mixture was filtered, and the filter cake was concentrated under reduced pressure to afford the title compound (30.0 mg, 83% yield; HC1 salt) as a white solid.

[0727] LCMS [M+1, M+3] = 417.0, 419.0.

[0728] 1 H 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).

[0729] Step 1. l-[4-Methoxy-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimido[5,4-b]indol-8-yl]-N,N- dimethyl-methanamine: Step 1. l-[4-Methoxy-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimido[5,4-b]indol-8-yl]-N,N- dimethyl-methanamine:

[0730]

[0731] Step 2. l-[4-Chloro-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimido[5,4-b]indol-8-yl]-N,N- dimethyl-methanamine: Step 3. 4-Chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol- 2-carbaldehyde:

[0732] 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'- bis(l,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 under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature 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.

[0733] LCMS [M+1, M+3] = 412.1, 414.1.

[0734] 1 H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 2H), 8.19 (dd, J = 0.8, 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 5.37 (q, J = 8.0 Hz, 2H), 1.28 - 1.25 (m, 12H).

[0735] Step 3. 4-Chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol- 2-carbaldehyde: ​

[0736] To a solution of 3-bromo-6-methylpyridazine (42 mg, 243 pmol, 2.0 equiv), K2CO3 (50 mg, 364 pmol, 3.0 equiv), 4-chloro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(2,2,2- trifluoroethyl)-5H-pyrrolo[5,4-b]indole (50.0 mg, 121.4 pmol, 1.0 equiv) in dioxane (0.5 mL) and H2O (0.1 mL) was added Pd(dppf)Cl2-CH2Cl2 (9.9 mg, 12.1 pmol, 0.1 equiv). The mixture was degassed with nitrogen, then stirred at 90 °C for 4 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The residue was triturated with acetonitrile and filtered to give the title compound (20.0 mg, 44% yield) as a gray solid.

[0737] LCMS [M+1, M+3] = 378.1, 380.1.

[0738] 1 H 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).

[0739] Table 13. The examples in Table 13 were prepared in a similar manner as described for Examples 204, 205, or 206, following Scheme 14.

[0740]

[0741]

[0742]

[0743]

[0744] ​ ​

[0745]

[0746] ​ ​

[0747] A mixture of 1-[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. Pd(PPh3)4(620 mg, 537 μmol, 0.1 equiv) was then added and the mixture was degassed again with nitrogen. The mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature 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 give the title compound (1.0 g, 36% yield) as a yellow solid.

[0748] LCMS [M+1] = 365.4.

[0749] ​ ​

[0750] A solution of 1-[4-methoxy-5-(2,2,2-trifluoroethyl)-2-vinyl-pyrimido[5,4- b]indol-8-yl]-N,N-dimethyl-methanamine (200 mg, 549 μmol, 1 equiv) in phosphoryl dichloride benzene (2 mL) was stirred at 120 °C for 1 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHC03solution. 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 Na2S04, 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.

[0751] LCMS [M+1, M+3] = 369.5, 371.5.

[0752] ​ ​

[0753] To a solution of 1-[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 H20 (2.5 mL) was added K2Os04.H20 (22.5 mg, 61 pmol, 0.05 equiv), NaI04(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 h. The reaction was diluted with ethyl acetate, filtered, concentrated under reduced pressure to give the title compound (450.0 mg, 99% yield) as a yellow solid which was used in the next step without further purification.

[0754] LCMS [M+1, M+3] = 371.3, 373.3.

[0755] Step 4. N-[[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methyl]-2-methoxy-4-methylsulfonylaniline: Indol-2-yl]methyl]-2-methoxy-4-methylsulfonylaniline:

[0756] 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 room temperature for 2 h. The mixture was diluted with water and the mixture was extracted with ethyl acetate. The extract was dried over Na2S04, filtered and concentrated. The residue was purified by preparative HPLC (Column 1 : Phenomenex luna C18 80 mm x 30 mm x 3 pm; mobile phase: 15-45% acetonitrile in water (+0.04% HC1), then second purification on Column 2: Waters Xbridge BEH C18 100 mm x 30 mm x 10 pm; mobile phase: 30-60% acetonitrile in water (+10 mM NH4HC03)) to give the title compound (10.4 mg, 50% yield) as a white solid.

[0757] LCMS [M+1, M+3] = 556.0, 558.0.

[0758] 1 H NMR (400 MHz, DMSO-d6) δ = 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).

[0759] Example 222. N-[[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-2-yl]methyl]-1-methylpyrazol-4-amine Indol-2-yl]methyl]-2-methoxy-4-methylsulfonylaniline:

[0760] Example 223. 4-chloro-8-[(dimethylamino)methyl]-N-[2-(1-methylpyrazol-4-yl)ethyl]-5-(2,2, 2-trifluoroethyl)pyrimido[5,4-b]indol-2-amine

[0761]

[0762] The title compound was prepared in a similar manner as described in Example 221.

[0763] LCMS [M+1, M+3] = 452.0, 454.0.

[0764] 1 H NMR (400 MHz, DMSO-d6) δ = 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).

[0765] Indol-2-yl]methyl]-2-methoxy-4-methylsulfonylaniline: Step 1. 8-[(dimethylamino)methyl]-2-[2-(1-methylpyrazol-4-yl)ethylamino]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-4-ol:

[0766]

[0767] Step 2. 4-chloro-8-[(dimethylamino)methyl]-N-[2-(1-methylpyrazol-4-yl)ethyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine: Example 224. N-benzyl-4-chloro-8-[(dimethylamino)methyl]-N-methyl-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine

[0768] 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 h. The reaction was cooled to room temperature and quenched with H2O (10 mL). The mixture was filtered, the filter cake was washed with H2O (30 mL), and dried under vacuum to give the title compound (200 mg, 59% yield) as a brown oil. This material was used without further purification in the next step.

[0769] LCMS: [M+1] = 448.2.

[0770] Indol-2-yl]methyl]-2-methoxy-4-methylsulfonylaniline: Step 1. 2-[benzyl(methyl)amino]-8-[(dimethylamino)methyl]-5-(2,2,2-trifluoroethyl)pyrimido [5,4-b]indol-4-ol:

[0771] POCI3 (1.5 mL) was added 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 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100 mm x 40 mm x 3 pm; mobile phase: 15-45% acetonitrile in water (+0.04% HC1)) to give the title compound (15.1 mg, 15% yield; hydrochloride salt) as a green solid.

[0772] LCMS: [M+1, M+3] = 466.2, 468.

[0773] 1 H NMR (400 MHz, DMSO-d6) d 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 (br t, J = 7.2 Hz, 2H), 2.75 - 2.69 (m, 8H).

[0774] Step 2. N-benzyl-4-chloro-8-[(dimethylamino)methyl]-N-methyl-5-(2,2,2-trifluoroethyl)pyrimido [5,4-b]indol-2-amine: Example 229. 4-chloro-8-[(dimethylamino)methyl]-N-(1-methylpyrazol-4-yl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine

[0775] Indol-2-yl]methyl]-2-methoxy-4-methylsulfonylaniline:

[0776]

[0777] Step 1. 8-[(dimethylamino)methyl]-4-methoxy-N-(1-methylpyrazol-4-yl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine: Step 2. 4-chloro-8-[(dimethylamino)methyl]-N-(1-methylpyrazol-4-yl)-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-2-amine:

[0778] N-methyl-1-phenyl-methanamine (2.0 mL, 15.5 mmol, 28.8 equiv) and 1-[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 μmol, 1 equiv) were combined in a flask and the mixture was stirred at 120 °C for 4 hours. The reaction mixture was cooled to room temperature and quenched with H2O (5 mL). The mixture was extracted with EtOAc (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 (200 mg, 84% yield) as a white solid.

[0779] LCMS: [M+H] = 444.4.

[0780] Example 233. 2-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)-N,N- dimethylethan-1-amine Step 1. 4-methoxy-5-(2,2,2-trifluoroethyl)-8-vinyl-5H-pyrimido[5,4-b]indole:

[0781] POCl3(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 μmol, 1.0 equiv) and the mixture was stirred at 110 °C for 2 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 9 by the addition of saturated aqueous NaHCO3solution. The aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 mm x 50 mm x 10 μm; mobile phase: 60-95% acetonitrile in water (+10 Mm NH4HCO3)) to afford the title compound (25.0 mg, 12% yield) as a white solid.

[0782] LCMS: [M+H, M+3] = 462.2, 464.1.

[0783] 1HNMR (400 MHz, DMSO-d6) δ 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).

[0784] Table 14. The examples in Table 14 were prepared in a similar manner as described above for Example 223 or Example 224.

[0785]

[0786]

[0787] Step 2. 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)ethan-1-ol: Step 3. 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)ethanal:

[0788] ​

[0789]

[0790] ​ ​

[0791] 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 μmol, 1 equiv), 1- methylpyrazol-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(ll)-dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl] phosphine methanesulfonate (45 mg, 53.7 μmol, 0.1 equiv) at room temperature under a nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature and quenched with H2O (1 mL). The mixture was extracted with EtOAc (3 x 1 mL). The combined organic layers were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, 10:1 ethyl acetate:methanol) to afford the title compound (145 mg, 62% yield) as a yellow solid.

[0792] LCMS: [M+H] = 434.3.

[0793] ​ ​

[0794] POCI3 (2.0 mL, 21.5 mmol, 71.5 eq) 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 μmol, 1 eq) and the mixture was stirred at 110 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100 mm x 40 mm x 3 μm; mobile phase: 10-40% acetonitrile in water (+0.04% HC1)) to give the title compound (24.8 mg, 19% yield; hydrochloride salt) as a white solid.

[0795] LCMS: [M+1, M+3] = 438.2, 440.1.

[0796] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0797] Table 15. The examples in Table 15 were prepared in a similar manner as described above for Example 229.

[0798]

[0799]

[0800] ​ ​

[0801]

[0802] ​

[0803] 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)Cl2-CH2Cl2 (187 mg, 228 μmol, 0.1 equiv) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.0 g, 45.6 mmol, 7.7 mL, 20.0 equiv). The mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature 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 give the title compound (520 mg, 74% yield) as a white solid.

[0804] LCMS [M+1] = 308.2.

[0805] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0806] ​ ​

[0807] 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 in THF). The mixture was then stirred at room temperature for 16 hours. The mixture was then cooled to 0 °C and 1 M aqueous NaOH (220.0 pL, 6.2 equiv) and H2O2 (241 pL, 2.5 mmol, 7.0 equiv; 30% aqueous solution) were added. The mixture was stirred at room temperature for 30 minutes. At 0 °C the mixture was quenched with saturated aqueous Na2SO3 (10 mL). 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 give the title compound (510 mg) as a white solid.

[0808] LCMS [M+1] = 326.1.

[0809] 1 H NMR (400 MHz, Chloroform-d) d 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, J = 6.4 Hz, 3H).

[0810] ​

[0811] To a solution of 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8- yl)ethan-1-ol (400 mg, 1.2 mmol, 1.0 equiv) in acetonitrile (8.0 mL) was added 2- iodobenzoic acid (999 mg, 3.5 mmol, 2.9 equiv). The mixture was stirred at 80 °C for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in petroleum ether) to give the title compound (120 mg, 30% yield) as a white solid.

[0812] LCMS [M+1] = 310.1.

[0813] 1H NMR (400 MHz, Chloroform-d) δ 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).

[0814] Step 4. 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-8-yl)-N,N- dimethylethan-1 -amine: Step 5. 2-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-8-yl)-N,N- dimethyl

[0815] 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 mL) was added N- methylaniline (310 pL, 2.0 equiv; 2M in THF) and AcOH (35 pL, 619 pmol, 2.0 equiv). The mixture was stirred at room temperature for 1 h, then NaBH3CN (23 mg, 371 pmol, 1.2 equiv) was added. The mixture was stirred at room temperature for 1 h. The mixture was poured into H2O (30 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 preparative TEC (SiO2, 5: 1 ethyl acetate: MeOH) to give the title compound (40.0 mg, 37% yield) as a white solid.

[0816] LCMS [M+1] = 353.1.

[0817] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0818] Step 5. 2-(4-chloro-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-8-yl)-N,N- dimethyl Example 234. N-[[4-chloro-8-[(dimethylamino)methyl]-5-(2,2,2- trifluoroethyl)pyrrolo[5,4-b]indol-2-yl]methyl]-1 -methylpyrazol-4-amine

[0819] A solution of 2-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indol-8-yl)-N,N-dimethylethan-1-amine (40.0 mg, 113.5 pmol, 1.0 equiv) in phosphoryl dichloride benzene (1.5 mL) was stirred at 160 °C for 2 h. The mixture was cooled to rt and quenched with saturated aqueous NaHC03(50 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPEC (column: Welch ultimate C18 150 mm x 25 mm x 7 pm; mobile phase: 10-40% acetonitrile in water (+ 0.2% formic acid)) to give the title compound (5.3 mg, 13% yield) as a white solid.

[0820] LCMS [M+1, M+3] = 357.0, 359.0.

[0821] 1 H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.53 (br s, 1H), 8.24 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 5.34 (q, J = 8.0 Hz, 2H), 3.12-3.05 (m, 2H), 2.85-2.76 (m, 2H), 2.45 (s, 6H).

[0822] Step 1. 8-iodo-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-4-ol: Step 2. 8-(1 -methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(2,2,2-trifluoroethyl)-5H- pyrrolo[5,4-b]indol-4-ol:

[0823]

[0824] The title compound was prepared in a similar manner as described in Example 233.

[0825] LCMS [M+1, M+3] = 412.0, 414.0.

[0826] 1 H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.53 (br s, 1H), 8.24 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 5.34 (q, J = 8.0 Hz, 2H), 3.12-3.05 (m, 2H), 2.85-2.76 (m, 2H), 2.45 (s, 6H).

[0827] Example 235. 4-Chloro-8-(1-methyl-4-piperidinyl)-5-(2,2,2-trifluoroethyl)- pyrimido[5,4-b]indole

[0828]

[0829] Step 3. 8-(1 -methylpiperidin-4-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-4- ol:

[0830] 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 aqueous NaOH (8.02 mL, 3 equiv; 1 M). The mixture was stirred at 80 °C for 18 h. The reaction mixture was cooled to rt and poured into water (20 mL). The mixture was extracted with ethyl acetate (3 x 15 mL), the combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound (1.0 g) as a white solid. This material was used without further purification in the next step.

[0831] LCMS [M+1] = 394.0.

[0832] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0833] Step 4. 4-chloro-8-(1 -methyl-4-piperidinyl)-5-(2,2,2-trifluoroethyl)pyrrolo[5,4- b]indole Example 236 and 237. 4-chloro-8-[(3R)-1 -methyl-3-piperidinyl]-5-(2,2,2- trifluoroethyl)pyrrolo[5,4-b]indole and 4-chloro-8-(3S)-1 -methyl-3-piperidinyl]-5- (2,2,2-trifluoroethyl)pyrrolo[5,4-b]indole

[0834] 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 Na2CO3 (121 mg, 1.14 mmol, 3 equiv) and Pd(dppf)Cl2 (28 mg, 38.2 pmol, 0.1 equiv). The mixture was stirred at 100 °C for 1.5 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 pm; mobile phase: 1-31% acetonitrile in water (+ formic acid modifier)) to give the title compound (86 mg, 62% yield) as a white solid.

[0835] LCMS [M+1] = 363.3.

[0836] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0837] Step 1. 5-[4-hydroxy-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-8-yl]-3,6-dihydro- 2H-pyridine-1 -carboxylic acid tert-butyl ester: Step 2. 3-(4-hydroxy-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-8-yl)piperidine-1 - carboxylic acid tert-butyl ester:

[0838] 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 PtO2 (260 mg, 1.1 mmol, 5.0 equiv) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at rt under hydrogen atmosphere (15 psi) for 2 h. The reaction mixture was filtered and concentrated to give the title compound (65.0 mg, crude) as a brown solid.

[0839] LCMS [M+1] = 365.2.

[0840] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0841] Step 3. 8-(piperidin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-4-ol:

[0842] A solution of 8-(1-methyl-4-piperidinyl)-5-(2,2,2-trifluoroethyl)pyrimido[5,4- b]indol-4-ol (60 mg, 165 μmol, 1 eq) in POCl3(0.5 mL) was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 150 mm x 25 mm x 10 μm; mobile phase: 0-27% acetonitrile in water (+ formic acid modifier)) to give the title compound (10.4 mg, 17% yield) as a yellow solid.

[0843] LCMS [M+1, M+3] = 383.0, 384.9.

[0844] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0845] Step 4. 8-[(3R)-1 -methyl-3-piperidinyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-4- ol and 8-[(3S)-1 -methyl-3-piperidinyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indol-4- ol: Step 5. 4-chloro-8-[(3R)-1 -methyl-3-piperidinyl]-5-(2,2,2-trifluoroethyl)pyrrolo[5,4- b]indole:

[0846]

[0847] Step 5. 4-chloro-8-[(3S)-1 -methyl-3-piperidinyl]-5-(2,2,2-trifluoroethyl)-pyrrolo[5,4- b]indole: Example 238 and 239. (R)-4-chloro-8-(1 -(4-methylpiperazin-1 -yl)ethyl)-5-(2,2,2- trifluoroethyl)pyrrolo[5,4-b]indole and (S)-4-chloro-8-(1 -(4-methylpiperazin-1 -yl)ethyl)- 5-(2,2,2-trifluoroethyl)pyrrolo[5,4-b]indole

[0848] To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-l -carboxylate (189 mg, 611 μmol, 1.2 equiv) and 8-iodo-5-(2,2,2- trifluoroethyl)-5H-pyrrolo[5,4-b]indol-4-ol (200 mg, 509 μmol, 1.0 equiv) in dioxane (2.0 mL) and H20 (0.4 mL) was added Na2C03(161.7 mg, 1.5 mmol, 3.0 equiv) and Pd(dppf)Cl3(37.2 mg, 50.9 μmol, 0.1 equiv) under nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h. The mixture was cooled to room temperature 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 over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in petroleum ether) to give the title compound (350 mg, 63% yield) as a yellow solid.

[0849] LCMS [M+1] = 449.1.

[0850] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0851] ​ ​

[0852] To the reaction flask was added 10% Pd / C (831 mg, 781 μmol, 1.0 equiv) under argon protection and methanol (2.0 mL) was added to immerse the catalyst. Then a solution of tert-butyl 5-[4-hydroxy-5-(2,2,2-trifluoroethyl)pyrrolo[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 three times. The mixture was stirred at 40 °C under hydrogen atmosphere for 12 h. The reaction mixture was filtered and concentrated to give the title compound (300 mg, 75% yield) as a yellow solid.

[0853] LCMS [M+1] = 451.1.

[0854] 1 H 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).

[0855] ​

[0856] HCl (3.0 mL, 18.0 eq; 4 M solution in dioxane) was added to a flask containing tert-butyl 3-(4-hydroxy-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4-b]indol-8- yl)piperidine-1-carboxylate (300 mg, 666 µmol, 1.0 eq). The mixture was stirred at room temperature 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.

[0857] LCMS [M+1] = 351.2.

[0858] 1 H 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).

[0859] ​ ​

[0860] To a solution of 8-(piperidin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indol-4-ol (230 mg, 657 pmol, 1.0 equiv) in DCM (11.5 mL) and methanol (9.2 mL) was added formaldehyde (145 pL, 5.2 mmol, 8.0 equiv; 37% aqueous solution) at room temperature. After 1 h, NaBH(OAc)3 (1.1 g, 5.6 mmol, 8.0 equiv) was added and the mixture was stirred at room temperature for 2 h. Saturated aqueous NaHC03 was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm x 10 pm); mobile phase: 30% methanol in C02(+0.1% NH3-H20)) to give 8-[(3R)-1 -methyl-3-piperidinyl]-5-(2,2,2- trifluoroethyl)pyrimido[5,4-b]indol-4-ol (85.0 mg, 35% yield).

[0861] LCMS [M+1] = 365.1.

[0862] 1 H NMR (400 MHz, Methanol-d4) d 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).

[0863] and 8-[(3S)-1 -methyl-3-piperidinyl]-5-(2,2,2-trifluoroethyl)pyrimido[5,4-b]indol-4-ol (88.0 mg, 36% yield).

[0864] LCMS [M+1] = 365.1.

[0865] 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).

[0866] ​ ​

[0867] POCI3 (1.0 mL) was added to a flask containing 8-[(3R)-1 -methyl-3- piperidinyl]-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 room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 μm; mobile phase: 12-42% acetonitrile in water (+ formic acid modifier)) to give the title compound (22.5 mg, 42% yield; formate salt) as a white solid.

[0868] LCMS [M+1, M+3] = 383.0, 385.0

[0869] 1 H 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).

[0870] ​ ​

[0871] POCI3 (1.0 mL) was added to a flask containing 8-[(3S)-1 -methyl-3- piperidinyl]-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 room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 μm; mobile phase: 12-42% acetonitrile in water (+ formic acid modifier)) to give the title compound (18.8 mg, 35% yield; formate salt) as a white solid.

[0872] LCMS [M+1, M+3] = 383.0, 385.0.

[0873] 1 H 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).

[0874] ​ (R)-4-chloro-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido [5,4-b]indole

[0875] Step 1. 1-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indol-8-yl)ethan-1-

[0876]

[0877] one: Step 2. 4-methoxy-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole:

[0878] To a solution 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 room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and poured into saturated aqueous KF solution (15 ml). The mixture was then 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 give the title compound (350 mg, 79% yield) as a yellow solid.

[0879] LCMS: [M+1] = 324.1.

[0880] 1 H 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).

[0881] Step 3. (R)-4-chloro-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole: Step 3. (R)-4-chloro-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole:

[0882] To a solution of 1-methylpiperazine (137 μL, 1.2 mmol, 2.0 equiv) in titanium(IV) isopropoxide (2.0 mL) was added 1-(4-methoxy-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4- b]indol-8-yl)ethan-1-one (200 mg, 619 μmol, 1.0 equiv) at room temperature. The mixture was stirred at 90 °C for 1 h, then NaBH3CN (311 mg, 4.9 mmol, 8.0 equiv) was added. The mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature 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 give the title compound (170 mg, 65% yield) as a yellow oil.

[0883] LCMS: [M+1] = 408.3.

[0884] The racemic title compound was separated by SFC (Column: DAICEL CHIRALPAK IG (250 mm x 30 mm x 10 pm); Mobile phase: 35% methanol in CO2 (+0.1% NH3 / H2O)) to give (R)-4-methoxy-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2- trifluoroethyl)-5H-pyrrolo[5,4-b]indole (80.0 mg, 45% yield):

[0885] 1 H NMR (400 MHz, Chloroform-d) d 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 (S)-4-methoxy-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2- trifluoroethyl)-5H-pyrrolo[5,4-b]indole (60.0 mg, 34% yield):

[0886] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0887] Step 3. (R)-4-chloro-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H- pyrimido[5,4-b]indole: Example 24 0.2-[4-chloro-8-[(dimethylamino)methyl]pyrimido[5,4-b]indol-5-yl]acetonitrile

[0888] Phenylphosphinic dichloride (0.8 mL) was added to a flask containing (R)-4- methoxy-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4- b]indole (80.0 mg, 196.3 pmol, 1.0 equiv) and the mixture was stirred at 140 °C for 2 h. The mixture was cooled to room temperature and poured into saturated aqueous NaHC03solution. The pH was adjusted to 7 by the addition of solid NaHC03. The aqueous phase was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: 10-40% acetonitrile in water (+ formic acid modifier)) to give the title compound (6.8 mg, 8% yield) as a colorless oil.

[0889] LCMS: [M+1, M+3] = 412.0, 414.0.

[0890] 1 H NMR (400 MHz, Chloroform-d) d 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).

[0891] Step 1. (4-chloro-5H-pyrimido[5,4-b]indol-8-yl)methanol: Step 2. 4-chloro-5H-pyrimido[5,4-b]indole-8-carbaldehyde:

[0892] Phenylphosphinic dichloride (0.8 mL) was added to a flask containing (S)-4- methoxy-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrrolo[5,4- b]indole (60.0 mg, 147.2 pmol, 1.0 equiv), and the mixture was stirred at 140 °C for 2 h. The mixture was cooled to room temperature and poured into saturated aqueous NaHC03solution. The pH was adjusted to pH = 7 by the addition of solid NaHC03. The aqueous phase was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 pm; mobile phase: 10-40% acetonitrile in water (+ formic acid modifier)) to give the title compound (6.6 mg, 10% yield) as a colorless oil.

[0893] LCMS: [M+1, M+3] = 412.3, 414.3.

[0894] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0895] Step 3. 2-(4-chloro-8-formyl-pyrimido[5,4-b]indol-5-yl)acetonitrile:

[0896]

[0897] Step 4. 2-[4-chloro-8-(dimethylamino)methyl]pyrimido[5,4-b]indol-5-yl]acetonitrile:

[0898] 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 nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding H2O (1.3 mL), 15% aqueous NaOH solution (1.3 mL) and H2O (3.9 mL) successively at 0 °C. After stirring at room temperature for 10 min, 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 give the title compound (800 mg, yield 69%) as a yellow solid.

[0899] LCMS: [M+1, M+3] = 234.1, 236.1.

[0900] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0901] Y220C TP53 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-[[3-methoxy-4-[3-[4-(tetrahydro-pyran-4-ylamino)-1- piperidinyl]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]pentanamide

[0902] A mixture of (4-chloro-5H-pyrimido[5,4-b]indol-8-yl)methanol (200.0 mg, 0.86 mmol, 1.0 equiv) and Mn02(744.1 mg, 8.5 mmol, 10 equiv) in DCE (6.0 mL) was degassed with nitrogen, then the mixture was stirred at 70 °C for 1 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (120 mg, 61% yield) as a yellow solid.

[0903] LCMS: [M+1, M+3] = 232.1, 234.1.

[0904] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0905] Preparation of (R)-4-chloro-8-(1-(4-methylpiperazin-1-yl)ethyl)-5-(2,2,2-trifluoroethyl)-5H-pyrimido[5,4-b]indole

[0906] 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 added to DMF (1.0 mL) and stirred at 50 °C for 3 h. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with brine, dried over Na2S04and concentrated under reduced pressure to give the title compound (60 mg, 51% yield) as a white solid.

[0907] LCMS: [M+1, M+3] = 271.1, 273.1.

[0908] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0909] BP1 synthesis, step 1a, 2-iodo-4-nitro-1-(2,2,2-trifluoroethyl)indole:

[0910] 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 room temperature for 30 min. NaBH(OAc)3 (78.3 mg, 369 pmol, 2.5 equiv) was then added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 pm; mobile phase: 0-27% acetonitrile in water (+ formic acid modifier)) to give the title compound (13.7 mg, 30% yield) as a yellow solid.

[0911] LCMS: [M+1, M+3] = 300.1, 302.0.

[0912] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0913] BP1 synthesis, step 2a, 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine: BP1 synthesis, step 3a, 2-iodo-N-tetrahydro-pyran-4-yl-1-(2,2,2-trifluoroethyl)indol-4-amine: BP1 synthesis, step 1b, tert-butyl N-[2-[2-[2-[2-[(3-methoxy-4-nitro-phenyl)sulfonylamino]ethoxy]ethoxy]- ethoxy]ethyl]carbamate: BP1 synthesis, step 2b, tert-butyl N-[2-[2-[2-[2-[(4-amino-3-methoxy-phenyl)sulfonylamino]ethoxy]ethoxy]- ethoxy]ethyl]carbamate:

[0914]

[0915] BP1 synthesis, step 2b, tert-butyl N-[2-[2-[2-[2-[(4-amino-3-methoxy-phenyl)sulfonylamino]ethoxy]ethoxy]- ethoxy]ethyl]carbamate:

[0916] 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) portionwise at 0 °C and stirred at 0 °C for 30 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (9.6 g, 41.0 mmol, 4.0 equiv) was added to the reaction mixture portionwise at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (20 mL) and the resulting mixture was partitioned between EtOAc (200 mL) and H2O (200 mL), the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, 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 give the title compound (5.0 g, crude) as a yellow solid.

[0917] 1 H 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).

[0918] ​ To a solution of 2-iodo-4-nitro-l-(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 NH4CI (687 mg, 12.8 mmol, 2.5 equiv). The mixture was stirred at 80 °C for 2 h. The reaction solution was filtered through a pad of celite and the filtrate was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (1.7 g, 97% yield) as a yellow solid.

[0919] LCMS [M+1] = 341.1.

[0920] ​To a solution of 2-iodo-l-(2,2,2-trifluoroethyl)indol-4-amine (600 mg, 1.7 mmol, 1.0 eq) in DMF (10 mL) was added chloro(trimethyl)silane (559.8 μL, 4.4 mmol, 2.5 eq) and tetrahydropyran-4-one (648.1 μL, 7.0 mmol, 4.0 eq). The mixture was stirred at 0 °C for 2 h. Borane-tetrahydrofuran complex (1 M, 8.8 mL, 5.0 eq) was added to the mixture under N2, and the resulting mixture was stirred at 0-20 °C for 12 h. The reaction was poured into saturated aqueous NH4Cl (1.5 ml), extracted with EtOAc (3 x 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (600 mg, 80% yield) as a white solid.

[0921] 1 H 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).

[0922] LCMS [M+1] = 425.1.

[0923] ​ ​ To a solution of tert-butyl N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]- ethyl]carbamate (906 mg, 3.1 mmol, 1.3 eq) in DCM (15 mL) was added TEA (1.6 mL, 11.9 mmol, 5.0 eq) and 3-methoxy-4-nitro-benzenesulfonyl chloride (600 mg, 2.4 mmol, 1.0 eq). The mixture was stirred at 15 °C for 1 h. 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 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.1 g, 91% yield) as a brown oil.

[0924] 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).

[0925] LCMS [M+1] = 408.2.

[0926] ​ ​ 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 h. The suspension was filtered through a pad of celite and the filter cake was washed with EtOH (3 x 20 mL). The filtrate was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was then re-extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.5 g, 80% yield) as a brown oil.

[0927] 1 H 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).

[0928] LCMS [M+1] = 378.3.

[0929] BP1 synthesis, step 3b, N-[2-[2-[2-[2-[[3-methoxy-4-(3-trimethylsilanylprop-2-ynylamino) phenyl]-sulfonylamino]ethoxy]ethoxy]ethoxy]ethyl]carbamic acid tert-butyl ester: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- trimethylsilanylprop-2-yne (396 mg, 3.1 mmol, 1.0 equiv). The mixture was stirred at 35 °C for 17 h, 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 h. The reaction mixture was diluted with EtOAc (50 mL) and H2O (30 mL), and the aqueous layer was extracted with EtOAc (2 x 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 (250 mm x 70 mm x 15 um); mobile phase: 40-75% ACN in water (+ NH4HCO3 modifier)) to give the title compound (480 mg, 26% yield) as a white solid.

[0930] 1 H 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).

[0931] LCMS [M+1] = 488.4.

[0932] BP1 synthesis, step 4b, N-[2-[2-[2-[2-[[3-methoxy-4-(prop-2-ynylamino)phenyl]sulfonyl amino]-ethoxy]ethoxy]ethoxy]ethyl]carbamic acid tert-butyl ester:To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-(3- trimethylsilanylprop-2-ynylamino)phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy] ethyl]carbamate (580.0 mg, 986.7 pmol, 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 h. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (30 mL), and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 79% yield) as off-white oil.

[0933] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0934] LCMS [M+1] = 416.3.

[0935] BP1 synthesis, step 5b, N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4-(tetrahydro-pyran-4-ylamino)- 1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]phenyl]sulfonylamino]ethoxy]ethoxy]ethoxy ethyl]carbamic acid tert-butyl ester:To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-(prop-2-ynylamino)phenyl]sulfonylamino]ethoxy]- ethoxy]ethoxy]ethyl]carboxylate (200 mg, 388 pmol, 1.0 equiv) in ACN (2.0 mL) was added dichloro-palladium-triphenylphosphine (27.2 mg, 38.7 pmol, 0.1 equiv) and cuprous iodide (I) (7.4 mg, 38.8 pmol, 0.1 equiv), 2-iodo-N-tetrahydropyran-4-yl-1-(2,2,2-trifluoroethyl)indol-4-amine (165 mg, 388 pmol, 1.0 equiv), and triethylamine (162 pL, 1.1 mmol, 3.0 equiv) under a nitrogen atmosphere. The mixture was stirred at 70 °C for 2 h. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (200 mg, 64% yield) as a white solid.

[0936] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0937] LCMS [M+1] = 812.3.

[0938] BP1 synthesis, step 6b, N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]-3-methoxy-4-[3-[4- (tetrahydro-pyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]benzene- sulfonamide:To a solution of tert-butyl N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4-(tetrahydro- pyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]phenyl]sulfonyl- amino]ethoxy]ethoxy]ethoxy]-ethyl]aminocarboxylate (200 mg, 246 pmol, 1.0 equiv) in DCM (0.6 mL) was added TFA (0.8 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (150 mg, 86% yield) as a brown oil. The crude product was used directly in the next step.

[0939] LCMS [M+1] = 712.4.

[0940] BP1 synthesis, step 7b, TR-FRET binding probe, BP1, 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6, 6a-hexahydro-thieno[3,4-d]imidazol-4-yl]-N-[2-[2-[2-[2-[[3-methoxy-4-[3-[4-(tetrahydro-pyran- 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- (tetrahydro-pyran-4-ylamino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]benzene- sulfonamide (40.0 mg, 56.2 pmol, 1.0 equiv) in DCM (1 mL) was added TEA (28.4 mg, 281 pmol, 39.1 pL, 5.0 equiv) and (2,5-dioxopyrrolidin-1-yl) 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,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 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Luna C18 200mm x 40mm x 10um; mobile phase: 35-70% ACN in water (+ formic acid modifier)) to give the title compound (11.2 mg, 21% yield) as a white solid.

[0941] 1H NMR (400 MHz, DMSO-d6) δ 7.80 (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).

[0942] LCMS [M+1] = 938.3.

[0943] Bioassay

[0944] Compounds were evaluated for potency (IC50) in a TR-FRET binding assay measuring the binding of biotinylated small molecule probe BP1 to Y220C TP53 mutant DBD 50). Specifically, 5 pL of a mixture consisting of 10 mM KH2PO4 pH 7.2, 32 nM BP1 and 48 nM Streptavidin-d2 (Cisbio), 150 mM NaCl, 0.01% BSA, 0.01% Tween-20 and 0.1 mM TCEP, was added to a 384 well plate containing a 10 point dose response titration of test compounds in duplicate in 60 nL DMSO (0.6% f.c. DMSO (v / v)). Another 5 microliter mixture consisting of 10 mM KH2PO4 pH 7.2, 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), 150 mM NaCl, 0.01% BSA, 0.01% Tween-20 and 0.1 mM TCEP was added to a 384 well plate. The mixtures were incubated at 20 °C. The TR-FRET reaction was monitored after 4 hours and 24 hours of incubation of the BP1 mixture and the compound mixture. The plates were read using an EnVision plate reader (Perkin Elmer) at Ex / Em 615 / 665. To determine the potency (IC 50 ) of the test compounds (competing binding to the TP53 Y220C protein in the presence of the biotinylated probe BP1), the TR-FRET ratio was normalized to the average ratio of the DMSO control wells (0% inhibition) and the average minimum ratio obtained with a 5 micromolar BP1 positive control compound (100% inhibition). The test compound dose responses were fitted using a non-linear regression with a 4-parameter fit, providing the IC 50 value and the nHill slope. The results are shown in Table 5 below and are expressed in the ranges described here: A: IC 50 < 0.100 pM; % inhibition > 90%; B: IC 50 = 0.100 - 1.00 pM; % inhibition = 70 - 90%; C: IC 50 = 1.00 - 10.0 pM; % inhibition = 50 - 70%; D: IC 50 = 10.0 - 60.0 pM; % inhibition = 10 - 50%; E: IC 50 > 60.0 pM; % inhibition < 10%.

[0945] The above TR-FRET assay can be used to assess the binding affinity of reversible and covalent TP53 Y220C ligands, stabilizers, and correctors, and can also distinguish reversible and covalent TP53 Y220C ligands, stabilizers, and correctors. To validate the TR-FRET assay described above, we characterized TP53 Y220C ligands, stabilizers, and correctors previously described in the scientific literature. Compounds PK9301 and PK9323 described by Joerger et al. (ACS Chem. Biology 2020, 15, 657-668) have been shown to bind to TP53 Y220C by X-ray crystallography and judged to stabilize the mutant protein by differential scanning fluorimetry (DSF), and in the above TR-FRET binding assay, IC 50 = 1.5 μΜ and 4.1 μΜ, respectively. Compound PK5196 described by Jeorger, Boeckler et al. (J. Am. Chem. Soc. 2012, 134, 6810-6818) has been shown to bind to TP53 Y220C by X-ray crystallography and judged to stabilize the mutant protein by differential scanning fluorimetry (DSF), nuclear magnetic resonance (NMR), and isothermal titration calorimetry (ITC), and in the above TR-FRET binding assay, IC 50 = 9.7 μΜ. PK9301, PK9323, and PK5196 are all reversible TP53 Y220C ligands / stabilizers, and thus show time-independent activity in the above TR-FRET assay. The same or nearly the same IC 50 values are observed at 4 hour and 24 hour time points. Covalent ligands / modifiers typically have time-dependent activity, as covalent modification of the target protein creates a persistent cumulative effect as the reaction with the protein proceeds. Compounds of Formula I typically exhibit time-dependent displacement of TR-FRET binding probe BP1 from TP53 Y220C, thereby distinguishing them from reversible TP53 Y220C ligands / stabilizers / correctors. We believe that, in some cases, covalent modification of the mutant TP53 Y220C can result in more persistent stabilization of the mutant protein and lead to more robust restoration of wild-type TP53 function relative to reversible ligands. This covalent mechanism of action can be advantageous for small molecule therapeutics directed against diseases associated with or attributed to the TP53 Y220C mutant protein, such as cancer.

[0946] Table 5.

[0947]

[0948]

[0949]

[0950]

[0951] While we have described a number of implementations, it is apparent that our basic example can be altered to provide other implementations that utilize compounds and methods of the present application. Thus, it will be appreciated that the scope of the present application is defined by the following claims rather than by the specific embodiments which are presented above by way of example.

[0952] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are expressly incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

Claims

1. A compound having formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted alkyl; R 2 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NR a R b 、-OR c 、-NHC(O)R c 、-C(O)NR d R e 、-C(O)R f and-SR g ; R 3 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, -NR a1 R b1 、-OR c1 、-NHC(O)R c1 、-C(O)NR d1 R e1 、-C(O)R f1 and-SR g1 ; R 4 is halogen, cyano, optionally substituted alkyl and optionally substituted alkoxy; X is selected from halogen, -S(O)2alkyl and -S(O)alkyl; R a 、R a1 、R b 、R b1 、R c and R c1 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, and optionally substituted heterocyclyl; R d 、R e and R g 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 R d and R e together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R d1 、R e1 and R g1 are 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' 1 R” 1 、-S(O)R' 1 and -S(O)2R' 1 ; or R d1 and R e1 together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R f and R f1 are 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” 1 are each independently selected from hydrogen and optionally substituted (C1-C4)alkyl; and p is 0, 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 0.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is selected from chlorine, bromine, fluorine, -SO2CH3 and -SOCH3.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is selected from chlorine, bromine, fluorine and -SO2CH3.

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

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

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from (C1-C4)alkyl and halogenated (C1-C4)alkyl.

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

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH2CF3.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, halogen, (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], -NR a R b 、-OR c 、-(C1-C4)alkylOR c 、-C(O)R f 、-C(O)NR d R e 、-(C1-C4)alkylNR d R e 、-(C1-C4)alkylNR a C(O)R b 、-(C1-C4)alkylC(O)R f 、-(C1-C4)alkylC(O)NR d R e and-SR g , 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 by 1 to 3 groups selected from R 5 The group substitution; R a 、R b and R c 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, each of said groups is optionally replaced by 1 to 3 groups selected from R 6 The group substitution; R d 、R e and R g Each is 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 R 7 or R d and R e Together with the nitrogen atom to which they are attached, they form a group each optionally substituted by 1 to 3 groups selected from R 7 a 4- to 6-membered heterocyclic group or a 5- to 7-membered heteroaryl group substituted with a group; R f is 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 by 1 to 3 groups selected from R 8 The group substitution; R a 、R 5 、R 6 、R 7 and R 8 each independently selected from halogen, (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 according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 selected from hydrogen, halogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, 5- to 7-membered heteroaryl, phenyl, 4- to 6-membered heterocyclyl, -NR a R b 、-OR c 、-C(O)NR d R e 、-(C1-C4)alkylNR d R e 、-(C1-C4)alkylNR a C(O)R b and -(C1-C4)alkyl C(O)NR d R e , 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 by 1 to 3 groups selected from R 5 substituted by a group.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, halogen, (C1-C4) alkyl, cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, -NR a R b 、-OR c 、-C(O)NR d R e 、-(C1-C4)alkylNR d R e 、-(C1-C4)alkylNR a C(O)R b and -(C1-C4)alkyl C(O)NR d R e wherein the cyclopropyl, pyrazolyl, phenyl, pyrrolidinyl, piperazinyl and piperidinyl are each optionally substituted by 1 to 3 groups selected from R 5 substituted by a group.

13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R a 、R b and R c 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, each of said groups is optionally replaced by 1 to 3 groups selected from R 6 substituted by a group.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 Each is independently selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, -(C1-C4)alkylOR' and S(O)2R'.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, chlorine, 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, 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, chlorine and -OCH2CF3.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2 For hydrogen.

18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from halogen, (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) alkyl, OR c1 , -(C1-C4) alkylphenyl, 4 to 10 membered heterocyclic group, -(C1-C4) alkyl[4 to 10 membered heterocyclic group], -NR a1 R b1 、-NHC(O)R c1 、-OR c1 、-(C1-C4)alkylOR c1 、-C(O)R f1 、-C(O)NR d1 R e1 、-(C1-C4)alkylNR g1 R h1 、-(C1-C4)alkylC(O)R f1 、-(C1-C4)alkylC(O)NR d1 R e1 and-SR g1 , 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 by 1 to 3 groups selected from R 5a The group substitution; R a1 、R b1 and R c1 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, each of said groups is optionally substituted by 1 to 3 groups selected from R 6a The group substitution; R d1 、R e1 、R g1 and R h1 Each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, -(C1-C4) alkyl, OR' 1 、-(C1-C4)alkylNR' 1 R” 1 、-(C1-C4)alkyl C(O)NR' 1 R” 1 、-(C1-C4)alkylC(O)R' 1 、-(C1-C4)alkyl C(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' 1 R” 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, each of said groups is optionally substituted by 1 to 3 groups selected from R 7a or R d1 and R e1 Together with the nitrogen atom to which they are attached, they form a group each optionally substituted by 1 to 3 groups selected from R 7a a 4- to 8-membered heterocyclic group or a 5- to 7-membered heteroaryl group substituted with R f1 is 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 by 1 to 3 groups selected from R 8a The group substitution; R 5a 、R 6a 、R 7a and R 8a Each is independently selected from halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyl, 5 to 7 membered heteroaryl, cyano, -NR' 1 R” 1 、-(C1-C4)alkylNR' 1 R” 1 、-(C1-C4)alkyl C(O)OR' 1 、-(C1-C4)alkyl C(O)NR' 1 R” 1 , oxo, -(C1-C4)alkyl OR' 1 、-C(O)NR' 1 R” 1 、-OR' 1 、C(O)OR' 1 、-C(O)R' 1 、-S(O)R' 1 、-S(O)2R' 1 , optionally 1 to 3 selected from R' 1 a 4- to 6-membered heterocyclic group substituted with a group of R' 1 and R” 1 Each is independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl and 4 to 7 membered heterocyclyl.

19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 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)alkylOR c1 、-NR a1 R b1 、-NHC(O)R c1 、-C(O)R f1 、-C(O)NR d1 R e1 and -(C1-C4)alkylNR g1 R h1 wherein the (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 10-membered heterocyclyl and 4- to 9-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from R 5a substituted by a group.

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from -(C1-C4)alkyl OR c1 , 4- to 10-membered heterocyclic group, -(C1-C4)alkyl[4- to 10-membered heterocyclic group], -NR a1 R b1 、-NHC(O)R c1 、-C(O)R f1 、-C(O)NR d1 R e1 、-(C1-C4)alkylNR g1 R h1 , wherein each 4 to 10 membered heterocyclyl is optionally substituted by 1 to 3 members selected from R 5a substituted by a group.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from -(C1-C4)alkyl OR c1 、-NR a1 R b1 、-NHC(O)R c1 、-C(O)R f1 、-C(O)NR d1 R e1 、-(C1-C4)alkylNR g1 R h1 , -(C1-C4)alkyl[piperazinyl], -(C1-C4)alkyl[piperidinyl], -(C1-C4)alkyl[morpholinyl], -(C1-C4)alkyl[pyrrolinyl], -(C1-C4)alkyl[diazepanyl], -(C1-C4)alkyl[azetidinyl], piperazinyl and tetrahydropyridinyl, wherein the piperidinyl, morpholinyl, pyrrolinyl, diazepanyl, tetrahydropyridinyl, azetidinyl and each occurrence of piperazinyl are optionally replaced by 1 to 3 groups selected from R 5a substituted by a group.

22. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, 5 to 7 membered heteroaryl, -NR' 1 R” 1 、-(C1-C4)alkylNR' 1 R” 1 、-(C1-C4)alkyl C(O)OR' 1 , oxo, -(C1-C4)alkyl OR' 1 、-C(O)NR' 1 R” 1 、-OR' 1 、C(O)OR' 1 、-C(O)R' 1 and optionally 1 to 3 selected from R' 1 A 4- to 6-membered heterocyclic group substituted with 23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, imidazolyl, piperazinyl, pyrazolyl, triazolyl, tetrazolyl, 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. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R c1 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 by 1 to 3 members selected from R 6a substituted by a group.

25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R c1 are each optionally represented by 1 to 3 selected from R 6a A piperidinyl or pyridinyl substituted group.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 6a It is a (C1-C4) alkyl group.

27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R a1 and R b1 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 by 1 to 3 groups selected from R 6a substituted by a group.

28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R a1 and R b1 are each independently selected from hydrogen and -(C1-C4)alkyl[5- to 7-membered heteroaryl], wherein the 5- to 7-membered heteroaryl is optionally substituted by 1 to 3 members selected from R 6a substituted by a group.

29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R a1 is hydrogen and R b1 is -(C1-C4)alkyl[pyridinyl], wherein the pyridinyl is optionally substituted by 1 to 3 groups selected from R 6a substituted by a group.

30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R f1 is optionally substituted by 1 to 3 members selected from R 8a A 4- to 6-membered heterocyclic group substituted with 31. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R f1 is optionally substituted by 1 to 3 members selected from R 8a A piperazinyl group substituted with a group.

32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 8a It is a (C1-C4) alkyl group.

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R d1 and R e1 Each independently selected from hydrogen, -(C1-C4)alkyl NR' 1 R” 1 , (C1-C4)alkyl[5- to 7-membered heteroaryl] and 4- to 8-membered heterocyclyl, wherein the 5- to 7-membered heteroaryl and 4- to 8-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from R 7a substituted by a group.

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R d1 and R e1 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 by 1 to 3 groups selected from R 7a substituted by a group.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R g1 and R h1 Each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, -(C1-C4) alkyl, OR' 1 、-(C1-C4)alkylNR' 1 R” 1 、-(C1-C4)alkyl C(O)NR' 1 R” 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 the phenyl, 5- to 7-membered heteroaryl and 4- to 8-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from R 7a substituted by a group.

36. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R g1 and R h1 are each independently selected from hydrogen, (C1-C4) alkyl, halo-(C1-C4) alkyl, -(C1-C4) alkyl[pyridyl], -(C1-C4) alkylO(C1-C4) alkyl, (C1-C4) alkylphenyl, -(C1-C4) alkylN[(C1-C4) alkyl]2, pyridyl, piperidyl, pyrrolidinyl, -(C1-C4) alkylC(O)N[(C1-C4) alkyl]2, halo-(C1-C4) alkyl, -(C1-C4) alkylC(O)(morpholinyl), wherein the phenyl, pyridyl, piperidyl, pyrrolidinyl and morpholinyl are each optionally substituted by 1 to 3 groups selected from R 7a substituted by a group.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 7a Selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, (C1-C4)alkoxy and cyano.

38. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from -CH2NHCH3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -CH2N(CH3)(CH2)2OCH3, -CH2N(CH3)(CH2)2N(CH3)2, -CH2NH(CH2CH3), -C H2N(CH3)(CH2)3N(CH3)2, -CH2NH(CH2)2N(CH2CH3)2, CH2NHC(CH3)3, -CH2N(CH3)CH2C(O)N(CH3)2, -C(O)NHCH2N(CH3)2, 39. The compound of claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

40. The 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 disorder responsive to 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 a composition according to claim 40.

42. The method of claim 41, wherein the disorder is cancer.

43. The method of claim 41 or 42, wherein the disorder is 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 hematological 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 syndrome (MDS), sarcoma, and melanoma.

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